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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Gadopiclenol


STR1
Chemical structure of gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid)]. The PCTA parent structure is shown in red. Two water molecules are included to show the coordination in solution.
Molecules 27 00058 g003 550

Gadopiclenol

ガドピクレノール;

FormulaC35H54N7O15. Gd
CAS933983-75-6
Mol weight970.0912

FDA APPROVED 2022/9/21, Elucirem

Diagnostic agent (MR imaging), WHO 10744, P 03277, UNII: S276568KOY

EluciremTM; G03277; P03277; VUEWAY

(alpha3,alpha6,alpha9-Tris(3-((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-kappaN3,kappaN6,kappaN9,kappaN15,kappaO3,kappaO6,kappaO9)gadolinium

Molecules 27 00058 g002 550
  • OriginatorGuerbet
  • ClassDiagnostic agents; Gadolinium-containing contrast agents; Macrocyclic compounds; Propylamines; Pyridines
  • Mechanism of ActionMagnetic resonance imaging enhancers
  • RegisteredCNS disorders
  • Phase IIIUnspecified
  • Phase IILiver cancer
  • 21 Sep 2022Registered for CNS disorders (Diagnosis) in USA (IV)
  • 13 Jun 2022Guerbet plans to launch Gadopiclenol in Europe
  • 13 Jun 2022The European Medicines Agency (EMA) accepts brand name EluciremTM for Gadopiclenol

PATENT

https://patents.google.com/patent/WO2020030618A1/en

MRI contrast agents used in daily diagnostic practice typically include gadolinium complex compounds characterized by high stability constants that guarantee against the in vivo release of the free metal ion (that is known to be extremely toxic for living organisms).

Another key parameter in the definition of the tolerability of a gadolinium-based contrast agent is the kinetic inertness (or kinetic stability) of Gd(III)-complex, that is estimated through the half-life (ti/2) of the dissociation (i.e. decomplexation) of the complex.

A high inertness becomes crucial in particular for those complex compounds having lower thermodynamic stability and/or longer retention time before excretion, in order to avoid or minimize possible decomplexation or transmetallation reactions.

EP1931673 (Guerbet) discloses PCTA derivatives of formula

Figure imgf000002_0001

and a synthetic route for their preparation.

EP 2988756 (same Applicant) discloses a pharmaceutical composition comprising the above derivatives together with a calcium complex of 1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid. According to the EP 2988756, the calcium complex compensates the weak thermodynamic stability observed for PCTA-based gadolinium complexes, by forming, through transmetallation, a strong complex with free lanthanide ion, thereby increasing the tolerability of the contrast agent.

Both EP1931673 and EP 2988756 further refer to enantiomers or diastereoisomers of the claimed compounds, or mixture thereof, preferentially chosen from the RRS, RSR, and RSS diastereoisomers. Both the above patents disclose, among the specific derivatives, (a3, a6, a9)-tris(3- ((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca- l(15),l l,13-triene-3,6,9-triacetato(3-)-(KN3,KN6,KN9,KN15,K03,K06,K09)gadolinium, more recently identified as gadolinium chelate of 2,2′,2″-(3,6,9-triaza-l(2,6)- pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid), (CAS registry number: 933983-75-6), having the following formula

Figure imgf000003_0001

otherwise identified as P03277 or Gadopiclenol.

For Gadopiclenol, EP1931673 reports a relaxivity of 11 mM _1_1Gd 1 (in water, at 0.5 T, 37°C) while EP 2988756 reports a thermodynamic equilibrium constant of 10 14 9 (log Kterm

= 14.9).

Furthermore, for this same compound a relaxivity value of 12.8 mM _11 in human serum (37°C, 1.41 T), stability (log Kterm) of 18.7, and dissociation half-life of about 20 days (at pH 1.2; 37°C) have been reported by the proprietor (Investigative Radiology 2019, Vol 54, (8), 475-484).

The precursor for the preparation of the PCTA derivatives disclosed by EP1931673 (including Gadopiclenol) is the Gd complex of the 3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),l l,13-triene-tri(a-glutaric acid) having the following formula

Figure imgf000003_0002

Gd(PCTA-tris-glutaric acid)

herein identified as “Gd(PCTA-tris-glutaric acid)”. In particular, Gadopiclenol is obtained by amidation of the above compound with isoserinol.

As observed by the Applicant, Gd(PCTA-tris-qlutaric acid) has three stereocenters on the glutaric moieties (identified with an asterisk (*) in the above structure) that lead to a 23 = 8 possible stereoisomers. More particularly, the above structure can generate four pairs of enantiomers, schematized in the following Table 1

Table 1

Figure imgf000004_0002

Isomer RRR is the mirror image of isomer SSS and that is the reason why they are called enantiomers (or enantiomer pairs). As known, enantiomers display the same physicochemical properties and are distinguishable only using chiral methodologies, such as chiral chromatography or polarized light.

On the other hand, isomer RRR is neither equal to nor is it the mirror image of any of the other above six isomers; these other isomers are thus identified as diastereoisomers of the RRR (or SSS) isomer. Diastereoisomers may display different physicochemical properties, (e.g., melting point, water solubility, relaxivity, etc.).

Concerning Gadopiclenol, its chemical structure contains a total of six stereocenters, three on the glutaric moieties of the precursor as above discussed and one in each of the three isoserinol moieties attached thereto, identified in the following structure with an asterisk (*) and with an empty circle (°), respectively:

Figure imgf000004_0001

This leads to a total theoretical number of 26 = 64 stereoisomers for this compound. However, neither EP1931673 nor EP 2988756 describe the exact composition of the isomeric mixture obtained by following the reported synthetic route, nor does any of them provide any teaching for the separation and characterization of any of these isomers, or disclose any stereospecific synthesis of Gadopiclenol. Summary of the invention

The applicant has now found that specific isomers of the above precursor Gd(PCTA- tris-glutaric acid) and of its derivatives (in particular Gadopiclenol) possess improved physico-chemical properties, among other in terms of relaxivity and kinetic inertness.

An embodiment of the invention relates to a compound selected from the group consisting of:

the enantiomer [(aR,a’R,a”R)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium (RRR enantiomer) having the formula (la):

Figure imgf000005_0001

the enantiomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetato(3-)KN3,KN6,KN9,KN15,K03,K06,K09]- gadolinium (SSS enantiomer) having the formula (lb):

Figure imgf000005_0002

the mixtures of such RRR and SSS enantiomers, and a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to an isomeric mixture of Gd(PCTA-tris- glutaric acid) comprising at least 50% of the RRR isomer [(aR,a’R,a”R)-a,a’,a”-tris(2- carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9- triacetato(3-)-KN3,KN6,KN9,KN15,K03,K06,K09]-gadolinium, of formula (la), or of the SSS isomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium of formula (lb), or of a mixture thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to the amides obtained by conjugation of one of the above compounds or isomeric mixture with an amino group, e.g. preferably, serinol or isoserinol.

An embodiment of the invention relates to an amide derivative of formula (II A)

F( N RI R2)3 (II A)

in which :

F is:

a RRR enantiomer residue of formula Ilia

Figure imgf000006_0001

a SSS enantiomer residue of formula Illb

Figure imgf000006_0002

or a mixture of such RRR and SSS enantiomer residues;

and each of the three -NRIR2 group is bound to an open bond of a respective carboxyl moiety of F, identified with a full circle (·) in the above structures;

Ri is H or a Ci-Ce alkyl, optionally substituted by 1-4 hydroxyl groups;

R2 is a Ci-Ce alkyl optionally substituted by 1-4 hydroxyl groups, and preferably a C1-C3 alkyl substituted by one or two hydroxyl groups.

Another embodiment of the invention relates to an isomeric mixture of an amide derivative of Gd(PCTA-tris-glutaric acid) having the formula (II B)

F'( N RI R2)3 (II B)

in which :

F’ is an isomeric mixture of Gd(PCTA-tris-glutaric acid) residue of formula (III)

Figure imgf000007_0001

said isomeric mixture of the Gd(PCTA-tris-glutaric acid) residue comprising at least 50 % of an enantiomer residue of the above formula (Ilia), of the enantiomer residue of the above formula (Illb), or of a mixture thereof; and each of the -NR1R2 groups is bound to an open bond of a respective carboxyl moiety of F’, identified with a full circle (·) in the above structure, and is as above defined for the compounds of formula (II A).

EXPERIMENTAL PART

HPLC characterization of the obtained compounds.

General procedures

Procedure 1: HPLC Characterization of Gd(PCTA-tris-glutaric acid) (isomeric mixture and individual/enriched isomers).

The HPLC characterization of the Gd(PCTA-tris-glutaric acid) obtained as isomeric mixture from Example 1 was performed with Agilent 1260 Infinity II system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector ( Agilent 1260 Infinity II system)

Stationary phase: Phenomenex Gemini® 5pm C18 lloA

Mobile phase: H2O/HCOOH 0.1% : Methanol

Elution : Gradient Time (min) H2O/HCOOH 0.1% Methanol

0 95 5

5 95 5

30 50 50

35 50 50

40 95 5

Flow 0.6 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

Injection volume 50 pL

Sample Cone. 0.2 mM Gd(PCTA-tris-glutaric acid) complex

Stop time 40 min

Retention time GdL = 18-21 min.

Obtained HPLC chromatogram is shown in Figure 1

The HPLC chromatogram of the enriched enantiomers pair C is shown in Figure 2.

Procedure 2: HPLC Characterization of Gadopiclenol (isomeric mixture) and compounds obtained by coupling of enantiomers pair C with R, S, or racemic isoserinol.

The HPLC characterization of Gadopiclenol either as isomeric mixture obtained from Example 2, or as the compound obtained by conjugation of enantiomers pair C of the Gd(PCTA-tris-glutaric acid) with R, S, or racemic isoserinol was performed with Thermo Finnigan LCQ DECA XPPIus system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA and MS detector (LCQ Deca XP-Plus – Thermo Finnigan )

Stationary phase: Phenomenex Gemini 5u C18 110A

Mobile phase: H2O/TFA 0.1% : Acetonitrile/0.1%TFA

Elution : Gradient Time (min) H2O/TFA 0.1% Acetonitrile/0.1%TFA

0 100 0

5 100 0

22 90 10

26 90 10

Flow 0.5 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

MS positive mode – Mass range 100-2000

Injection volume 50 pL

Sample cone. 0.2 mM Gd complex

Stop time 26 min

Retention time GdL = 20-22min.

Obtained HPLC chromatograms are shown in Figure 6.

Procedure 3: Chiral HPLC method for the separation of enantiomers of the compound C

A specific chiral HPLC method was set up in order to separate the RRR and SSS enantiomers of the enantiomers pair C (compound VI), prepared as described in Example 3. The separation and characterization of the enantiomers were performed with Agilent 1200 system or Waters Alliance 2695 system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC System HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector

Stationary phase SUPELCO Astec CHIROBIOTIC 5 pm 4.6x250mm

Mobile phase H2O/HCOOH 0.025% : Acetonitrile

Elution : isocratic 2% Acetonitrile for 30 minutes

Flow 1 mL/min

Column Temperature 40°C

Detection 210-270 nm. Obtained HPLC chromatogram is shown in Figure 5a) compared to the chromatograms of the pure RRR enantiomer (compound XII of Example 5, Tr. 7.5 min.) and the pure SSS enantiomer (Compound XVII of Example 6, Tr. 8.0 min), shown in figure 5b) and 5c), respectively.

Example 1: Synthesis of Gd(PCTA-tris-glutaric acid) (isomeric mixture)

Gd(PCTA-tris-glutaric acid) as an indiscriminate mixture of stereoisomers has been prepared by using the procedure reported in above mentioned prior-art, according to the following synthetic Scheme 1 :

Scheme 1

Figure imgf000030_0001

a) Preparation of Compound II

Racemic glutamic acid (33.0 g, 0.224 mol) and sodium bromide (79.7 g, 0.782 mol) were suspended in 2M HBr (225 ml_). The suspension was cooled to -5°C and NaN02 (28.0 g, 0.403 mol) was slowly added in small portions over 2.5 hours, maintaining the inner temperature lower than 0 °C. The yellow mixture was stirred for additional 20 minutes at a temperature of -5°C; then concentrated sulfuric acid (29 ml.) was dropped in the mixture. The obtained dark brown mixture was warmed to RT and then extracted with diethyl ether (4×150 ml_). The combined organic phases were washed with brine, dried over Na2S04 and concentrated to a brown oil (21.2 g), used in the following step without further purification. The oil was dissolved in ethanol (240 ml_), the resulting solution was cooled in ice and thionyl chloride (14.5 ml_, 0.199 mol) was slowly added. The slightly yellow solution was stirred at RT for 2 days. Then the solvent was removed in vacuum and the crude oil was dissolved in dichloromethane (200 ml.) and washed with 5% aq. NaHCC>3 (4×50 ml_), water (1×50 ml.) and brine (1×50 ml_). The organic phase was concentrated and purified on silica eluting with petroleum ether-ethyl acetate 3: 1, obtaining 19.5 g of pure product. (Yield 33%).

b) Preparation of Compound IV

A solution of Compound II (17.2 g, 0.0645 mol) in acetonitrile (40 ml.) was added to a suspension of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene (pyclen) Compound (III) (3.80 g, 0.018 mol) and K2CO3 (11.2 g, 0.0808 mol) in acetonitrile (150 ml_). The yellow suspension was heated at 65 °C for 24 h, then the salts were filtered out and the organic solution was concentrated. The orange oil was dissolved in dichloromethane and the product was extracted with 1M HCI (4 x 50 ml_). The aqueous phases were combined, cooled in ice and brought to pH 7-8 with 30% aq. NaOH. The product was then extracted with dichloromethane (4 x 50 ml.) and concentrated to give a brown oil (10.1 g, yield 73%). The compound was used in the following step without further purification.

c) Preparation of compound V

Compound IV (9.99 g, 0.013 mol) was dissolved in Ethanol (40 ml.) and 5M NaOH (40 ml_). The brown solution was heated at 80 °C for 23 h. Ethanol was concentrated; the solution was cooled in ice and brought to pH 2 with cone HCI. The ligand was purified on resin Amberlite XAD 1600, eluting with water-acetonitrile mixture, obtaining after freeze- drying 5.7 g as white solid (yield 73%). The product was characterized in HPLC by several peaks.

d) Preparation of compound VI

Compound V (5.25 g, 0.0088 mol) was dissolved in deionized water (100 ml.) and the solution was brought to pH 7 with 2M NaOH (20 ml_). A GdCh solution (0.0087 mol) was slowly added at RT, adjusting the pH at 7 with 2M NaOH and checking the complexation with xylenol orange. Once the complexation was completed, the solution was concentrated and purified on resin Amberlite XAD 1600 eluting with water-acetonitrile gradient, in order to remove salts and impurities. After freeze-drying the pure compound was obtained as white solid (6.79 g, yield 94%). The product was characterized in HPLC; the obtained HPLC chromatogram, characterized by several peaks, is shown in Figure 1 A compound totally equivalent to compound VI, consisting of an isomeric mixture with a HPLC chromatogram substantially superimposable to that of Figure 1 is obtained even by using (S)-methyl a-bromoglutarate obtained starting from L-glutamic acid.

Example 2: Synthesis of Gadopiclenol (isomeric mixture)

Gadopiclenol as an indiscriminate mixture of stereoisomers has been prepared as disclosed in EP11931673 B1 by coupling the isomeric mixture of Gd(PCTA-tris-glutaric acid) obtained from Example 1 with racemic isoserinol according to the following synthetic Scheme 2:

Scheme 2

Figure imgf000032_0001

Preparation of compound VII

Compound VI (0.90 g, 0.0011 mol) obtained from Example 1 was added to a solution of racemic isoserinol (0.40 g, 0.0044 mol) in water adjusted to pH 6 with cone. HCI. Then N- ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCI) (1.0 g, 0.0055 mol) and hydroxybenzotriazole (HOBT) (0.12 g, 0.00088 mol) were added and the resulting solution was stirred at pH 6 and RT for 24 h. The product was then purified on preparative HPLC on silica C18, eluting with water/acetonitrile gradient. Fractions containing the pure compound were concentrated and freeze-dried, obtaining a white solid (0.83 g, yield 78%). The product was characterized in HPLC; the obtained HPLC chromatogram is shown in Figure 4a.

Example 3: Isolation of the enantiomers pair related to the peak C.

Compound VI obtained as described in Example 1 (step d) (1.0 g, 0.0013 mol) was dissolved in water (4 ml.) and the solution was acidified to pH 2-3 with cone. HCI. The obtained solution was loaded into a pre-packed column of silica C18 (Biotage® SNAP ULTRA C18 120 g, HP-sphere C18 25 pm) and purified with an automated flash chromatography system eluting with deionized water (4 CV) and then a very slow gradient of acetonitrile. Fractions enriched of the enantiomers pair related to the peak C were combined, concentrated and freeze-dried obtaining a white solid (200 mg).

The HPLC chromatogram of the obtained enriched enantiomers pair C is shown in Figure 2.

Corresponding MS spectrum (Gd(H4L)+:752.14 m/z) is provided in Figure 3

Example 4: Coupling of the enantiomers pair C with isoserinol.

a) Coupling of the enantiomers pair C with R-isoserinol.

Enriched enantiomers pair C collected e.g. as in Example 3 (34 mg, titer 90%, 0.040 mmol) was dissolved in deionized water (5 ml_), and R-isoserinol (16 mg, 0.17 mmol) was added adjusting the pH at 6 with HCI 1M. Then, EDCI-HCI (39 mg, 0.20 mmol) and HOBT (3 mg, 0.02 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (21 mg, yield 54%).

The HPLC chromatogram of the obtained product is shown in Figure 6b.

b) Coupling of the enantiomers pair C with S-isoserinol

Enriched enantiomers pair C collected e.g. as in Example 3 (55 mg, titer 90%, 0.066 mmol) was dissolved in deionized water (5 mL), and S-isoserinol (34 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (64 mg, 0.33 mmol) and HOBT (4.5 mg, 0.033 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (52 mg, yield 81%).

HPLC chromatogram of the obtained product is shown in Figure 6c.

c) Coupling of the enantiomers pair C with racemic isoserinol.

The enriched enantiomers pair C collected e.g. as in Example 3 (54 mg, titer 90%, 0.065 mmol) was dissolved in deionized water (5 mL), and racemic isoserinol (27 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (62 mg, 0.32 mmol) and HOBT (4.3 mg, 0.032 mmol) were added and the solution was stirred at RT at pH 6 for 24 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (60 mg, yield 95%).

HPLC chromatogram of the obtained product is shown in Figure 6d. Example 5: Stereoselective synthesis of the RRR Gd(PCTA-tris-glutaric acid) (compound XII).

RRR enriched Gd(PCTA-tris-glutaric acid) acid has been prepared by following the synthetic Scheme 3 below

Scheme 3

Figure imgf000034_0001

comprising :

a) Preparation of Compound VIII

The preparation was carried out as reported in Tetrahedron 2009, 65, 4671-4680.

In particular: 37% aq. HCI (50 pL) was added to a solution of (S)-(+)-5- oxotetrahydrofuran-2-carboxylic acid (2.48 g, 0.019 mol) (commercially available) in anhydrous methanol (20 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHCC>3 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (2.97 g, yield 89%).

b) Preparation of Compounds IX and X

Compound VIII (445 mg, 2.52 mmol) obtained at step a) was dissolved in anhydrous dichloromethane (6 ml.) and triethylamine (0.87 ml_, 6.31 mmol) was added. The solution was cooled at -40°C and then (triflic) trifluoromethansulfonic anhydride (0.49 ml_,2.91 mmol) was slowly added. The dark solution was stirred at -40°C for 1 h, then a solution of Compound III (104 mg, 0.506 mmol) in anhydrous dichloromethane (3 ml.) and triethylamine (1 ml_, 7.56 mmol) were added and the solution was slowly brought to RT and stirred at RT overnight. The organic solution was then washed with 2M HCI (4x 10 ml_), the aqueous phase was extracted again with dichloromethane (3 x 10 ml_). The organic phases were combined and concentrated in vacuum, obtaining 400 mg of a brown oil that was used in the following step with no further purification.

c) Preparation of Compound XI

Compound X (400 mg, 0.59 mmol) was dissolved in methanol (2.5 ml.) and 5M NaOH (2.5 ml_). The brown solution was heated at 80°C for 22 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 1 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (64 mg, yield 18 %). The HPLC showed a major peak.

d) Compound XII

Compound XI (32 mg, 0.054 mmol) was dissolved in deionized water (4 mL) and the pH was adjusted to 7 with 1M NaOH. GdCl3-6H20 (20 mg, 0.054 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The clear solution was stirred at RT overnight and the end of the complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired RRR isomer as major peak: about 80% in area %. The mixture was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (36 mg, yield 90%).

By reaction of the collected compound with isoserinol e.g. by using the procedure of the Example 2, the corresponding RRR amide derivative can then be obtained.

Example 6: stereoselective synthesis of the SSS Gd(PCTA-tris-glutaric acid) (compound XVII).

SSS enriched Gd(PCTA-tris-glutaric acid) acid has been similarly prepared by following the synthetic Scheme 4 below Scheme 4

Figure imgf000036_0001

comprising :

a) Preparation of Compound XIII

37% aq. HCI (100 pl_) was added to a solution of (R)-(-)-5-oxotetrahydrofuran-2- carboxylic acid (5.0 g, 0.038 mol) (commercially available) in anhydrous methanol (45 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHC03 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (6.7 g, yield 99%).

b) Preparation of Compounds XIV and XV

Compound XIII (470 mg, 2.67 mmol) was dissolved in anhydrous dichloromethane (6 ml.) and trimethylamine (0.93 ml_, 6.67 mmol) was added. The solution was cooled down at -40°C and then trifluoromethanesulfonic anhydride (0.50 ml_, 3.07 mmol) was slowly dropped. The dark solution was stirred at -40°C for 1 h, then Compound III (140 mg, 0.679 mmol) and trimethylamine (0.93 ml_, 6.67 mmol) were added and the solution was slowly brought to RT overnight. The organic solution was then washed with water (3 x 5 ml.) and 2M HCI (4 x 5 ml_). The aqueous phase was extracted again with dichloromethane (3 x 10 ml_). the organic phases were combined and concentrated in vacuum, obtaining 350 mg of a brown oil that was used in the following step with no further purification. c) Preparation of Compound XVI

Compound XV (350 mg, 0.514 mmol) was dissolved in methanol (4.5 ml.) and 5M NaOH (4.5 ml_). The obtained brown solution was heated at 80°C for 16 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (52 mg, yield 17%). The HPLC showed a major peak.

d) Preparation of Compound XVII

Compound XVI (34 mg, 0.057 mmol) was dissolved in deionized water (5 mL) and the pH was adjusted to 7 with 1 M HCI. GdCl3-6H20 (20 mg, 0.0538 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The solution was stirred at RT overnight and the end of complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired SSS isomer as major peak: about 85% in area %. The solution was brought to pH 2.5 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product SSS were combined, concentrated and freeze-dried (39 mg, yield 87%).

Example 7: Kinetic studies of the dissociation reactions of Gd(PCTA-tris- glutaric acid) (isomeric mixture) in 1.0 M HCI solution (25°C)

The kinetic inertness of a Gd(III)-complex is characterized either by the rate of dissociation measured in 0.1-1.0 M HCI or by the rate of the transmetallation reaction, occurring in solutions with Zn(II) and Cu(II) or Eu(III) ions. However, the dissociation of lanthanide(III)-complexes formed with macrocyclic ligands is very slow and generally proceeds through a proton-assisted pathway without the involvement of endogenous metal ions like Zn2+ and Cu2+.

We characterized the kinetic inertness of the complex Gd(PCTA-tris-glutaric acid) by the rates of the dissociation reactions taking place in 1.0 M HCI solution. The complex (isomeric mixture from Example 1) (0.3 mg) was dissolved in 2.0 mL of 1.0 M HCI solution and the evolution of the solution kept at 25 °C was followed over time by HPLC. The HPLC measurements were performed with an Agilent 1260 Infinity II system by use of the analytical Procedure 1.

The presence of a large excess of H+ ([HCI] = 1.0 M), guarantees the pseudo-first order kinetic conditions.

GdL + yH÷ ^ Gd3+ + HyL y=7 and 8 (Eg. 1) where L is the protonated PCTA-tri-glutaric acid, free ligand, and y is the number of protons attached to the ligand.

The HPLC chromatogram of Gd(PCTA-tris-glutaric acid) is characterized by the presence of four signals (A, B, C and D) having the same m/z ratio (Gd(H4L)+ :752.14 m/z) in the MS spectrum. Each of these peaks is reasonably ascribable to one of the 4 pairs of enantiomers generated by the three stereocenters on the three glutaric arms of the molecule, formerly identified in Table 1. The HPLC chromatogram of this complex in the presence of 1.0 M HCI changes over time: in particular, the areas of peaks A, B, C, and D decrease, although not in the same way for the different peaks, while new signals corresponding to non-complexed diastereoisomers are formed and grow over time. Differences in the decrease of the integral areas of the peaks can be interpreted by a different dissociation rate of the enantiomer pairs associated to the different peaks.

In the presence of [H + ] excess the dissociation reaction of enantiomer pairs of Gd(PCTA-tris-glutaric acid) can be treated as a pseudo-first-order process, and the rate of the reactions can be expressed with the following Eq. 2, where kA, kB, kc and kD are the pseudo-first-order rate constants that are calculated by fitting the area-time data pair, and [A]t, [B]t, [C]t and [D]t are the total concentration of A, B, C and D compounds at time t.

Figure imgf000038_0001

The decrease of the area values of signals of A, B, C, and D has been assessed and plotted over time. Area values of A, B, C and D signals as a function of time are shown in Figure 7.

Area value at time t can be expressed by the following equation:

A. = A + (A0 – A )e kxt

(Eg. 3)

where At, A0 and Ae are the area values at time t, at the beginning and at the end of the reactions, respectively, kx pseudo-first-order rate constants (/fX=/fA, kB, kc and kD) characterizing the dissociation rate of the different enantiomer pairs of Gd(PCTA-tris-glutaric acid) complex were calculated by fitting the area – time data pairs of Figure 7 to the above equation 3. kx rate constants and half-lives (ti/2= In2/ x) are thus obtained, as well as the average the half-life value for the isomeric mixture of Gd(PCTA-tris-glutaric acid), calculated by considering the percentage composition of the mixture. Obtained values are summarized in the following Table 2, and compared with corresponding values referred in the literature for some reference contrast agents. (Gd-DOTA or DOTAREM™). Table 2. Rate constants ( kx ) and half-lives (ti/2= In2/ x) characterizing the acid catalyzed dissociation of the different stereoisomers of Gd(PCTA-tris-glutaric acid), Dotarem® and Eu(PCTA) in 1.0 M HCI (pH 0) ( 25°C)

A B C D

Ms 1) (4.5±0.1) x105 (1.1±0.1)x104 (1.6±0.1)x10-6 (1.2±0.1)x10-5 fi/2 (hour) 4.28 ± 0.03 1.76 ± 0.02 120 ± 3 15.8 ± 0.5

fi/2 (hour)

Figure imgf000039_0001

average

Dotarem a

k, (S‘1) 8.0×10-6

fi/2 (hour) 23 hour

Eu(PCTA) b

*1 (s·1) 5.08X10·4

fi/2 (hour) 0.38 hour

a) Inorg. Chem. 1992, 31 ,1095-1099.

b) Tircso, G. et al. Inorg Chem 2006, 45 (23), 9269-80.

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A gadolinium-based paramagnetic contrast agent, with potential imaging enhancing activity upon magnetic resonance imaging (MRI). Upon administration of gadopiclenol and placement in a magnetic field, this agent produces a large magnetic moment and creates a large local magnetic field, which can enhance the relaxation rate of nearby protons. This change in proton relaxation dynamics, increases the MRI signal intensity of tissues in which this agent has accumulated; therefore, contrast and visualization of those tissues is enhanced compared to unenhanced MRI.

FDA Approves New MRI Contrast Agent Gadopiclenol

September 22, 2022

https://www.diagnosticimaging.com/view/fda-approves-new-mri-contrast-agent-gadopiclenol

Requiring only half of the gadolinium dose of current non-specific gadolinium-based contrast agents (GBCAs), gadopiclenol can be utilized with magnetic resonance imaging (MRI) to help detect lesions with abnormal vascularity in the central nervous system and other areas of the body.

Gadopiclenol, a new magnetic resonance imaging (MRI) contrast agent that offers high relaxivity and reduced dosing of gadolinium, has been approved by the Food and Drug Administration (FDA).1

Approved for use with MRI in adults and pediatric patients two years of age or older, gadopiclenol is a macrocyclic gadolinium-based contrast agent that aids in the diagnosis of lesions with abnormal vascularity in the brain, spine, abdomen, and other areas of the body.

Recently published research demonstrated that gadopiclenol provides contrast enhancement and diagnostic efficacy at half of the gadolinium dosing of other gadolinium-based contrast agents (GBCAs) such as gadobutrol and gadobenate dimeglumine.2

Co-developed by Bracco Diagnostics and Guerbet, gadopiclenol will be manufactured and marketed as Vueway™ (Bracco Diagnostics) and Elucirem™ (Guerbet).1,3

Alberto Spinazzi, M.D., the chief medical and regulatory officer at Bracco Diagnostics, said gadopiclenol is “a first of its kind MRI agent that delivers the highest relaxivity and highest kinetic stability of all GBCAs on the market today.”

Reference

1. Bracco Diagnostics. Bracco announces FDA approval of gadopiclenol injection, a new macrocyclic high-relaxivity gadolinium-based contrast agent which will be commercialized as VUEWAY™ (gadopiclenol) injection and VUEWAY™ (gadopiclenol) phamarcy bulk package by Bracco. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/bracco-announces-fda-approval-of-gadopiclenol-injection-a-new-macrocyclic-high-relaxivity-gadolinium-based-contrast-agent-which-will-be-commercialized-as-vueway-gadopiclenol-injection-and-vueway-gadopiclenol-pharmacy-bulk-p-301630124.html . Published September 21, 2022. Accessed September 21, 2022.

2. Bendszus M, Roberts D, Kolumban B, et al. Dose finding study of gadopiclenol, a new macrocyclic contrast agent, in MRI of central nervous system. Invest Radiol. 2020;55(3):129-137.

3. Guerbet. Guerbet announces U.S. Food and Drug Administration (FDA) approval of Elucirem™ (gadopiclenol) injection for use in contrast-enhanced MRI. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/guerbet-announces-us-food-and-drug-administration-fda-approval-of-elucirem-gadopiclenol-injection-for-use-in-contrast-enhanced-mri-301630085.html . Published September 21, 2022. Accessed September 21, 2022.

////Gadopiclenol, FDA 2022, APPROVALS 2022, ガドピクレノール, WHO 10744, P 03277,  EluciremTM, G03277; P03277, VUEWAY, Guerbet

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Eflapegrastim


2D chemical structure of 1384099-30-2
STR1

Eflapegrastim

エフラペグラスチム;

Molecular Formula

  • C15-H28-N2-O6(C2-H4-O)n

Molecular Weight

  • 376.4468
FormulaC3070H4764N806O927S23.(C2H4O)n

UNII: UT99UG9QJX

HM10460A
SPI-2012

  • HNK460

Reducing neutropenia and the incidence of infecton in patients with cancer

(2S)-1-{3-[2-(3-{[(1S,2R)-1-carboxy-2-hydroxypropyl]amino}propoxy)ethoxy]propyl}pyrrolidine-2-carboxylic acid

APPROVED FDA 2022/9/9, Rolvedon

CAS: 1384099-30-2

LAPS-GCSF, ROLONTIS

Antineutropenic, Leukocyte growth factor

Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 1-ether with immunoglobulin G4 [1-[1-(3-hydroxypropyl)proline]] (human Fc fragment), (3→3′)-disulfide with immunoglobulin G4 (human Fc fragment), 1′′-ether with granulocyte colony-stimulating factor [N-(3-hydroxypropyl),17-serine,65-serine] (human) (ACI)

A long-acting, recombinant analog of the endogenous human granulocyte colony-stimulating factor (G-CSF) with hematopoietic activity. Similar to G-CSF, eflapegrastim binds to and activates specific cell surface receptors and stimulates neutrophil progenitor proliferation and differentiation, as well as selected neutrophil functions. Therefore, this agent may decrease the duration and incidence of chemotherapy-induced neutropenia. Eflapegrastim extends the half-life of G-CSF, allowing for administration once every 3 weeks.

  • A long-acting GCSF that consists of 17th serine-G-CSF conjugated to the G4 fragment HMC001 via a PEG linker.

PATENT

 WO2021113597

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021113597

Neutropenia is a relatively common disorder most often due to chemotherapy treatments, adverse drug reactions, or autoimmune disorders. Chemotherapy-induced neutropenia is a common toxicity caused by the administration of anticancer drugs. It is associated with life-threatening infections and may alter the chemotherapy schedule, thus impacting on early and long term outcome. Febrile Neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy regimens such as docetaxel, doxorubicin, cyclophosphamide (TAC); dose-dense doxorubicin plus cyclophosphamide (AC), with or without subsequent weekly or semiweekly paclitaxel; and docetaxel plus cyclophosphamide (TC). It usually leads to prolonged hospitalization, intravenous administration of broad-spectrum antibiotics, and is often associated with significant morbidity and mortality.

Current therapeutic modalities employ granulocyte colony-stimulating factor (G-CSF) and/or antibiotic agents to combat this condition. G-CSF or its other polypeptide derivatives are easy to denature or easily de-composed by proteolytic enzymes in blood to be readily removed through the kidney or liver. Therefore, to maintain the blood concentration and titer of the G-CSF containing drugs, it is necessary to frequently administer the protein drug to patients, which causes excessive suffering in patients. To solve such problems, G-CSF was chemically attached to polymers having a high solubility such as polyethylene glycol (“PEG”), thereby increasing its blood stability and maintaining suitable blood concentration for a longer time.

Filgrastim, tbo-filgrastim, and pegfilgrastim are G-CSFs currently approved by the US Food and Drug Administration (FDA) for the prevention of chemotherapy-induced neutropenia, While the European guidelines also include lenograstim as a recommended G-CSF in solid tumors and non-myeloid malignancies, it is not approved for use in the US. Binding of PEG to G-CSF, even though may increase blood stability, does dramatically reduce the titer needed for optimal physiologic effect. Thus there is a need to address this shortcoming in the art.

PATENT

WO2021112654

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021112654

Eflapegrastim

[54]

Eflapegrastim, as known as Rolontis ®, SPI-2012, HM10460A, and 17,65S-G-CSF, is a long-acting granulocyte-colony stimulating factor (G-CSF) that has been developed to reduce the severity and duration of severe neutropenia, as well as complications of neutropenia, associated with the use of myelosuppressive anti-cancer drugs or radiotherapy. Eflapegrastim consists of a recombinant human G-CSF analog (ef-G-CSF) and a recombinant fragment of the Fc region of human immunoglobulin G4 (IgG4), linked by a Bifunctional polyethylene glycol linker. In certain embodiments, the recombinant human G-CSF analog (ef-G-CSF) varies from human G-CSF (SED ID NO: 1) at positions 17 and 65 which are substituted with serine (SED ID NO: 2). Without wishing to be bound by theory, it is believed that the Fc region of human IgG4 increases the serum half-life of ef-G-CSF.

[55]

ef-G-CSF is produced by transformed E. coli in soluble form in the periplasmic space. Separately, the Fc fragment is produced in transformed E. coli as an inclusion body. The ef-G-CSF and the Fc fragment are independently isolated and purified through successive purification steps. The purified ef-G-CSF (SEQ ID NO: 2) and Fc fragment (SEQ ID NOs: 3 and 4) are then linked via a 3.4 kDa PEG molecule that was designed with reactive groups at both ends. Eflapegrastim itself is the molecule resulting from the PEG linker binding at each of the N-termini of ef-G-CSF and the Fc fragment. The G-CSF analog is conjugated to the 3.4 kDa polyethylene glycol analogue with propyl aldehyde end groups at both ends, (OHCCH 2CH 2(OCH 2CH 2nOCH 2CH 2CHO) at the nitrogen atom of its N-terminal Thr residue via reductive amination to form a covalent bond. The resulting G-CSF-PEG complex is then linked to the N-terminal Pro at the nitrogen of the recombinant Fc fragment variant produced in E. coli via reductive amination to yield the final conjugate of Eflapegrastim.

[56]

Example 1: Preparation of Eflapegrastim ( 17,65S-G-CSF-PEG-Fc)

[120]

Step 1: Preparation of Immunoglobulin Fc Fragment Using Immunoglobulin

[121]

Preparation of an immunoglobulin Fc fragment was prepared as follows.

[122]

200 mg of 150-kDa immunoglobulin G (IgG) (Green Cross, Korea) dissolved in 10 mM phosphate buffer was treated with 2 mg of a proteolytic enzyme, papain (Sigma) at 37℃ for 2 hrs with gentle agitation.

[123]

After the enzyme reaction, the immunoglobulin Fc fragment regenerated thus was subjected to chromatography for purification using sequentially a Superdex column, a protein A column and a cation exchange column. In detail, the reaction solution was loaded onto a Superdex 200 column (Pharmacia) equilibrated with 10 mM sodium phosphate buffer (PBS, pH 7.3), and the column was eluted with the same buffer at a flow rate of 1 ml/min. Unreacted immunoglobulin molecules (IgG) and F(ab’)2, which had a relatively high molecular weight compared to the immunoglobulin Fc fragment, were removed using their property of being eluted earlier than the Ig Fc fragment. Fab fragments having a molecular weight similar to the Ig Fc fragment were eliminated by protein A column chromatography (FIGURE 1). The resulting fractions containing the Ig Fc fragment eluted from the Superdex 200 column were loaded at a flow rate of 5 ml/min onto a protein A column (Pharmacia) equilibrated with 20 mM phosphate buffer (pH 7.0), and the column was washed with the same buffer to remove proteins unbound to the column. Then, the protein A column was eluted with 100 mM sodium citrate buffer (pH 3.0) to obtain highly pure immunoglobulin Fc fragment. The Fc fractions collected from the protein A column were finally purified using a cation exchange column (polyCAT, PolyLC Company), wherein this column loaded with the Fc fractions was eluted with a linear gradient of 0.15-0.4 M NaCl in 10 mM acetate buffer (pH 4.5), thus providing highly pure Fc fractions. The highly pure Fc fractions were analyzed by 12% SDS-PAGE (lane 2 in FIGURE 2).

[124]

Step 2: Preparation of 17,65S-G-CSF-PEG Complex

[125]

3.4-kDa polyethylene glycol having an aldehyde reactive group at both ends, ALD-PEG-ALD (Shearwater), was mixed with human granulocyte colony stimulating factor ( 17,65S-G-CSF, MW: 18.6 kDa) dissolved in 100 mM phosphate buffer in an amount of 5 mg/ml at a 17,65S-G-CSF: PEG molar ratio of 1:5. To this mixture, a reducing agent, sodium cyanoborohydride (NaCNBH 3, Sigma), was added at a final concentration of 20 mM and was allowed to react at 4℃ for 3 hrs with gentle agitation to allow PEG to link to the amino terminal end of 17,65S-G-CSF. To obtain a 1:1 complex of PEG and 17,65S-G-CSF, the reaction mixture was subjected to size exclusion chromatography using a Superdex R column (Pharmacia). The 17,65S-G-CSF-PEG complex was eluted from the column using 10 mM potassium phosphate buffer (pH 6.0) as an elution buffer, and 17,65S-G-CSF not linked to PEG, unreacted PEG and dimer byproducts where PEG was linked to 17,65S-G-CSF molecules were removed. The purified 17,65S-G-CSF-PEG complex was concentrated to 5 mg/ml. Through this experiment, the optimal reaction molar ratio for 17,65S-G-CSF to PEG, providing the highest reactivity and generating the smallest amount of byproducts such as dimers, was found to be 1:5.

[126]

Step 3: Preparation of the 17,65S-G-CSF-PEG-Fc Conjugate

[127]

To link the 17,65S-G-CSF-PEG complex purified in the above step 2 to the N-terminus of an immunoglobulin Fc fragment, the immunoglobulin Fc fragment (about 53 kDa) prepared in Step 1 was dissolved in 10 mM phosphate buffer and mixed with the 17,65S-G-CSF-PEG complex at an 17,65S-G-CSF-PEG complex:Fc molar ratio of 1:1, 1:2, 1:4 and 1:8. After the phosphate buffer concentration of the reaction solution was adjusted to 100 mM, a reducing agent, NaCNBH 3, was added to the reaction solution at a final concentration of 20 mM and was allowed to react at 4℃ for 20 hrs with gentle agitation. Through this experiment, the optimal reaction molar ratio for 17,65S-G-CSF-PEG complex to Fc, providing the highest reactivity and generating the fewest byproducts such as dimers, was found to be 1:2.

[128]

Step 4: Isolation and Purification of the G-CSF-PEG-Fc Conjugate

[129]

After the reaction of the above step 3, the reaction mixture was subjected to Superdex size exclusion chromatography so as to eliminate unreacted substances and byproducts and purify the 17,65S-G-CSF-PEG-Fc protein conjugate produced. After the reaction mixture was concentrated and loaded onto a Superdex column, 10 mM phosphate buffer (pH 7.3) was passed through the column at a flow rate of 2.5 ml/min to remove unbound Fc and unreacted substances, followed by column elution to collect 17,65S-G-CSF-PEG-Fc protein conjugate fractions. Since the collected 17,65S-G-CSF-PEG-Fc protein conjugate fractions contained a small amount of impurities, unreacted Fc and interferon alpha dimers, cation exchange chromatography was carried out to remove the impurities. The 17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyCAT LP column (PolyLC) equilibrated with 10 mM sodium acetate (pH 4.5), and the column was eluted with a linear gradient of 0-0.5 M NaCl in 10 mM sodium acetate buffer (pH 4.5) using 1 M NaCl. Finally, the 17,65S-G-CSF-PEG-Fc protein conjugate was purified using an anion exchange column. The 17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyWAX LP column (PolyLC) equilibrated with 10 mM Tris-HCl (pH 7.5), and the column was then eluted with a linear gradient of 0-0.3 M NaCl in 10 mM Tris-HCl (pH 7.5) using 1 M NaCl, thus isolating the 17,65S-G-CSF-PEG-Fc protein conjugate in a highly pure form.

[130]

[131]

Example 2: Efficacy Study of Eflapegrastim by Different Dosing Regimens in Rats with Docetaxel/Cyclophosphamide induced Neutropenia

[132]

The efficacy of Eflapegrastim (HM10460A), a long acting G-CSF analogue, was compared with Pegfilgrastim by different dosing regimens in a chemotherapy-induced neutropenic rat model.

[133]

In the following study, the Eflapegrastim was created essentially as described in Example 1.

[134]

(i) Materials for Study

[135]

[Table 1] Test Articles

NameBatch/Lot No.Storage ConditionPurity (%)Expiration DateSupplier
HM10460A9066170012~8 ℃RP-HPLC: 98.6% IE-HPLC: 97.4%
SE-HPLC: 98.6%
01/31/2019
Pegfilgrastim10703342~8 ℃Amgen

[136]

[Table 2] Vehicles

NameCompositionStorage ConditionSupplier
Dulbecco’s phosphate buffered saline (DPBS)2~8 ℃Sigma-Aldrich

[137]

[Table 3] Neutropenia-Inducing Agents

NameBatch/Lot No.Storage ConditionPurity (%)Expiration DateSupplier
Cyclo-phosphamideC32500002~8 ℃Sigma-Aldrich
Docetaxel17006RT (20 – 25 ℃)10/31/2020Hanmi Pharmaceutical Co.

[138]

Preparing HM10460A Solutions for Subcutaneous Administration

[139]

Preparation of a 61.8 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 92.7 μL was diluted with DPBS 17907.3 μL.

[140]

Preparation of a 372.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[141]

Preparation of a 496.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 744.0μL was diluted with DPBS 17256.0 μL.

[142]

The test article was prepared based on G-CSF protein dosage on drug label(HM10460A.)

[143]

The HM10460A solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[144]

Preparing Pegfilgrastim Solutions for Subcutaneous Administration

[145]

Preparation of a 103.3 ㎍/kg Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 93.0 μL was diluted with DPBS 17907.0 μL.

[146]

Preparation of a 620.0 ㎍/k Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[147]

The Pegfilgrastim solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[148]

Preparing Solutions of Neutropenia-Inducing Agents

[149]

To induce neutropenia in rats, Docetaxel/cyclophosphamide was administered using a 1/3 human equivalent dose (Docetaxel 4 mg/kg and CPA 32 mg/kg) (“TC”).

[150]

Preparation of a 32 mg/kg cyclophosphamide solution for subcutaneous administration: cyclophosphamide powder (CPA, Sigma, USA) 2560.0 g was diluted with distilled water (DW, Daihan, Korea) 80000.0 μL.

[151]

Preparation of a 4 mg/kg docetaxel solution for subcutaneous administration: Docel inj. (Hanmi Pharmaceutical, Korea) (42.68 mg/mL) 29070.0 μL was diluted with a commercial formulation buffer (FB, Etahnol 127.4mg/mL in DW) 30930.0 μL.

[152]

The docetaxel and cyclophosphamide solutions for subcutaneous administration were then diluted with FB to a final dose concentration of 1 mL/kg. HM10460A and Pegfilgrastim were diluted with DPBS to a final dose concentration of 2 mL/kg.

[153]

(ii) Methods

[154]

Test System

[155]

[Table 4]

Species and StrainRats
Crl: CD Sprague Dawley (SD)
Justification for SpeciesSD rats were chosen due to their extensive characterization collected from various preclinical studies, especially with the study done to test G-CSF analogue1), 2).
SupplierOrient Bio corp. Korea 143-1, Sangdaewondong, Jungwon-gu, Seongnam-si, Gyeonggi-do, Korea
Number of animalsMale 125 (at group allocation)
Age8 weeks (at group allocation)
Body weight range239.54 ~ 316.46 g (at start of dosing)
Neutropenia induction with chemotherapyNormal SD rats were administered with Docetaxel 4 mg/kg and CPA 32 mg/kg once intraperitoneally to induce neutropenia. Docetaxel and CPA were injected to induce neutropenia in a rat model according to 4 different regimens: Concomitant (G2-G7), 2 hour (G8-G13), 5 hour (G14-G19), and 24 hour (G20-G25) prior to test article administration.

[156]

Animal Care and Identification

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Eflapegrastim

25/10/2019by Christian Hilscher

Neutropenia in Breast Cancer: Spectrum Pharmaceuticals has submitted an updated regulatory submission to the US FDA for its biologic Rolontis

10/25/2019 Spectrum Pharmaceutical announced that it has filed an updated Biologics License Application (BLA) with the US Food and Drug Administration (FDA) for Rolontis (eflapegrastim).

The BLA for Rolontis is supported by data from two identically designed Phase 3 clinical trials – ADVANCE and RECOVER – that evaluated the safety and efficacy of eflapegrastim in 643 patients with early breast cancer for the treatment of neutropenia with myelosuppressive chemotherapy.

In both studies, eflapegrastim demonstrated the pre-specified hypothesis of non-inferiority (NI) in Duration of Severe Neutropenia (DSN) and a similar safety profile to pegfilgrastim .

Eflapegrastim also demonstrated non-inferiority to pegfilgrastim in DSN across all 4 cycles in both studies (all NI p<0.0001), the company writes.
© arznei-news.de – Source: Spectrum Pharmaceuticals

Eflapegrastim, sold under the brand names Rolvedon among others, is a long-acting G-CSF analog developed by Hanmi Pharmaceutical and licensed to Spectrum Pharmaceuticals.[2] Eflapegrastim is a leukocyte growth factor.[1] It is used to reduce the risk of febrile neutropenia in people with non-myeloid malignancies receiving myelosuppressive anti-cancer agents.[1]

Eflapegrastim was approved for medical use in the United States in September 2022.[1][3][4]

Medical uses

Eflapegrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.[1]

Its efficacy has been shown to be non-inferior to pegfilgrastim.[1]

References

  1. Jump up to:a b c d e f “Archived copy” (PDF). Archived (PDF) from the original on 19 September 2022. Retrieved 19 September 2022.
  2. ^ pharmaceutical, hanmi. “Pipeline – R&D”Hanmi PharmaceuticalArchived from the original on 2 February 2017. Retrieved 23 January 2017.
  3. ^ “Rolvedon: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA)Archived from the original on 19 September 2022. Retrieved 18 September 2022.
  4. ^ “Spectrum Pharmaceuticals Receives FDA Approval for Rolvedon (eflapegrastim-xnst) Injection”Business Wire (Press release). 9 September 2022. Archived from the original on 9 September 2022. Retrieved 18 September 2022.

External links

  • “Eflapegrastim”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02643420 for “SPI-2012 vs Pegfilgrastim in the Management of Neutropenia in Participants With Breast Cancer With Docetaxel and Cyclophosphamide (ADVANCE) (ADVANCE)” at ClinicalTrials.gov
  • Clinical trial number NCT02953340 for “SPI-2012 vs Pegfilgrastim in Management of Neutropenia in Breast Cancer Participants With Docetaxel and Cyclophosphamide” at ClinicalTrials.gov
Clinical data
Trade namesRolvedon
Other namesEflapegrastim-xnst, HM-10460A, SPI-2012
Routes of
administration
Subcutaneous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1384099-30-2
ChemSpiderNone
UNIIUT99UG9QJX
KEGGD11188

////////////Eflapegrastim, Rolvedon, APPROVALS 2022, FDA 2022, エフラペグラスチム , HM10460A, SPI-2012, HNK460, ROLONTIS

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Terlipressin acetate


Terlipressin.png
Terlipressin acetate.png
2D chemical structure of 1884420-36-3

Terlipressin acetate

テルリプレシン酢酸塩

C52H74N16O15S2. (C2H4O2)x

CAS: 914453-96-6 ACETATEFREE  FORM 14636-12-5

Terlipressin acetate (JAN);
Heamopressin (TN);
Terlivaz (TN)

Cardiovascular agent

Antidiuretic, Vasoconstrictor, Arginine vasopressin receptor agonist

USFDA APPROVED 2022/9/14

An inactive peptide prodrug that is slowly converted in the body to lypressin. It is used to control bleeding of ESOPHAGEAL VARICES and for the treatment of HEPATORENAL SYNDROME.

SVG Image
IUPAC CondensedH-Gly-Gly-Gly-Cys(1)-Tyr-Phe-Gln-Asn-Cys(1)-Pro-Lys-Gly-NH2.CH3CO2H
SequenceGGGCYFQNCPKG
IUPACglycyl-glycyl-glycyl-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparagyl-L-cysteinyl-L-prolyl-L-lysyl-glycinamide (4->9)-disulfide acetic acid
  • EINECS 238-680-8
  • Terlipressin
  • Terlipressina
  • Terlipressina [INN-Spanish]
  • Terlipressine
  • Terlipressine [INN-French]
  • Terlipressinum
  • Terlipressinum [INN-Latin]
  • UNII-7Z5X49W53P

acetic acid;(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]pyrrolidine-2-carboxamide

FREE FORM

Molecular Structure of 14636-12-5 (Terlipressin)
Formula:C52H74N16O15S2
Molecular Weight:1227.39

14636-12-5

(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(1S)-5-amino-1-(carbamoylmethylcarbamoyl)pentyl]pyrrolidine-2-carboxamide;N-(N-(N-Glycylglycyl)glycyl)-8-L-lysinevasopressin;Glypressin;Terlipressin Acetate;Remestyp;Thymosin α1 Acetate;Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 (disulfide bridge 4:9);Glycylpressin;

/////////

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Terlipressin, sold under the brand name Terlivaz among others, is an analogue of vasopressin used as a vasoactive drug in the management of low blood pressure. It has been found to be effective when norepinephrine does not help. Terlipressin is a vasopressin receptor agonist.[1]

Medical uses

Terlipressin is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.[1]

Indications for use include norepinephrine-resistant septic shock[2] and hepatorenal syndrome.[3] In addition, it is used to treat bleeding esophageal varices.[4]

Contraindications

Terlipressin is contraindicated in people experiencing hypoxia or worsening respiratory symptoms and in people with ongoing coronary, peripheral or mesenteric ischemia.[1] Terlipressin may cause fetal harm when used during pregnancy.[1]

Society and culture

Terlipressin is available in New Zealand,[5] Australia, the European Union,[6] India, Pakistan & UAE. It is sold under various brand names including Glypressin.

Clinical data
Trade namesTerlivaz
AHFS/Drugs.comInternational Drug Names
Routes of
administration
Intravenous
ATC codeH01BA04 (WHO)
Legal status
Legal statusUS: ℞-only [1]
Pharmacokinetic data
Protein binding~30%
Identifiers
showIUPAC name
CAS Number14636-12-5 
PubChem CID72081
DrugBankDB02638 
ChemSpider65067 
UNII7Z5X49W53P
KEGGD06672 
CompTox Dashboard (EPA)DTXSID7048952 
ECHA InfoCard100.035.149 
Chemical and physical data
FormulaC52H74N16O15S2
Molar mass1227.38 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

References

  1. Jump up to:a b c d e “Archived copy” (PDF). Archived (PDF) from the original on 2022-09-19. Retrieved 2022-09-19.
  2. ^ O’Brien A, Clapp L, Singer M (2002). “Terlipressin for norepinephrine-resistant septic shock”. Lancet359 (9313): 1209–10. doi:10.1016/S0140-6736(02)08225-9PMID 11955542S2CID 38463837.
  3. ^ Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón J, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J (2000). “Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome”. J Hepatol33 (1): 43–8. doi:10.1016/S0168-8278(00)80158-0PMID 10905585.
  4. ^ Ioannou G, Doust J, Rockey D (2003). Ioannou GN (ed.). “Terlipressin for acute esophageal variceal hemorrhage”Cochrane Database Syst Rev (1): CD002147. doi:10.1002/14651858.CD002147PMC 7017851PMID 12535432.
  5. ^ http://www.medsafe.govt.nz/profs/datasheet/g/Glypressin01mgmlFerringinj.pdf Archived 2021-12-20 at the Wayback Machine[bare URL PDF]
  6. ^ “Terlipressin”Archived from the original on 2019-06-26. Retrieved 2018-01-23.

External links

////Terlipressin acetate, テルリプレシン酢酸塩 , FDA 2022, APPROVALS

2022, CC(=O)O.C1CC(N(C1)C(=O)C2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2)CC(=O)N)CCC(=O)N)CC3=CC=CC=C3)CC4=CC=C(C=C4)O)NC(=O)CNC(=O)CNC(=O)CN)C(=O)NC(CCCCN)C(=O)NCC(=O)N

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Spesolimab


(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYSFT SSWIHWVKQA PGQGLEWMGE INPGNVRTNY
NENFRNKVTM TVDTSISTAY MELSRLRSDD TAVYYCTVVF YGEPYFPYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPEAAGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(Light chain)
QIVLTQSPGT LSLSPGERAT MTCTASSSVS SSYFHWYQQK PGQAPRLWIY RTSRLASGVP
DRFSGSGSGT DFTLTISRLE PEDAATYYCH QFHRSPLTFG AGTKLEIKRT VAAPSVFIFP
PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL
TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC
(Disulfide bridge: H22-H96, H146-H202, H222-L215, H228-H’228, H231-H’231, H263-H323, H369-H427, H’22-H’96, H’146-H’202, H’222-L’215, H’263-H’323, H’369-H’427, L23-L89, L135-L195, L’23-L’89, L’135-L’195)

Spesolimab

スペソリマブ (遺伝子組換え)

FormulaC6480H9988N1736O2012S46
cas2097104-58-8
Mol weight145878.0547
Antipsoriatic, Anti-IL-36 receptor antagonist

fda approved 2022/9/1, spevigo

BI 655130; Spesolimab-sbzo

  • OriginatorBoehringer Ingelheim
  • ClassAnti-inflammatories; Antipsoriatics; Monoclonal antibodies; Skin disorder therapies
  • Mechanism of ActionInterleukin 36 receptor antagonists
  • Orphan Drug StatusYes – Generalised pustular psoriasis
  • RegisteredGeneralised pustular psoriasis
  • Phase II/IIIUlcerative colitis
  • Phase IICrohn’s disease; Hidradenitis suppurativa; Palmoplantar pustulosis
  • DiscontinuedAtopic dermatitis
  • 01 Sep 2022First global approval – Registered for Generalised pustular psoriasis in USA (IV)
  • 01 Sep 2022Adverse events data from the Effisayil 1 phase II trial in Generalised pustular psoriasis released by Boehringer Ingelheim
  • 03 Aug 2022Boehringer Ingelheim anticipates regulatory approval in Generalised pustular psoriasis by 2022

Spesolimab (BI 655130) is a humanised monoclonal antibody, being developed by Boehringer Ingelheim, for the treatment of generalised pustular psoriasis, Crohn’s disease, palmoplantar pustulosis, ulcerative colitis and hidradenitis suppurativa.

What causes Palmoplantar Pustulosis?

Researchers have found some possible causes including smoking, infections, certain medications and genetics. Smoking: Many patients who have PPP are smokers or have smoked in the past. Smoking may cause sweat glands to become inflamed, especially on the hands and feet, which causes pustules to form.

FDA approves the first treatment option for generalized pustular psoriasis flares in adults

  • More than half of patients treated with SPEVIGO® (spesolimab-sbzo) injection, for intravenous use showed no visible pustules one week after receiving treatment
  • Spesolimab is a monoclonal antibody that inhibits interleukin-36 (IL-36) signaling

https://www.boehringer-ingelheim.us/press-release/fda-approves-first-treatment-option-generalized-pustular-psoriasis-flares-adults

Ridgefield, Conn., September 1, 2022 – Boehringer Ingelheim announced today the U.S. Food and Drug Administration has approved SPEVIGO, the first approved treatment option for generalized pustular psoriasis (GPP) flares in adults. SPEVIGO is a novel, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a key part of a signaling pathway within the immune system shown to be involved in the cause of GPP.

“GPP flares can greatly impact a patient’s life and lead to serious, life-threatening complications,” said Mark Lebwohl, M.D., lead investigator and publication author, and Dean for Clinical Therapeutics, Icahn School of Medicine at Mount Sinai, Kimberly and Eric J. Waldman Department of Dermatology, New York. “The approval of SPEVIGO is a turning point for dermatologists and clinicians. We now have an FDA-approved treatment that may help make a difference for our patients who, until now, have not had any approved options to help manage GPP flares.”

Distinct from plaque psoriasis, GPP is a rare and potentially life-threatening neutrophilic skin disease, which is characterized by flares (episodes of widespread eruptions of painful, sterile pustules). In the United States, it is estimated that 1 out of every 10,000 people has GPP. Given that it is so rare, recognizing the signs and symptoms can be challenging and consequently lead to delays in diagnosis.

“This important approval reflects our successful efforts to accelerate our research with the aim to bring innovative treatments faster to the people most in need,” said Carinne Brouillon, Member of the Board of Managing Directors, responsible for Human Pharma, Boehringer Ingelheim. “We recognize how devastating this rare skin disease can be for patients, their families and caregivers. GPP can be life-threatening and until today there have been no specific approved therapies for treating the devastating GPP flares. It makes me proud that with the approval of SPEVIGO we can now offer the first U.S. approved treatment option for those in need.” 

In the 12-week pivotal Effisayil 1 clinical trial, patients experiencing a GPP flare (N=53) were treated with SPEVIGO or placebo. After one week, patients treated with SPEVIGO showed no visible pustules (54%) compared to placebo (6%). 

In Effisayil 1, the most common adverse reactions (≥5%) in patients that received SPEVIGO were asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection.

“GPP can have an enormous impact on patients’ physical and emotional wellbeing. With the FDA approval of this new treatment, people living with GPP now have hope in knowing that there is an option to help treat their flares,” said Thomas Seck, M.D., Senior Vice President, Medicine and Regulatory Affairs, Boehringer Ingelheim. “SPEVIGO represents Boehringer Ingelheim’s commitment to delivering meaningful change for patients living with serious diseases with limited treatment options.”

About SPEVIGO
SPEVIGO is indicated for the treatment of GPP flares in adults. SPEVIGO is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO. Reactions have included drug reaction with eosinophilia and systemic symptoms (DRESS).

What is SPEVIGO?
SPEVIGO is a prescription medicine used to treat generalized pustular psoriasis (GPP) flares in adults. It is not known if SPEVIGO is safe and effective in children.

U.S. FDA grants Priority Review for spesolimab for the treatment of flares in patients with generalized pustular psoriasis (GPP), a rare, life-threatening skin disease

https://www.boehringer-ingelheim.us/press-release/us-fda-grants-priority-review-spesolimab-treatment-flares-patients-generalized

December 15, 2021 – Boehringer Ingelheim today announced that the U.S. Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) and granted Priority Review for spesolimab for the treatment of generalized pustular psoriasis (GPP) flares. 

FDA grants Priority Review to applications for medicines that, if approved, would offer significant improvement over available options in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. The FDA has granted spesolimab Orphan Drug Designation for the treatment of GPP, and Breakthrough Therapy Designation for spesolimab for the treatment of GPP flares in adults.

“The FDA acceptance of our filing for spesolimab is a critical step in our efforts to bring this first-in-class treatment to people living with GPP,” said Matt Frankel, M.D., Vice President, Clinical Development and Medical Affairs, Specialty Care, Boehringer Ingelheim. “There is an urgent unmet need for an approved treatment option that can rapidly clear painful GPP flares.”

GPP is a rare, life-threatening neutrophilic skin disease, which is distinct from plaque psoriasis. It is characterized by episodes of widespread eruptions of painful, sterile pustules (blisters of non-infectious pus). There is a high unmet need for treatments that can rapidly and completely resolve the signs and symptoms of GPP flares. Flares greatly affect a person’s quality of life and can lead to hospitalization with serious complications, including heart failure, renal failure, sepsis, and death.

About spesolimab
Spesolimab is a novel, humanized, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a signaling pathway within the immune system shown to be involved in the pathogeneses of several autoimmune diseases, including GPP. Spesolimab is also under investigation for the prevention of GPP flares and for the treatment of other neutrophilic skin diseases, such as palmoplantar pustulosis (PPP) and hidradenitis suppurativa (HS).

About generalized pustular psoriasis (GPP)
GPP is a rare, heterogenous and potentially life-threatening neutrophilic skin disease, which is clinically distinct from plaque psoriasis. GPP is caused by neutrophils (a type of white blood cell) accumulating in the skin, resulting in painful, sterile pustules all over the body. The clinical course varies, with some patients having a relapsing disease with recurrent flares, and others having a persistent disease with intermittent flares. While the severity of GPP flares can vary, if left untreated they can be life-threatening due to complications such as sepsis and multisystem organ failure. This chronic, systemic disease has a substantial quality of life impact for patients and healthcare burden. GPP has a varied prevalence across different geographical regions and more women are affected than men.

Boehringer Ingelheim Immunology: Pioneering Science, Inspired By Patients
Living with fibrotic and inflammatory diseases greatly impacts patients’ lives emotionally and physically. These patients are our guides, partners and inspiration as we redefine treatment paradigms. As a family-owned company, we can plan long-term. Our goal is to discover and develop first-of-their-kind therapies. With a deep understanding of molecular pathways, we are pioneering scientific breakthroughs that target, repair and prevent many fibrotic and inflammatory diseases. By building on long-term external collaborations, we strive to bring treatment breakthroughs to patients in the shortest time. We won’t rest until we can give people the chance to live the lives they want.

Boehringer Ingelheim
Boehringer Ingelheim is working on breakthrough therapies that improve the lives of humans and animals. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term perspective. Around 52,000 employees serve more than 130 markets in the three business areas, Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. Learn more at www.boehringer-ingelheim.com.

MPR-US-101971

////////Spesolimab, monoclonal antibody, fda 2022, approvals 2022, Orphan Drug Status, Generalised pustular psoriasis, BI 655130, Spesolimab-sbzo, peptide, monoclonal antibody

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Vutrisiran sodium, ALN 65492, Votrisiran


RNA, (Um-​sp-​(2′-​deoxy-​2′-​fluoro)​C-​sp-​Um-​Um-​Gm-​(2′-​deoxy-​2′-​fluoro)​G-​Um-​Um-​(2′-​deoxy-​2′-​fluoro)​A-​Cm-​Am-​Um-​Gm-​(2′-​deoxy-​2′-​fluoro)​A-​Am-​(2′-​deoxy-​2′-​fluoro)​A-​Um-​Cm-​Cm-​Cm-​Am-​sp-​Um-​sp-​Cm)​, complex with RNA (Um-​sp-​Gm-​sp-​Gm-​Gm-​Am-​Um-​(2′-​deoxy-​2′-​fluoro)​U-​Um-​(2′-​deoxy-​2′-​fluoro)​C-​(2′-​deoxy-​2′-​fluoro)​A-​(2′-​deoxy-​2′-​fluoro)​U-​Gm-​Um-​Am-​Am-​Cm-​Cm-​Am-​Am-​Gm-​Am) 3′-​[[(2S,​4R)​-​1-​[29-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​14,​14-​bis[[3-​[[3-​[[5-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​1-​oxopentyl]​amino]​propyl]​amino]​-​3-​oxopropoxy]​methyl]​-​1,​12,​19,​25-​tetraoxo-​16-​oxa-​13,​20,​24-​triazanonacos-​1-​yl]​-​4-​hydroxy-​2-​pyrrolidinyl]​methyl hydrogen phosphate] (1:1)

Vutrisiran Sodium

Nucleic Acid Sequence

Sequence Length: 44, 23, 2113 a 9 c 8 g 14 umultistranded (2); modified

Vutrisiran sodium

  • ALN 65492
  • Votrisiran

C530H672F9N171Na43O323P43S6 : 17289.77
[1867157-35-4 , Vutrisiran]

FormulaC530H672F9N171O323P43S6.43Na  ORC530H672F9N171Na43O323P43S6
CAS1867157-35-4 , VURISIRAN
Mol weight17289.7661

FDA APPROVED, AMVUTTRA, 2022/6/13

ブトリシランナトリウム
EfficacyGene expression regulator
  DiseasePolyneuropathy of hereditary transthyretin-mediated amyloidosis [D
CommentRNA interference (RNAi) drug
Treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis)

UNII28O0WP6Z1P UNII

Vutrisiran
Vutrisiran Sodium is a sodium salt of an siRNA derivative targeting transthyretin (TTR) covalently linked to a triantennary GalNAc3 complex at the 3’ end of the sense strand. The siRNA moiety is composed of a duplex oligonucleotide of sense strand consisting of chemically modified 21 nucleotide residues and antisense strand consisting of chemically modified 23 nucleotide residues each.

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) that targets wild-type and mutant transthyretin (TTR) messenger RNA (mRNA).7 This siRNA therapeutic is indicated for the treatment of neuropathies associated with hereditary transthyretin-mediated amyloidosis (ATTR), a condition caused by mutations in the TTR gene.2 More than 130 TTR mutations have been identified so far,3 but the most common one is the replacement of valine with methionine at position 30 (Val30Met).2 The Val30Met variant is the most prevalent among hereditary ATTR patients with polyneuropathy, especially in Portugal, France, Sweden, and Japan.2

TTR mutations lead to the formation of misfolded TTR proteins, which form amyloid fibrils that deposit in different types of tissues. By targeting TTR mRNA, vutrisiran reduces the serum levels of TTR.6,7 Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a residue that enables the delivery of siRNA to hepatocytes.5,7 This delivery platform gives vutrisiran high potency and metabolic stability, and allows for subcutaneous injections to take place once every three months.8 Another siRNA indicated for the treatment of polyneuropathy associated with hereditary ATTR is patisiran.2 Vutrisiran was approved by the FDA in June 2022.

CLIP

https://www.nature.com/articles/s41392-020-0207-x

figure 1

Schematic illustrations of the working mechanisms of miRNA (a) and siRNA (b)

figure 2

Structures of chemical modifications and analogs used for siRNA and ASO decoration. According to the modification site in the nucleotide acid, these structures can be divided into three classes: phosphonate modification, ribose modification and base modification, which are marked in red, purple and blue, respectively. R = H or OH, for RNA or DNA, respectively. (S)-cEt-BNA (S)-constrained ethyl bicyclic nucleic acid, PMO phosphorodiamidate morpholino oligomer

figure 3

Representative designs for the chemical modification of siRNA. The sequences and modification details for ONPATTRO®, QPI-1007, GIVLAARI™ and inclisiran are included. The representative siRNA modification patterns developed by Alnylam (STC, ESC, advanced ESC and ESC+) and arrowhead (AD1-3 and AD5) are shown. Dicerna developed four GalNAc moieties that can be positioned at the unpaired G–A–A–A nucleotides of the DsiRNA structure. 2′-OMe 2′-methoxy, 2′-F 2′-fluoro, GNA glycol nucleic acid, UNA unlocked nucleic acid, SS sense strand, AS antisense strand

figure 6

siRNA delivery platforms that have been evaluated preclinically and clinically. Varieties of lipids or lipidoids, siRNA conjugates, peptides, polymers, exosomes, dendrimers, etc. have been explored and employed for siRNA therapeutic development by biotech companies or institutes. The chemical structures of the key component(s) of the discussed delivery platforms, including Dlin-DMA, Dlin-MC3-DMA, C12-200, cKK-E12, GalNAc–siRNA conjugates, MLP-based DPC2.0 (EX-1), PNP, PEI, PLGA-based LODER, PTMS, GDDC4, PAsp(DET), cyclodextrin-based RONDEL™ and dendrimer generation 3 are shown. DLin-DMA (1,2-dilinoleyloxy-3-dimethylaminopropane), DLin-MC3-DMA (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate, DPC Dynamic PolyConjugates, MLP membrane-lytic peptide, CDM carboxylated dimethyl maleic acid, PEG polyethylene glycol, NAG N-acetylgalactosamine, PNP polypeptide nanoparticle, PEI poly(ethyleneimine), LODER LOcal Drug EluteR, PLGA poly(lactic-co-glycolic) acid, PTMS PEG-PTTMA-P(GMA-S-DMA) poly(ethylene glycol)-co-poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl))] ethane methacrylate-co-poly(dimethylamino glycidyl methacrylate), GDDC4 PG-P(DPAx-co-DMAEMAy)-PCB, where PG is guanidinated poly(aminoethyl methacrylate) PCB is poly(carboxybetaine) and P(DPAx-co-DMAEMAy) is poly(dimethylaminoethyl methacrylate-co-diisopropylethyl methacrylate), PEG-PAsp(DET) polyethylene glycol-b-poly(N′-(N-(2-aminoethyl)-2-aminoethyl) aspartamide), PBAVE polymer composed of butyl and amino vinyl ether, RONDEL™ RNAi/oligonucleotide nanoparticle delivery

Vutrisiran SodiumVutrisiran Sodium is a sodium salt of an siRNA derivative targeting transthyretin (TTR) covalently linked to a triantennary GalNAc3 complex at the 3’ end of the sense strand. The siRNA moiety is composed of a duplex oligonucleotide of sense strand consisting of chemically modified 21 nucleotide residues and antisense strand consisting of chemically modified 23 nucleotide residues each.C530H672F9N171Na43O323P43S6 : 17289.77
[1867157-35-4 , Vutrisiran]

REF

Nucleic Acids Research (2019), 47(7), 3306-3320. 

Drug Metabolism & Disposition (2019), 47(10), 1183-1201.  

PATENT

WO 2020128816

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020128816

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt or prodrug thereof and an additional therapeutic agent for the treatment of transthyretin amyloidosis. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent for the treatment of transthyretin amyloidosis.

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent. The compositions and methods of the invention are useful in stabilizing transthyretin, inhibiting transthyretin misfolding, proteolysis, and treating amyloid diseases associated thereto.

Transthyretin (TTR) is a 55 kDa homotetrameric protein present in serum and cerebral spinal fluid and which functions as a transporter of L-thyroxine (T4) and holo-retinol binding protein (RBP). TTR has been found to be an amyloidogenic protein that, under certain conditions, can be transformed into fibrils and other aggregates which can lead to disease pathology such as polyneuropathy or cardiomyopathy in humans.

US Patent Nos. 7,214,695; 7,214,696; 7,560,488; 8, 168.683; and 8,653,119 each of which is incorporated herein by reference, discloses benzoxazole derivatives which act as transthyretin stabilizers and are of the formula

or a pharmaceutically acceptable salt thereof; wherein Ar is 3,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl. Particularly, 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis) of the formula

is disclosed therein. Tafamidis is an orally active transthyretin stabilizer that inhibits tetramer dissociation and proteolysis that has been approved in certain jurisdictions for the treatment of transthyretin polyneuropathy (TTR-PN) and is currently in development for the treatment of transthyretin cardiomyopathy (TTR-CM). US Patent No. 9,249, 112, also incorporated herein by reference, discloses polymorphic forms of the meglumine salt of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis meglumine). US Patent No. 9,770,441 discloses polymorphic forms of the free acid of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis), and is also incorporated by reference herein.

Summary of the Invention

The present invention provides pharmaceutical compositions and methods comprising the compound 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent. Particular embodiments of this invention are pharmaceutical compositions and methods comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agents selected from the group consisting of agents that lower plasma levels of TTR such as an antisense therapy, TTR gene editing therapy, transcriptional modulators, translational modulators, TTR protein degraders and antibodies that bind and reduce TTR levels; amyloid reduction therapies such as anti amyloid antibodies (either TTR selective or general), stimulators of amyloid clearance, fibril disruptors and therapies that inhibit amyloid nucleation; other TTR stabilizers; and TTR modulators such as therapeutics which inhibit TTR cleavage. Particularly, the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and

methods comprising a polymorphic form of tafamidis free acid or a polymorphic form of tafamidis meglumine salt with one or more additional therapeutic agents.

The present invention also provides a method of treating or preventing transthyretin amyloidosis in a patient, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of 2-(3,5-dichlorophenyl)-1,3-benzoxazole- 6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agents.

A particular embodiment of the present method of treatment is the method comprising a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent are administered orally. Additional embodiments of this invention are methods of treatment as described above wherein the 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent are administered parenterally (intravenously or subcutaneously). Further embodiments of this invention are methods of treatment wherein the 2-(3,5-dichlorophenyl)-1, 3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally and the one or more additional therapeutic agent is administered either orally or parenterally. Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR 5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR 5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR

cardiomyopathy, the method comprising administering to a patient in need thereof a therapeutically effective amount of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agents.

Brief Description of the Drawings

REF

Biochemical Pharmacology (Amsterdam, Netherlands) (2021), 189, 114432.

PATENT

WO 2021041884 

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021041884

Exemplary RNAi agents that reduce the expression of TTR include patisiran and vutrisiran.

The ter s “antisense polynucleotide agent”, “antisense oligonucleotide”, “antisense compound”, and “antisense agent” as used interchangeably herein, refer to an agent comprising a single-stranded oligonucleotide that specifically binds to the target nucleic acid molecules via hydrogen bonding (e.g., Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding) and inhibits the expression of the targeted nucleic acid by an antisense mechanism of action, e.g., by RNase H. In some embodiments, an antisense agent is a nucleic acid therapeutic that acts by reducing the expression of a target gene, thereby reducing the expression of the polypeptide encoded by the target gene. Exemplary antisense agents that reduce the expression of TTR include inotersen and Ionis 682884/ ION-TTR-LRx (see, e.g., WO2014179627 which is incorporated by reference in its entirety). Further antisense agents that reduce the expression of TTR are provided, for example in WO2011139917 and WO2014179627, each of which is incorporated by reference in its entirety.

REF

Clinical Pharmacology & Therapeutics (Hoboken, NJ, United States) (2021), 109(2), 372-382

Annals of Plastic Surgery (2021), 86(2S_Suppl_1), S23-S29.

Journal of Cardiovascular Pharmacology (2021), 77(5), 544-548. 

Annals of Pharmacotherapy (2021), 55(12), 1502-1514.

Kidney International (2022), 101(2), 208-211

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figure 7

Tissues targeted by siRNA and miRNA therapeutics currently being investigated at the clinical stage. The corresponding therapeutic names are shown beside the tissues

CLIP

Vutrisiran An Investigational RNAi Therapeutic for ATTR Amyloidosis Vutrisiran has not been approved by the U.S. Food and Drug Administration, European Medicines Agency, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of this investigational therapeutic. Overview • Vutrisiran is an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, which encompasses both hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis.1, 2 • Vutrisiran inhibits the production of disease-causing transthyretin (TTR) protein by the liver, leading to a reduction in the level of TTR in the blood.1, 2 • Vutrisiran is administered subcutaneously (under the skin) and utilizes one of Alnylam’s delivery platforms known as the Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform.1, 2 • Vutrisiran is administered every three months.2 • Vutrisiran is under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA). Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In the U.S. vutrisiran has received an action date under the Prescription Drug User Fee Act (PDUFA) of April 14, 2022. The Company received orphan drug designation in Japan. Alnylam has global commercial rights to vutrisiran, assuming regulatory approvals. Clinical Development • A Phase 1 clinical study of vutrisiran was conducted in 80 healthy volunteers (60 received vutrisiran and 20 received placebo). Vutrisiran demonstrated an acceptable safety profile and a single dose reduced serum TTR for a period of at least 90 days.2 • The safety and efficacy of vutrisiran are being evaluated in the HELIOS Phase 3 clinical program, currently consisting of two clinical trials: HELIOS-A and HELIOS-B. • HELIOS-A is a randomized, open-label, global multi-center Phase 3 study of 164 adult patients with hATTR amyloidosis with polyneuropathy.1 • The primary endpoint of HELIOS-A is change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months. • Secondary endpoints at 9 months include the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score and the 10-Meter Walk Test (10-MWT). • The 9-month endpoints will be analyzed at 18 months with the addition of other secondary endpoints. • HELIOS-B is a randomized, double-blind, placebo-controlled Phase 3 study of 655 adult patients with ATTR amyloidosis with cardiomyopathy (including both hATTR and wtATTR amyloidosis).3 • The primary endpoint will evaluate the efficacy of vutrisiran versus placebo for the composite outcome of all-cause mortality and recurrent cardiovascular (CV) events (CV hospitalizations and urgent heart failure (HF) visits) at 30-36 months. • Secondary endpoints include the change from baseline in the 6-minute walk test (6-MWT), health status measured using the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), echocardiographic assessments of mean left ventricular wall thickness and global longitudinal strain, the N-terminal prohormone B-type natriuretic peptide (NT-proBNP) as a cardiac biomarker, and all-cause mortality, rate of recurrent CV events, and composite of all-cause mortality and recurrent all-cause hospitalizations and urgent HF visits at month 30 or 30-36 months. Page 2 © 2021 Alnylam Pharmaceuticals, Inc. All rights reserved. TTRsc02-USA-00012 v4 About ATTR Amyloidosis • ATTR amyloidosis is a rare, underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by misfolded TTR that accumulates as amyloid fibrils in multiple tissues including the nerves, heart, and GI tract. There are two types of ATTR amyloidosis: hATTR amyloidosis and wtATTR amyloidosis.4,5,6 • hATTR amyloidosis is an inherited condition that is caused by variants (i.e., mutations) in the transthyretin (TTR) gene.5,7,8 TTR protein is produced primarily in the liver and is normally a carrier of vitamin A.9 The variant results in misfolded TTR proteins that accumulate as amyloid deposits in multiple tissues, including the nerves, heart and gastrointestinal (GI) tract.5, 6, 7 It is a multisystem disease that can include sensory and motor, autonomic, and cardiac symptoms. The condition can have a debilitating impact on a patient’s life and may lead to premature death with a median survival of 4.7 years following diagnosis.8,10 It is estimated that there are approximately 50,000 patients with hATTR amyloidosis worldwide.11 • wtATTR amyloidosis is a non-hereditary condition that occurs when misfolded wild-type TTR accumulates as amyloid deposits in multiple organs. It predominantly manifests as cardiac symptoms, but other systems are also involved, and commonly leads to heart failure and mortality within 2.5 to 5.5 years.12,13,14,15,16,17,18,19 wtATTR amyloidosis affects an estimated 200,000-300,000 people worldwide.20 • Alnylam is committed to developing multiple treatment options for people who are living with ATTR amyloidosis to help manage the debilitating and progressive nature of the disease. For more information about vutrisiran, please contact media@alnylam.com. For more information on HELIOS-A (NCT03759379) and HELIOS-B (NCT04153149) please visit http://www.clinicaltrials.gov or contact media@alnylam.com. Current information as of November 2021

CLIP

Alnylam announces extension of review period for new drug vutrisiran to treat ATTR amyloidosis

https://www.medthority.com/news/2022/4/alnylam-announces-3-month-extension-of-review-period-for-new-drug-application-for-vutrisiran-to-treat-attr-amyloidosis/

Alnylam announces 3-month extension of review period for new drug application for vutrisiran to treat ATTR amyloidosis.

Alnylam Pharmaceuticals, Inc., a RNAi therapeutics company, announced that the FDA has extended the review timeline of the New Drug Application (NDA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, to allow for the review of newly added information related to the new secondary packaging and labelling facility.

Alnylam recently learned that the original third-party secondary packaging and labelling facility the Company planned to use for the vutrisiran launch was recently inspected and the inspection requires classification for the FDA to take action on the vutrisiran NDA. The inspection observations were not directly related to vutrisiran. In order to minimize delays to approval, Alnylam has identified a new facility to pack and label vutrisiran and submitted an amendment to the NDA for review by the FDA. The updated Prescription Drug User Fee Act (PDUFA) goal date to allow for this review is July 14, 2022. No additional clinical data have been requested by the FDA.

////////////Vutrisiran sodium,  APPROVALS 2022, FDA 2022, FDA APPROVED, AMVUTTRA, 2022/6/13, ブトリシランナトリウム , ALN 65492, Votrisiran, siRNA

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Tirzepatide


YXEGTFTSDY SIXLDKIAQK AFVQWLIAGG PSSGAPPPS

Tirzepatide.svg
tirzepatide
ChemSpider 2D Image | tirzepatide | C225H347N47O69
Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing | Organic Process Research & Development

Tirzepatide

チルゼパチド

LY3298176,

FormulaC225H348N48O68
CAS2023788-19-2
Mol weight4813.4514

FDA APPROVED 2022/5/13, Mounjaro

ClassAntidiabetic agent
GLP-1 receptor agonist
EfficacyAntidiabetic, Gastric inhibitory polypeptide receptor agonist, Glucagon-like peptide 1 (GLP-1) receptor agonist
  DiseaseType 2 diabetes mellitus

Tirzepatide is an agonist of human glucose-dependent insulinotropic polypeptide (GIP) and human glucagon-like peptide-1 (GLP-1) receptors, whose amino acid residues at positions 2 and 13 are 2-methylAla, and the C-terminus is amidated Ser. A 1,20-icosanedioic acid is attached to Lys at position 20 via a linker which consists of a Glu and two 8-amino-3,6-dioxaoctanoic acids. Tirzepatide is a synthetic peptide consisting of 39 amino acid residues.

C225H348N48O68 : 4813.45
[2023788-19-2]

L-​Serinamide, L-​tyrosyl-​2-​methylalanyl-​L-​α-​glutamylglycyl-​L-​threonyl-​L-​phenylalanyl-​L-​threonyl-​L-​seryl-​L-​α-​aspartyl-​L-​tyrosyl-​L-​seryl-​L-​isoleucyl-​2-​methylalanyl-​L-​leucyl-​L-​α-​aspartyl-​L-​lysyl-​L-​isoleucyl-​L-​alanyl-​L-​glutaminyl-​N6-​[(22S)​-​22,​42-​dicarboxy-​1,​10,​19,​24-​tetraoxo-​3,​6,​12,​15-​tetraoxa-​9,​18,​23-​triazadotetracont-​1-​yl]​-​L-​lysyl-​L-​alanyl-​L-​phenylalanyl-​L-​valyl-​L-​glutaminyl-​L-​tryptophyl-​L-​leucyl-​L-​isoleucyl-​L-​alanylglycylglycyl-​L-​prolyl-​L-​seryl-​L-​serylglycyl-​L-​alanyl-​L-​prolyl-​L-​prolyl-​L-​prolyl-

Other Names

  • L-Tyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-L-lysyl-L-isoleucyl-L-alanyl-L-glutaminyl-N6-[(22S)-22,42-dicarboxy-1,10,19,24-tetraoxo-3,6,12,15-tetraoxa-9,18,23-triazadotetracont-1-yl]-L-lysyl-L-alanyl-L-phenylalanyl-L-valyl-L-glutaminyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-alanylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide

Tirzepatide, sold under the brand name Mounjaro,[1] is a medication used for the treatment type 2 diabetes.[2][3][4] Tirzepatide is given by injection under the skin.[2] Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.[2]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control.[2] Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.[2] Tirzepatide was approved for medical use in the United States in May 2022.[2]

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.1c00108

Abstract Image

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

PATENT

  • WO2016111971
  • US2020023040
  • WO2019245893
  • US2020155487
  • US2020155650
  • WO2020159949CN112592387
  • WO2021066600CN112661815
  • WO2021154593
  • US2021338769

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Medical uses

Tirzepatide in indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[2]

Contraindications

Tirzepatide should not be used in people with a personal or family history of medullary thyroid cancer or in people with multiple endocrine neoplasia syndrome type 2.[2]

Adverse effects

Preclinical, phase I, and phase II trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract.[5] The most frequently observed adverse effects are nausea, diarrhoea and vomiting, which increased in incidence with the dosage amount (i.e. higher likelihood the higher the dose). The number of patients who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[6] To a slightly lesser extent, patients also reported reduced appetite.[5] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[7][8]

Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[9] The compound is administered as a weekly subcutaneous injection.[10] It completed phase III trials globally in 2021.[11][12]

Mechanism of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[3] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[13] However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[13] Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[3]

Chemistry

Structure

Tirzepatide is an analog of the human GIP hormone with a C20 fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound.[9] The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin.[14]

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[15] This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment.

Large-scale manufacturing processes have been reported for this compound.[16]

History

Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[15] The patent was published late that year. After passing phase 3 clinical trials, Lilly applied for FDA approval in October 2021 with a priority review voucher.[17]

Following the completion of the pivotal SURPASS-2 trial no. NCT03987919, the company announced on 28 April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[18] Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk.[19][20]

In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%).[21] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin).[3] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[3] A meta-analysis published by Dutta et al. showed that over 1-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed to date to tackle the global problem of “diabesity“.[22]

Society and culture

Names

Tirzepatide is the international nonproprietary name (INN).[23]

References

  1. Jump up to:a b “Highlights of prescribing information” (PDF). accessdata.fda.gov. FDA. May 2022. Retrieved 14 May 2022.
  2. Jump up to:a b c d e f g h i “FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes”U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Retrieved 13 May 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. (January 2021). “Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes”The Journal of Clinical Endocrinology and Metabolism106 (2): 388–396. doi:10.1210/clinem/dgaa863PMC 7823251PMID 33236115.
  4. ^ Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. (December 2018). “LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept”Molecular Metabolism18: 3–14. doi:10.1016/j.molmet.2018.09.009PMC 6308032PMID 30473097.
  5. Jump up to:a b Min T, Bain SC (January 2021). “The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials”Diabetes Therapy12 (1): 143–157. doi:10.1007/s13300-020-00981-0PMC 7843845PMID 33325008.
  6. ^ Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. (November 2018). “Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial”The Lancet392 (10160): 2180–2193. doi:10.1016/S0140-6736(18)32260-8PMID 30293770.
  7. ^ Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. (June 2020). “Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens”Diabetes, Obesity & Metabolism22 (6): 938–946. doi:10.1111/dom.13979PMC 7318331PMID 31984598.
  8. ^ Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á (February 2022). “Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial”. JAMA327 (6): 534–545. doi:10.1001/jama.2022.0078PMID 35133415.
  9. Jump up to:a b Ahangarpour M, Kavianinia I, Harris PW, Brimble MA (January 2021). “Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design”. Chemical Society Reviews. Royal Society of Chemistry. 50 (2): 898–944. doi:10.1039/d0cs00354aPMID 33404559S2CID 230783854.
  10. ^ Bastin M, Andreelli F (2019). “Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential”Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy12: 1973–1985. doi:10.2147/DMSO.S191438PMC 6777434PMID 31686879.
  11. ^ “Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly’s SURPASS program” (Press release). Eli Lilly and Company. 17 February 2021. Retrieved 28 October 2021 – via PR Newswire.
  12. ^ “Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes”Business Insider. RTTNews. 19 October 2021. Retrieved 28 October 2021.
  13. Jump up to:a b Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. (September 2020). “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist”JCI Insight5 (17). doi:10.1172/jci.insight.140532PMC 7526454PMID 32730231.
  14. ^ Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, et al. (October 2021). “The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs”Scientific Reports11 (1): 21179. Bibcode:2021NatSR..1121179Odoi:10.1038/s41598-021-00654-3PMC 8551270PMID 34707178.
  15. Jump up to:a b US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, “GIP and GLP-1 co-agonist compounds”, issued 2016-10-25, assigned to Eli Lilly and Co
  16. ^ Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). “Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing”. Organic Process Research & Development25 (7): 1628–1636. doi:10.1021/acs.oprd.1c00108S2CID 237690232.
  17. ^ Sagonowsky, Eric (26 October 2021). “As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth”Fierce Pharma. Retrieved 9 April 2022.
  18. ^ Kellaher, Colin (28 April 2022). “Eli Lilly’s Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study >LLY”Dow Jones Newswires. Retrieved 29 April 2022 – via MarketWatch.
  19. ^ Kahan, Scott; Garvey, W. Timothy (28 April 2022). “SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide”healio.com. Retrieved 29 April 2022.
  20. ^ Taylor, Nick Paul (28 April 2022). “SURMOUNT-able: Lilly’s tirzepatide clears high bar set by Novo’s Wegovy in obesity”FierceBiotech. Retrieved 29 April 2022.
  21. ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes”. The New England Journal of Medicine385 (6): 503–515. doi:10.1056/NEJMoa2107519PMID 34170647S2CID 235635529.
  22. ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (November–December 2021). “Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis”. Indian Journal of Endocrinology and Metabolism25 (6): 475–489. doi:10.4103/ijem.ijem_423_21.
  23. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

Further reading

External links

  • “Tirzepatide”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03954834 for “A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)” at ClinicalTrials.gov
  • Clinical trial number NCT03987919 for “A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)” at ClinicalTrials.gov
  • Clinical trial number NCT03882970 for “A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3)” at ClinicalTrials.gov
  • Clinical trial number NCT03730662 for “A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)” at ClinicalTrials.gov
  • Clinical trial number NCT04039503 for “A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)” at ClinicalTrials.gov

CLIP

https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and

FDA approves Lilly’s Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes

May 13, 2022

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Mounjaro delivered superior A1C reductions versus all comparators in phase 3 SURPASS clinical trials

While not indicated for weight loss, Mounjaro led to significantly greater weight reductions versus comparators in a key secondary endpoint

Mounjaro represents the first new class of diabetes medicines introduced in nearly a decade and is expected to be available in the U.S. in the coming weeks

INDIANAPOLIS, May 13, 2022 /PRNewswire/ — The U.S. Food and Drug Administration (FDA) approved Mounjaro™ (tirzepatide) injection, Eli Lilly and Company’s (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones.1

“Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro’s efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials,” said Juan Pablo Frías, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro 5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

“Lilly has a nearly 100-year heritage of advancing care for people living with diabetes – never settling for current outcomes. We’re not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels,” said Mike Mason, president, Lilly Diabetes. “We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community.”

Mounjaro is expected to be available in the United States in the coming weeks. Lilly is committed to helping people access the medicines they are prescribed and will work with insurers, health systems and providers to help enable patient access to Mounjaro. Lilly plans to offer a Mounjaro savings card for people who qualify. Patients or healthcare professionals with questions about Mounjaro can visit www.Mounjaro.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).

Tirzepatide is also under regulatory review for the treatment of type 2 diabetes in Europe, Japan and several additional markets. A multimedia gallery is available on Lilly.com.

About the SURPASS clinical trial program
The SURPASS phase 3 global clinical development program for tirzepatide began in late 2018 and included five global registration trials and two regional trials in Japan. These studies ranged from 40 to 52 weeks and evaluated the efficacy and safety of Mounjaro 5 mg, 10 mg and 15 mg as a monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. The active comparators in the studies were injectable semaglutide 1 mg, insulin glargine and insulin degludec. Collectively, the five global registration trials consistently demonstrated A1C reductions for participants taking Mounjaro across multiple stages of their type 2 diabetes journeys, from an average around five to 13 years of having diabetes.2-8

  • SURPASS-1 (NCT03954834) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=121), 10 mg (N=121) and 15 mg (N=120) as monotherapy to placebo (N=113) in adults with type 2 diabetes inadequately controlled with diet and exercise alone. From a baseline A1C of 7.9%, Mounjaro reduced participants’ A1C by a mean of 1.8%* (5 mg) and 1.7%* (10 mg and 15 mg) compared to 0.1% for placebo. In a key secondary endpoint, from a baseline weight of 189 lb., Mounjaro reduced participants’ weight by a mean of 14 lb.* (5 mg), 15 lb.* (10 mg) and 17 lb.* (15 mg) compared to 2 lb. for placebo.2,3
  • SURPASS-2 (NCT03987919) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=470), 10 mg (N=469) and 15 mg (N=469) to injectable semaglutide 1 mg (N=468) in adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. From a baseline A1C of 8.3%, Mounjaro reduced participants’ A1C by a mean of 2.0% (5 mg), 2.2%* (10 mg) and 2.3%* (15 mg) compared to 1.9% for semaglutide. In a key secondary endpoint, from a baseline weight of 207 lb., Mounjaro reduced participants’ weight by a mean of 17 lb. (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to 13 lb. for semaglutide.4,5
  • SURPASS-3 (NCT03882970) was a 52-week study comparing the efficacy of Mounjaro 5 mg (N=358), 10 mg (N=360) and 15 mg (N=358) to titrated insulin degludec (N=359) in adults with type 2 diabetes treated with metformin with or without an SGLT-2 inhibitor. From a baseline A1C of 8.2%, Mounjaro reduced participants’ A1C by a mean of 1.9%* (5 mg), 2.0%* (10 mg) and 2.1%* (15 mg) compared to 1.3% for insulin degludec. From a baseline weight of 208 lb., Mounjaro reduced participants’ weight by a mean of 15 lb.* (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to an increase of 4 lb. for insulin degludec.6
  • SURPASS-4 (NCT03730662) was a 104-week study comparing the efficacy and safety of Mounjaro 5 mg (N=328), 10 mg (N=326) and 15 mg (N=337) to insulin glargine (N=998) in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The primary endpoint was measured at 52 weeks. From a baseline A1C of 8.5%, Mounjaro reduced participants’ A1C by a mean of 2.1%* (5 mg), 2.3%* (10 mg) and 2.4%* (15 mg) compared to 1.4% for insulin glargine. From a baseline weight of 199 lb., Mounjaro reduced weight by a mean of 14 lb.* (5 mg), 20 lb.* (10 mg) and 23 lb.* (15 mg) compared to an increase of 4 lb. for insulin glargine.7
  • SURPASS-5 (NCT04039503) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=116), 10 mg (N=118) and 15 mg (N=118) to placebo (N=119) in adults with inadequately controlled type 2 diabetes already being treated with insulin glargine, with or without metformin. From a baseline A1C of 8.3%, Mounjaro reduced A1C by a mean of 2.1%* (5 mg), 2.4%* (10 mg) and 2.3%* (15 mg) compared to 0.9% for placebo. From a baseline weight of 210 lb., Mounjaro reduced participants’ weight by a mean of 12 lb.* (5 mg), 17 lb.* (10 mg) and 19 lb.* (15 mg) compared to an increase of 4 lb. for placebo.8

*p<0.001 for superiority vs. placebo or active comparator, adjusted for multiplicity
p<0.05 for superiority vs. semaglutide 1 mg, adjusted for multiplicity

About Mounjaro™ (tirzepatide) injection1
Mounjaro™ (tirzepatide) injection is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

PURPOSE AND SAFETY SUMMARY WITH WARNINGS
Important Facts About MounjaroTM (mown-JAHR-OH). It is also known as tirzepatide.

  • Mounjaro is an injectable prescription medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose).
  • It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age.

Warnings
Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have a symptom, tell your healthcare provider.

  • Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC).
  • Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Do not use Mounjaro if you are allergic to tirzepatide or any of the ingredients in Mounjaro.

Mounjaro may cause serious side effects, including:

Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery.

Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat.

Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro.

Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools.

Common side effects
The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn’t go away.

Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch.

Before using

  • Your healthcare provider should show you how to use Mounjaro before you use it for the first time.
  • Before you use Mounjaro, talk to your healthcare provider about low blood sugar and how to manage it.

 Review these questions with your healthcare provider:

  • Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food?
  • Do you take other diabetes medicines, such as insulin or sulfonylureas?
  • Do you have a history of diabetic retinopathy?
  • Are you pregnant or plan to become pregnant or breastfeeding or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby.
  • Do you take birth control pills by mouth? These may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control when you start Mounjaro or when you increase your dose.
  • Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements?

How to take

  • Read the Instructions for Use that come with Mounjaro.
  • Use Mounjaro exactly as your healthcare provider says.
  • Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.
  • Use Mounjaro 1 time each week, at any time of the day.
  • Do not mix insulin and Mounjaro together in the same injection.
  • If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly.

Learn more
For more information, call 1-800-LillyRx (1-800-545-5979) or go to www.mounjaro.com.

This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you.

MounjaroTM and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please click to access full Prescribing Information and Medication Guide.

TR CON CBS MAY2022

About Lilly
Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedIn. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Mounjaro™ (tirzepatide 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg) injection as a treatment to improve glycemic control in adults with type 2 diabetes, the timeline for supply of Mounjaro to become available, and certain other milestones and ongoing clinical trials of Mounjaro and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of research, development and commercialization. Among other things, there can be no guarantee that Mounjaro will be commercially successful, that future study results will be consistent with results to date, or that we will meet our anticipated timelines for the commercialization of Mounjaro. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

  1. Mounjaro. Prescribing Information. Lilly USA, LLC.
  2. Rosenstock, J, et. al. Efficacy and Safety of Once Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist Versus Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1). Abstract 100-OR. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  3. Rosenstock, J, et. al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6.
  4. Frías JP, Davies MJ, Rosenstock J, et al; for the SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6)(suppl):503-515. doi: 10.1056/NEJMoa2107519
  5. Frias, J.P. Efficacy and Safety of Tirzepatide vs. Semaglutide Once Weekly as Add-On Therapy to Metformin in Patients with Type 2 Diabetes. Abstract 84-LB. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  6. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4
  7. Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7
  8. Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-545. doi:10.1001/jama.2022.0078

CLIP

https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-225-weight-loss-adults-obesity-or

Lilly’s tirzepatide delivered up to 22.5% weight loss in adults with obesity or overweight in SURMOUNT-1

April 28, 2022

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Participants taking tirzepatide lost up to 52 lb. (24 kg) in this 72-week phase 3 study

63% of participants taking tirzepatide 15 mg achieved at least 20% body weight reductions as a key secondary endpoint

INDIANAPOLIS, April 28, 2022 /PRNewswire/ — Tirzepatide (5 mg, 10 mg, 15 mg) achieved superior weight loss compared to placebo at 72 weeks of treatment in topline results from Eli Lilly and Company’s (NYSE: LLY) SURMOUNT-1 clinical trial, with participants losing up to 22.5% (52 lb. or 24 kg) of their body weight for the efficacy estimandi. This study enrolled 2,539 participants and was the first phase 3 global registration trial evaluating the efficacy and safety of tirzepatide in adults with obesity, or overweight with at least one comorbidity, who do not have diabetes. Tirzepatide met both co-primary endpoints of superior mean percent change in body weight from baseline and greater percentage of participants achieving body weight reductions of at least 5% compared to placebo for both estimandsii. The study also achieved all key secondary endpoints at 72 weeks.

For the efficacy estimand, participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb. or 16 kg on 5 mg), 21.4% (49 lb. or 22 kg on 10 mg) and 22.5% (52 lb. or 24 kg on 15 mg), compared to placebo (2.4%, 5 lb. or 2 kg). Additionally, 89% (5 mg) and 96% (10 mg and 15 mg) of people taking tirzepatide achieved at least 5% body weight reductions compared to 28% of those taking placebo.

In a key secondary endpoint, 55% (10 mg) and 63% (15 mg) of people taking tirzepatide achieved at least 20% body weight reductions compared to 1.3% of those taking placebo. In an additional secondary endpoint not controlled for type 1 error, 32% of participants taking tirzepatide 5 mg achieved at least 20% body weight reductions. The mean baseline body weight of participants was 231 lb. (105 kg).

“Obesity is a chronic disease that often does not receive the same standard of care as other conditions, despite its impact on physical, psychological and metabolic health, which can include increased risk of hypertension, heart disease, cancer and decreased survival,” said Louis J. Aronne, MD, FACP, DABOM, director of the Comprehensive Weight Control Center and the  Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, obesity expert at NewYork-Presbyterian/Weill Cornell Medical Center and Investigator of SURMOUNT-1. “Tirzepatide delivered impressive body weight reductions in SURMOUNT-1, which could represent an important step forward for helping the patient and physician partnership treat this complex disease.”

For the treatment-regimen estimandiii, results showed:

  • Average body weight reductions: 15.0% (5 mg), 19.5% (10 mg), 20.9% (15 mg), 3.1% (placebo)
  • Percentage of participants achieving body weight reductions of ≥5%: 85% (5 mg), 89% (10 mg), 91% (15 mg), 35% (placebo)
  • Percentage of participants achieving body weight reductions of ≥20%: 30% (5 mg, not controlled for type 1 error), 50% (10 mg), 57% (15 mg), 3.1% (placebo)

The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies approved for the treatment of obesity. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity, usually occurring during the dose escalation period. For those treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (24.6%, 33.3%, 31.0%), diarrhea (18.7%, 21.2%, 23.0%), vomiting (8.3%, 10.7%, 12.2%) and constipation (16.8%, 17.1%, 11.7%) were more frequently experienced compared to placebo (9.5% [nausea], 7.3% [diarrhea], 1.7% [vomiting], 5.8% [constipation]).

Treatment discontinuation rates due to adverse events were 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) and 2.6% (placebo). The overall treatment discontinuation rates were 14.3% (5 mg), 16.4% (10 mg), 15.1% (15 mg) and 26.4% (placebo).

Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and the potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

“Tirzepatide is the first investigational medicine to deliver more than 20 percent weight loss on average in a phase 3 study, reinforcing our confidence in its potential to help people living with obesity,” said Jeff Emmick, MD, Ph.D., vice president, product development, Lilly. “Obesity is a chronic disease that requires effective treatment options, and Lilly is working relentlessly to support people with obesity and modernize how this disease is approached. We’re proud to research and develop potentially innovative treatments like tirzepatide, which helped nearly two thirds of participants on the highest dose reduce their body weight by at least 20 percent in SURMOUNT-1.”

Tirzepatide is a novel investigational once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist, representing a new class of medicines being studied for the treatment of obesity. Tirzepatide is a single peptide that activates the body’s receptors for GIP and GLP-1, two natural incretin hormones. Obesity is a chronic, progressive disease caused by disruptions in the mechanisms that control body weight, often leading to an increase in food intake and/or a decrease in energy expenditure. These disruptions are multifactorial and can be related to genetic, developmental, behavioral, environmental and social factors. To learn more, visit Lilly.com/obesity.

Lilly will continue to evaluate the SURMOUNT-1 results, which will be presented at an upcoming medical meeting and submitted to a peer-reviewed journal. Additional studies are ongoing for tirzepatide as a potential treatment for obesity or overweight.

About tirzepatide

Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well.

About SURMOUNT-1 and the SURMOUNT clinical trial program

SURMOUNT-1 (NCT04184622) is a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease. The trial randomized 2,539 participants across the U.S., Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10 mg and/or 15 mg is superior in percentage of body weight reductions from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo. Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg).

The SURMOUNT phase 3 global clinical development program for tirzepatide began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six clinical trials, four of which are global studies. Results from SURMOUNT-2, -3, and -4 are anticipated in 2023.

About Lilly 

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedInP-LLY

CLIP

https://www.pu-kang.com/Tirzepatide-results-superior-A1C-and-body-weight-reductions-compared-to-insulin-glargine-in-adults-with-type-2-diabetes-id3348038.html

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Newly published data show that participants maintained A1C and weight control up to two years in SURPASS-4, the largest and longest SURPASS trial completed to dateNo increased cardiovascular risk identified with tirzepatide; hazard ratio of 0.74 observed for MACE-4 events

SURPASS-4 is the largest and longest clinical trial completed to date of the phase 3 program studying tirzepatide as a potential treatment for type 2 diabetes. The primary endpoint was measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In newly published data from the treatment period after 52 weeks, participants taking tirzepatide maintained A1C and weight control for up to two years.

The overall safety profile of tirzepatide, assessed over the full study period, was consistent with the safety results measured at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time.

“We are encouraged by the continued A1C and weight control that participants experienced past the initial 52 week treatment period and up to two years as we continue to explore the potential impact of tirzepatide for the treatment of type 2 diabetes,” said John Doupis, M.D., Ph.D., Director, Diabetes Division and Clinical Research Center, Iatriko Paleou Falirou Medical Center, Athens, Greece and Senior Investigator for SURPASS-4.

Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.

SURPASS-4 was an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased CV risk who were treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Of the total participants randomized, 1,819 (91%) completed the primary 52-week visit and 1,706 (85%) completed the study on treatment. The median study duration was 85 weeks and 202 participants (10%) completed two years.

Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43.5 units per day.

About tirzepatide
Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes, for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).

About SURPASS-4 and the SURPASS clinical trial program
SURPASS-4 (NCT03730662) is a randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to insulin glargine in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The trial randomized 2,002 study participants in a 1:1:1:3 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or insulin glargine. Participants were located in the European Union, North America (Canada and the United States), Australia, Israel, Taiwan and Latin America (Brazil, Argentina and Mexico). The primary objective of the study was to demonstrate that tirzepatide (10 mg and/or 15 mg) is non-inferior to insulin glargine for change from baseline A1C at 52 weeks in people with type 2 diabetes and increased CV risk. The primary and key secondary endpoints were measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE). Study participants enrolled had to have a mean baseline A1C between 7.5 percent and 10.5 percent and a BMI greater than or equal to 25 kg/m2 at baseline. All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg). All participants in the titrated insulin glargine treatment arm started with a baseline dose of 10 units per day and titrated following a treat-to-target algorithm to reach a fasting blood glucose below 100 mg/dL.

The SURPASS phase 3 global clinical development program for tirzepatide has enrolled more than 20,000 people with type 2 diabetes across 10 clinical trials, five of which are global registration studies. The program began in late 2018, and all five global registration trials have been completed.

About Diabetes

Approximately 34 million Americans2 (just over 1 in 10) and an estimated 463 million adults worldwide3 have diabetes. Type 2 diabetes is the most common type internationally, accounting for an estimated 90 to 95 percent of all diabetes cases in the United States alone2. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.

Clinical data
Trade namesMounjaro
Other namesLY3298176, GIP/GLP-1 RA
License dataUS DailyMedTirzepatide
Routes of
administration
subcutaneous
Drug classAntidiabeticGLP-1 receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number2023788-19-2
PubChem CID156588324
IUPHAR/BPS11429
DrugBankDB15171
ChemSpider76714503
UNIIOYN3CCI6QE
KEGGD11360
ChEMBLChEMBL4297839
Chemical and physical data
FormulaC225H348N48O68
Molar mass4813.527 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Tirzepatide, FDA 2022, APPROVALS 2022, Mounjaro, PEPTIDE, チルゼパチド ,  LY3298176,

UNIIOYN3CCI6QE

pharma1

chart 1 Structure of GLP-1 & TZP & Exenatide & Somalutide

Lutetium Lu 177 vipivotide tetraxetan


PSMA-617 Lu-177.png
2D chemical structure of 1703749-62-5
177Lu vipivotide tetraxetan -177LU-PSMA-617.svg
ChemSpider 2D Image | (~177~Lu)Lutetium 2,2',2''-[10-(2-{[(trans-4-{[(2S)-1-{[(5S)-5-carboxy-5-({[(1S)-1,3-dicarboxypropyl]carbamoyl}amino)pentyl]amino}-3-(2-naphthyl)-1-oxo-2-propanyl]carbamoyl}cyclohexyl)methyl]amino}-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate (non-preferred name) | C49H68177LuN9O16
177Lu vipivotide tetraxetan -177LU-PSMA-617.svg

Lutetium Lu 177 vipivotide tetraxetan

FDA APPROVED 2022/3/23, Pluvicto

To treat prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer following other therapies

FormulaC49H65N9O16. Lu. 3H
CAS1703749-62-5
Mol weight1214.0819
Antineoplastic, Radioactive agent
  DiseaseProstate cancer (PSMA positive)

ルテチウム(177Lu)ビピボチドテトラキセタン;

UNII-G6UF363ECX, WHO 11429

G6UF363ECX

177Lu-Psma-617

Vipivotide tetraxetan Lu-177

177Lu-Labeled PSMA-617

2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium-177(3+)

(177Lu)Lutetium 2,2′,2”-[10-(2-{[(trans-4-{[(2S)-1-{[(5S)-5-carboxy-5-({[(1S)-1,3-dicarboxypropyl]carbamoyl}amino)pentyl]amino}-3-(2-naphthyl)-1-oxo-2-propanyl]carbamoyl}cyclohexyl)methyl]amino}-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate (non-preferred name)

1983157-55-6[RN]

PSMA-617 LU-177

Lutetium Lu 177 Vipivotide Tetraxetan is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium Lu 177 (177Lu), with potential antineoplastic activity against PSMA-expressing tumor cells. Upon intravenous administration of lutetium Lu 177 vipivotide tetraxetanvipivotide tetraxetan targets and binds to PSMA-expressing tumor cells. Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation. PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.

Lutetium (177Lu) vipivotide tetraxetan, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[2] Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.[2][3]

The most common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.[2]

Lutetium (177Lu) vipivotide tetraxetan is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium Lu 177 (177Lu), with potential antineoplastic activity against PSMA-expressing tumor cells.[4] Upon intravenous administration of lutetium Lu 177 vipivotide tetraxetan, vipivotide tetraxetan targets and binds to PSMA-expressing tumor cells.[4] Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation.[4] PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.[4]

Lutetium (177Lu) vipivotide tetraxetan was approved for medical use in the United States in March 2022.[2][5]

///////////

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History[edit]

Efficacy was evaluated in VISION (NCT03511664), a randomized (2:1), multicenter, open-label trial that evaluated lutetium (177Lu) vipivotide tetraxetan plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[2] All participants received a GnRH analog or had prior bilateral orchiectomy.[2] Participants were required to have received at least one androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens.[2] Participants received lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone.[2]

The U.S. Food and Drug Administration granted the application for lutetium (177lu) vipivotide tetraxetan priority review and breakthrough therapy designations.[2]

References

  1. ^ “Highlights of prescribing information: PLUVICTOTM (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use” (PDF). Advanced Accelerator Applications USA, Inc. Novartis. March 2022.
  2. Jump up to:a b c d e f g h i j “FDA approves Pluvicto for metastatic castration-resistant prostate can”U.S. Food and Drug Administration. 23 March 2022. Retrieved 23 March 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ Neels OC, Kopka K, Liolios C, Afshar-Oromieh A (December 2021). “Radiolabeled PSMA Inhibitors”Cancers13 (24): 6255. doi:10.3390/cancers13246255PMC 8699044PMID 34944875.
  4. Jump up to:a b c d “Lutetium Lu 177 Vipivotide Tetraxetan (Code C148145)”. NCI Thesaurus. 28 February 2022. Retrieved 23 March 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ “Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer” (Press release). Novartis. 23 March 2022. Retrieved 23 March 2022.

External links

 
Clinical data
Trade namesPluvicto
Other names177Lu-PSMA-617, Lutetium Lu 177 vipivotide tetraxetan (USAN US)
License dataUS DailyMedPluvicto
Routes of
administration
Intravenous
Drug classRadiopharmaceutical
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1703749-62-5
PubChem CID122706785
ChemSpider58828499
UNIIG6UF363ECX
KEGGD12335
Chemical and physical data
3D model (JSmol)Interactive image
showSMILES
show

////////////Lutetium Lu 177 vipivotide tetraxetan, ルテチウム(177Lu)ビピボチドテトラキセタン, FDA 2022, APPROVALS 2022, PROSTRATE CANCER, WHO 11429

C1CC(CCC1CNC(=O)CN2CCN(CCN(CCN(CC2)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(CC3=CC4=CC=CC=C4C=C3)C(=O)NCCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O.[Lu+3]

Vipivotide tetraxetan Chemical Structure

Vipivotide tetraxetan (Synonyms: PSMA-617)

CAS No. : 1702967-37-0

Vipivotide tetraxetan (PSMA-617) is a high potent prostate-specific membrane antigen (PSMA) inhibitor, with a Ki of 0.37 nM.

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NEW DRUG APPROVALS

one time

$10.00

Ganaxolone


Ganaxolone.svg

Ganaxolone.png

Ganaxolone

  • Molecular FormulaC22H36O2
  • Average mass332.520 Da
(3a,5a)-3-Hydroxy-3-methylpregnan-20-one
 
(3α,5α)-3-Hydroxy-3-methylpregnan-20-one
 
38398-32-2 [RN]
 
3α-hydroxy-3β-methyl-5α-pregnan-20-one
 
7476
  • CCD-1042

FDA APPROVED 3/18/2022, Ztalmy

To treat seizures in cyclin-dependent kinase-like 5 deficiency disorder

Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD).[1][2]

Ganaxolone was approved for medical use in the United States in March 2022.[1]

Ganaxolone is the 3β-methylated synthetic analog of allopregnanolone; it belongs to a class of compounds referred to as neurosteroids. Ganaxolone is an allosteric modulator of GABAA receptors acting through binding sites which are distinct from the benzodiazepine binding site. It has activity in a broad range of animal models of epilepsy. Ganaxolone has been shown to be well tolerated in adults and children. In early phase II studies, Ganaxolone has been shown to have activity in adult patients with partial-onset seizures and epileptic children with history of infantile spasms. It is currently undergoing further development in infants with newly diagnosed infantile spasms, in women with catamenial epilepsy, and in adults with refractory partial-onset seizures.

Ganaxolone is in phase III clinical studies for the treatment of partial seizures in adults. Phase II clinical trials is ongoing for treatment of uncontrolled seizures in PCDH19 female pediatric epilepsy and Fragile X syndrome.

Ganaxolone was originally developed by CoCensys (aquired by Purdue Pharma). In 2003, Marinus Pharmaceuticals obtained the compound from Purdue Pharma.

In 2015, it was granted as orphan drug designation for the treatment of PCDH19 female epilepsy.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019209850&_cid=P10-L0YZTI-42413-1

In an embodiment, the disclosure provides a method for using pregnenolone to make 21-OH ganaxolone and other intermediary compounds which are useful for preparing neurosteroid derivatives. The method of making 21-OH ganaxolone is shown below in Route 1.

Route 1

Referring to Route 1, Synthesis of 1-((3S,8R,10S,13S,14S,17S)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethenone :

Pregnenolone (3.17 g, 10 mmol) was dissolved in 30 mL of THF and 5 mL of acetic acid. To it, 10% W/C (0.3 g) was added. The resulting mixture was shaken under 60 psi hydrogen at 60°C overnight. It was filtered through a Celite ® pad and concentrated to give 3.2 g of the desired product (100%). 1 H NMR (400 MHz, CDCl3) δ 3.58 (tt, J = 11.0, 4.8 Hz, 1H), 2.50 (t, J = 9.0 Hz, 1H), 2.19 – 2.11 (m, 2H), 2.09 (s, 3H ), 2.06 – 1.93 (m, 2H), 1.85 – 1.75 (m, 1H), 1.74 -1.50 (m, 6H), 1.47 – 1.04 (m, 9H), 1.04 – 0.82 (m, 2H), 0.79 (s , 3H), 0.72 – 0.61 (m, 1H), 0.58 (d, J = 2.4 Hz, 3H).

[0107] Synthesis of (8R,10S,13S,14S,17S)-l7-acetyl-l0,l3-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one:

To a solution of the above product (1-((3S,8R,10S,13S,14S,17S)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone, 3.2 g, 10 mmol) in 40 mL of THF and 10 mL of acetic acid was added NaBr (1.03 g, 0.1 eq.). It was cooled in an ice bath and was followed by the dropwise addition of NaOCl (82 mL, 10-15%, 18 eq.) at such a rate that the internal temperature was maintained <40 °C. After addition, it was stirred at room temperature for 2h. Thin layer chromatography (TLC) indicated it was complete. The mixture was diluted with dichloromethane and layers were separated. The organic layer was washed with Na 2 S 2 O 3 (10% aq.), H 2 O, NaHCO 3 (sat.) and NaCl (sat.). Drying over Na 2SO 4 and concentration afforded 3.8 g of the crude product, which was recrystallized from CH 2 Cl 2 /Hex to give 2.57 g of the desired product (81%). 1 H NMR (400 MHz, CDC13): 2.51 (t, 1H), 2.2-2.4 (m, 3H), 2.1-2.2 (m, 1H), 2.10 (s, 3H), 1.98-2.01 (m, 2H) , 1.6-1.7 (m, 4H), 1.55-1.6 (m, 1H), 1.3-1.4 (m, 7H), 1.1-1.2 (m, 2H), 0.99 (s, 3H), 0.95-0.98 (m, 1H), 0.75-0.78 (m, 1H), 0.62 (s, 3H).

Synthesis of 1-((2’R,8R,10S,13S,14S,17S)-10,11-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2′-oxiran]-17-yl)ethanone.

Under argon, trimethyl sulfoxonium iodide (2.6 g, 1.7 eq.) and sodium t-butoxide (1.18 g, 1.75 eq.) in DMSO (20 mL) was heated at 65 °C for 2h. After it was cooled to RT, the above di-ketone ((8R, 10S, 13 S, 14S, 17S)-17-acetyl- 10,13 -dimethyl tetradecahy dro-1H-cyclopenta[a]phenanthren-3(2H) -one, 2.2 g, 7 mmol) was added scoop-wise so that the internal temperature was maintained between 25-35 °C. The resulting mixture was stirred at RT for 2h. After TLC indicated it was complete, it was quenched with 30 mL of H 2 O, stirred for 10 min and was kept in fridge overnight. The precipitate was filtered, washed with 20 mL of (4:1 of H 2 O /MeOH), dried to give 94% of the desired product (W = 2.17 g). 1H NMR (400 MHz, CDC13) δ 2.63 (s, 2H), 2.53 (t, J = 8.9 Hz, 1H), 2.20 – 2.13 (m, 1H), 2.11 (s, 3H), 2.10 – 1.95 (m, 2H), 1.87 (dd, J = 13.9, 13.1 Hz, 1H), 1.76 – 1.59 (m, 4H), 1.58 – 1.48 (m, 1H), 1.48 – 1.24 (m, 5H), 1.24 – 1.07 (m, 3H), 1.02 – 0.87 (m, 2H), 0.86 (dd, J = 3.7, 2.2 Hz, 1H), 0.84 (s, 3H), 0.81 – 0.74 (m, 1H), 0.61 (s, 3H).

[0109] Synthesis of 1-((3R,8R,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (ganaxolone) .

To a solution of the above epoxide (1.5 g, 4.56 mmol) in 15 mL of THF and 15 mL of MeOH were added Nal (1.02 g, 1.5 eq.) and HO Ac (0.6 mL, 2.2 eq.). The resulting mixture was heated at 65°C for 2h. After TLC indicated that the epoxy was completely converted to an iodo compound, it was cooled to RT. Sodium acetate (1.02 g, 2.7 eq.) and 150 mg of 10% Pd/C were added and the mixture was transferred to a hydrogenation bottle with the aid of MeOH (10 mL) and was hydrogenated under 50 psi hydrogen over the weekend. It was filtered throughCelite ® and the filtrate was concentrated. The residue was then partitioned between dichloromethane and water. The aqueous solution was extracted twice with CH 2 Cl 2 and the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The Biotage flash purification with 10-35% EtOAc in hexane to give 0.5 g of the desired product (33%).

The synthesis was repeated with 1.1 g of the epoxy and 1 g of the product was obtained (90%).

Both lots of product were combined and recrystallized with CH 2 Cl 2 and hexane to give 0.522 g of the product with 96.6% purity by HPLC. 1 H NMR (400 MHz, Chloroform-d) δ 2.51 (t, J = 8.9 Hz, 1H), 2.18 – 2.10 (m, 1H), 2.09 (s, 3H), 2.01 – 1.93 (m, 1H), 1.72 – 1.57 (m, 4H), 1.57 – 1.41 (m, 5H), 1.41 – 1.30 (m, 3H), 1.30 – 1.20 (m, 3H), 1.18 (s, 3H), 1.17 – 1.09 (m, 2H) , 1.00 – 0.85 (m, 1H), 0.78 (ddd, J = 10.6, 7.7, 5.4 Hz, 1H), 0.73 (d, J = 0.6 Hz, 3H), 0.58 (s, 3H). UV: Absorbances at 206.2 nm. TLC: (Silica Gel plates) 20% EtOAc/Hexane; R f = 0.50. HPLC: Sunfire C18 5m 250 x 4.6mm; flow 1.0 mL/min; Waters 996 PDA detection at 210 nm; solvent 80% Acetonitrile in H 2 O (0.1% formic acid) over 30 min; retention time 8.24 min; 96.6%.

SYN

https://patents.google.com/patent/WO2016164763A1/en

 

SYN

US3953429.

SYN
 J. Med. Chem. 199740, 61-72.

https://pubs.acs.org/doi/10.1021/jm960021x

Two naturally occurring metabolites of progesterone, 3α-hydroxy-5α- and 5β-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABAA receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3β-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5α- and 5β-series as determined by inhibition of [35S]TBPS binding. In the 5α-series, 3β-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3β-XCH2, where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [35S]TBPS binding. In the 5β-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3β-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5β-sterols tested are full inhibitors of [35S]TBPS binding. Electrophysiological measurements using α1β2γ2L receptors expressed in oocytes show that 3β-methyl- and 3β-(azidomethyl)-3α-hydroxy-5α-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3α-hydroxy-3β-(trifluoromethyl)-5α-pregnan-20-one (24) is a low-efficacy modulator, confirming the results obtained from [35S]TBPS binding. These results indicate that modification of the 3β-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABAA receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites 1 and 2 are inactive when administered orally, suggesting that 3β-substitution slows metabolism of the 3-hydroxyl, resulting in orally bioavailable steroid modulators of the GABAA receptor.

PATENT

WO9303732A1.,

https://patents.google.com/patent/WO1993003732A1/nl

SYN

GB 1380248

Addition of the sulfur ylide generated from trimethylsulfoxonium iodide and NaH to the 20-ethylene ketal of pregnane-3,20-dione (I) furnished the spiro oxirane derivative (II). This was reduced to the tertiary alcohol (III) by means of LiAlH4 in refluxing THF. Then, acid hydrolysis of the ethylene ketal function of (III) provided the title compound. Alternatively, the intermediate ketal (III) was prepared by addition of methylmagnesium bromide to ketone (I), followed by chromatographic separation of the resultant mixture of 3-alpha and 3-beta methyl adducts.

Starting from the unprotected diketone (IV), selective addition of dimethyloxosulfonium methylide to the 3 keto group furnished oxirane (V). This was then reduced to the title alcohol by treatment with tributylstannyl hydride and AIBN.

Regioselective addition of dimethylsulfoxonium methylide to 5-alpha-pregnane-3,20-dione (I) gave the epoxide (II). Opening of the epoxide ring of (II) with sodium methoxide produced the hydroxy ether (III). Bromination of (III) with Br2 in the presence of a catalytic amount of HBr afforded bromo ketone (IV). This was then condensed with imidazole (V) in refluxing acetonitrile to furnish the title compound.

Regioselective addition of dimethylsulfoxonium methylide to 5-alpha-pregnane-3,20-dione (I) gave the epoxide (II). Opening of the epoxide ring of (II) with sodium methoxide produced the hydroxy ether (III). Bromination of (III) with Br2 in the presence of a catalytic amount of HBr afforded bromo ketone (IV). This was then condensed with 6-hydroxyquinoline (V) in the presence of potassium tert-butoxide to furnish the quinolinyl ether (VI). The quinoline ring was then oxidized with m-chloroperbenzoic acid, yielding the title N-oxide.

3. WO9318053A1.

4. WO9427608A1.

WO2011019821A2 / US8362286B2.

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Pharmacology

Mechanism of action

The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.[3][4]

Ganaxolone is thought to modulate both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons.[2] Ganaxolone’s activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling.[2]

Ganaxolone binds to allosteric sites of the GABAA receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron.[2] This causes an inhibitory effect on neurotransmission, reducing the chance of a successful action potential (depolarization) from occurring.[2][3][4]

Chemistry

ResearchGanaxolone is a synthetic pregnane steroid. Other pregnane neurosteroids include alfadolonealfaxoloneallopregnanolone (brexanolone), hydroxydioneminaxolonepregnanolone (eltanolone), and renanolone, among others.

Ganaxolone is being investigated for potential medical use in the treatment of epilepsy. It is well tolerated in human trials, with the most commonly reported side effects being somnolence (sleepiness), dizziness, and fatigue.[5] Trials in adults with focal onset seizures and in children with infantile spasms have recently been completed.[6][7] There are ongoing studies in patients with focal onset seizures, PCDH19 pediatric epilepsy, and behaviors in Fragile X syndrome.[6][7]

Ganaxolone has been shown to protect against seizures in animal models,[3][4] and to act a positive allosteric modulator of the GABAA receptor.[2][8]

Clinical trials

The most common adverse events reported across clinical trials have been somnolence (sleepiness), dizziness, and fatigue.[5] In 2015, the MIND Institute at the University of California, Davis, announced that it was conducting, in collaboration with Marinus Pharmaceuticals, a randomized, placebo-controlled, Phase 2 clinical trial evaluating the effect of ganaxolone on behaviors associated with Fragile X syndrome in children and adolescents.[9][10][11]

References

  1. Jump up to:a b c https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215904s000lbl.pdf
  2. Jump up to:a b c d e f Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW (March 1997). “Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor”. The Journal of Pharmacology and Experimental Therapeutics280 (3): 1284–95. PMID 9067315.
  3. Jump up to:a b c Kaminski RM, Livingood MR, Rogawski MA (July 2004). “Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice”. Epilepsia45 (7): 864–7. doi:10.1111/j.0013-9580.2004.04504.xPMID 15230714S2CID 21974013.
  4. Jump up to:a b c Reddy DS, Rogawski MA (May 2010). “Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model”Epilepsy Research89 (2–3): 254–60. doi:10.1016/j.eplepsyres.2010.01.009PMC 2854307PMID 20172694.
  5. Jump up to:a b Monaghan EP, Navalta LA, Shum L, Ashbrook DW, Lee DA (September 1997). “Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity”Epilepsia38 (9): 1026–31. doi:10.1111/j.1528-1157.1997.tb01486.xPMID 9579942S2CID 27584114.
  6. Jump up to:a b Nohria V, Giller E (January 2007). “Ganaxolone”Neurotherapeutics4 (1): 102–5. doi:10.1016/j.nurt.2006.11.003PMC 7479704PMID 17199022.
  7. Jump up to:a b Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O (October 2007). “Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy”Epilepsia48 (10): 1870–4. doi:10.1111/j.1528-1167.2007.01182.xPMID 17634060S2CID 24656918.
  8. ^ Reddy DS, Rogawski MA (December 2000). “Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself”. The Journal of Pharmacology and Experimental Therapeutics295 (3): 1241–8. PMID 11082461.
  9. ^ “Fragile X Research and Treatment Center: Clinical Research Studies” (PDF)UC Davis MIND Institute. 10 February 2015. Archived from the original (PDF) on 5 June 2015. Retrieved 27 January 2016.
  10. ^ “Ganaxolone Treatment in Children With Fragile X Syndrome”Clinicaltrials.gov. 7 November 2012. Retrieved 27 January 2016.
  11. ^ “UC Davis Health System. UC Davis researchers win $3 million grant from U.S. Congress to study fragile X” (Press release). UC Davis Health System. 8 February 2011. Archived from the original on 3 February 2016. Retrieved 27 January 2016.

External links

  • “Ganaxolone”Drug Information Portal. U.S. National Library of Medicine.
Ganaxolone
Ganaxolone.svg
Clinical data
Trade names Ztalmy
Other names GNX; CCD-1042; 3β-Methyl-5α-pregnan-3α-ol-20-one; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one
License data
Routes of
administration
By mouth
Drug class Neurosteroid
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.937 Edit this at Wikidata
Chemical and physical data
Formula C22H36O2
Molar mass 332.528 g·mol−1
3D model (JSmol)
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////////////Ganaxolone, ZTALMY, FDA 2022, APPROVALS 2022, CCD 1042

[H][C@@]12CC[C@H](C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC[C@@]2([H])C[C@](C)(O)CC[C@]12C

 

Ciltacabtagene autoleucel


Official Patient Website | CARVYKTI™ (ciltacabtagene autoleucel)

Ciltacabtagene autoleucel

FDA APPROVED, 2022/2/28, 

Carvykti

Treatment of multiple myeloma

  • JNJ-68284528
  • LCAR-B38M CAR-T cells

Ciltacabtagene autoleucel is a BCMA-directed CAR T-cell therapy used in the treatment of relapsed or refractory multiple myeloma in previously treated patients.

U.S. FDA Approves CARVYKTI™ (ciltacabtagene autoleucel), Janssen’s First Cell Therapy, a BCMA-Directed CAR-T Immunotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

In the pivotal clinical study, 98 percent of patients with relapsed or refractory multiple myeloma responded to a one-time treatment with ciltacabtagene autoleucel and 78 percent of patients who responded experienced a stringent complete response

HORSHAM, Pa., February 28, 2022 – The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) has approved CARVYKTI™ (ciltacabtagene autoleucel; cilta-cel) for the treatment of adults with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1 The approval is based on data from the pivotal CARTITUDE-1 study, which included patients who had received a median of six prior treatment regimens (range, 3-18), and had previously received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.1 In December 2017, Janssen entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize ciltacabtagene autoleucel.

CARVYKTI™ is a chimeric antigen receptor T-cell (CAR-T) therapy featuring two B-cell maturation antigen (BCMA)-targeting single domain antibodies.1 In the pivotal CARTITUDE-1 study, one-time treatment with ciltacabtagene autoleucel resulted in deep and durable responses, with 98 percent (95 percent Confidence Interval [CI], 92.7-99.7) of patients with RRMM responding to therapy (98 percent overall response rate [ORR] (n=97).1 Notably, 78 percent (95 percent CI, 68.8-86.1) of the patients achieving this level of response (n=76) experienced a stringent complete response (sCR), a measure in which a physician is unable to observe any signs or symptoms of disease via imaging or other tests after treatment.1 At a median of 18 months follow-up, median duration of response (DOR) was 21.8 months.1

CARVYKTI™ is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI™ REMS Program.1 The Safety Information for CARVYKTI™ includes a Boxed Warning regarding Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged and/or recurrent cytopenias.1 Warnings and Precautions include prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies, and effects on ability to drive and use machines.1 The most common adverse reactions (≥20 percent) are pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogens unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.1

“We are committed to harnessing our science, deep disease understanding and capabilities to bring forward cell therapies like CARVYKTI as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma,” said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC. “We extend our sincere gratitude to the patients, their families and the teams of researchers and study centers who have participated in the clinical study of CARVYKTI and enabled today’s approval.”

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. Despite the development of additional treatment options in recent years, most people living with multiple myeloma face poor prognoses after experiencing disease progression following treatment with three major therapy classes, which include an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody. 3

“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” said Sundar Jagannath, M.D., Director of the Center of Excellence for Multiple Myeloma and Professor of Medicine, Hematology and Medical Oncology, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and principal study investigator. “The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time.”

As a personalized medicine, CARVYKTI™ treatment requires extensive training, preparation, and certification to ensure a positive experience for patients. Through a phased approach, Janssen and Legend Biotech will activate a limited network of certified treatment centers as the company works to scale its production capacity and increase the availability of CARVYKTI™ throughout the U.S. in 2022 and beyond, to ensure that we can provide CARVYKTI™ treatment to oncologists and their patients in a reliable and timely manner.

“This approval of Janssen’s first cell therapy is a testament to our continuing commitment in oncology to deliver new therapeutic options and drive toward our vision of the elimination of cancer,” said Mathai Mammen, M.D., Ph.D., Executive Vice President, Pharmaceuticals, Janssen Research & Development, LLC, Johnson & Johnson. “Today’s approval underscores our determination to develop therapies that can help patients living with what remains an intractable blood cancer today and at the same time offer hope for the future.”

The longer-term efficacy and safety profile of ciltacabtagene autoleucel is being assessed in the ongoing CARTITUDE-1 study. Two-year follow-up results recently presented at the American Society of Hematology (ASH) 2021 Annual Meeting showed that 98 percent of patients treated with ciltacabtagene autoleucel for RRMM responded to therapy (98 percent overall response rate [ORR] (n=97), and a majority of patients achieving sustained depth of response with 83 percent of patients achieving an sCR at the 22-month follow-up.4

About CARVYKTI™ (ciltacabtagene autoleucel)
CARVYKTI™ is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express the B-cell maturation antigen (BCMA). BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The CARVYKTI™ CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.1

In December 2017, Janssen Biotech, Inc. entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize ciltacabtagene autoleucel.

In April 2021, Janssen announced the submission of a Marketing Authorisation Application to the European Medicines Agency seeking approval of CARVYKTI™ for the treatment of patients with relapsed and/or refractory multiple myeloma. In addition to a U.S. Breakthrough Therapy Designation granted in December 2019, ciltacabtagene autoleucel received a Breakthrough Therapy Designation in China in August 2020. Janssen also received an Orphan Drug Designation for CARVYKTI™ from the U.S. FDA in February 2019, and from the European Commission in February 2020.

About the CARTITUDE-1 Study
CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, multi-center study evaluating ciltacabtagene autoleucel for the treatment of patients with relapsed or refractory multiple myeloma, who previously received a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody, and who had disease progression on or after the last regimen. All patients in the study had received a median of six prior treatment regimens (range, 3-18). Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.1

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects some white blood cells called plasma cells, which are found in the bone marrow.3 When damaged, these plasma cells rapidly spread and replace normal cells in the bone marrow with tumors. In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.5 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.2

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Ciltacabtagene autoleucel, sold under the brand name Carvykti, is a medication used to treat multiple myeloma.[1][2]

The most common adverse reactions include pyrexia, cytokine release syndrome, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting.[2]

Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy.[1][2] Each dose is customized using the recipient’s own T-cells, which are collected and genetically modified, and infused back into the recipient.[1][2]

Ciltacabtagene autoleucel was approved for medical use in the United States in February 2022.[2][3][4]

Medical uses

Ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.[1][2]

History

The safety and efficacy of ciltacabtagene autoleucel were evaluated in CARTITUDE-1 (NCT03548207), an open label, multicenter clinical trial evaluating ciltacabtagene autoleucel in 97 participants with relapsed or refractory multiple myeloma who received at least three prior lines of therapy which included a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen; 82% had received four or more prior lines of antimyeloma therapy.[1][2]

The U.S. Food and Drug Administration (FDA) granted the application for ciltacabtagene autoleucel priority reviewbreakthrough therapy, and orphan drug designations.[2]

References

  1. Jump up to:a b c d e f “Carvykti- ciltacabtagene autoleucel injection, suspension”DailyMed. 9 March 2022. Retrieved 16 March 2022.
  2. Jump up to:a b c d e f g h “FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma”U.S. Food and Drug Administration (FDA). 7 March 2022. Retrieved 16 March 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Carvykti”U.S. Food and Drug Administration (FDA). 8 March 2022. Retrieved 16 March 2022.
  4. ^ “U.S. FDA Approves Carvykti (ciltacabtagene autoleucel), Janssen’s First Cell Therapy, a BCMA-Directed CAR-T Immunotherapy for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma”Janssen Pharmaceutical Companies (Press release). 1 March 2022. Retrieved 16 March 2022.

External links

Clinical data
Trade namesCarvykti
Other namesJNJ-68284528
License dataUS DailyMedCiltacabtagene_autoleucel
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
DrugBankDB16738
UNII0L1F17908Q

//////////Ciltacabtagene autoleucel, JNJ 68284528, Carvykti, FDA 2022, APPROVALS 2022, JNJ-68284528, LCAR-B38M CAR-T cells

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Sutimlimab-jome


(Heavy chain)
EVQLVESGGG LVKPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVAT ISSGGSHTYY
LDSVKGRFTI SRDNSKNTLY LQMNSLRAED TALYYCARLF TGYAMDYWGQ GTLVTVSSAS
TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFEGGPSVFL
FPPKPKDTLM ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV
VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP PSQEEMTKNQ
VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSRLTV DKSRWQEGNV
FSCSVMHEAL HNHYTQKSLS LSLGK
(Light chain)
QIVLTQSPAT LSLSPGERAT MSCTASSSVS SSYLHWYQQK PGKAPKLWIY STSNLASGVP
SRFSGSGSGT DYTLTISSLQ PEDFATYYCH QYYRLPPITF GQGTKLEIKR TVAAPSVFIF
PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST
LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC
(Disulfide bridge: H22-H96, H132-L216, H145-H201, H224-H’224, H227-H’227, H259-H319, H365-H423, H’22-H’96, H’132-L’216, H’145-H’201, H’259-H’319, H’365-H’423, L23-L89, L136-L196, L’23-L’89, L’136-L’196)

Sutimlimab-jome

スチムリマブ (遺伝子組換え)

FormulaC6436H9912N1700O2016S46
CAS2049079-64-1
Mol weight144832.7369
  • BIVV009
  • Sutimlimab
  • Sutimlimab [INN]
  • Sutimlimab [WHO-DD]
  • TNT009
  • UNII-GNWE7KJ995
  • WHO 10757
EfficacyAnti-anemic, Anti-complement C1s antibody
CommentMonoclonal antibody

FDA APPROVED 2/4/2022, To decrease the need for red blood cell transfusion due to hemolysis in cold agglutinin disease, Enjaymo

A Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway. 

Enjaymo Approved for Cold Agglutinin Disease - MPR

Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD).[1][2][3] It is given by intravenous infusion.[1]

The most common side effects include respiratory tract infection, viral infection, diarrhea, dyspepsia (indigestion), cough, arthralgia (joint stiffness), arthritis, and swelling in the lower legs and hands.[2]

Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.[4]

This drug is being developed by Bioverativ, a Sanofi company.[5] Sutimlimab was approved for medical use in the United States in February 2022.[2][6]

Sutimlimab-jome, a classical complement inhibitor, is a humanized monoclonal antibody expressed by recombinant in Chinese hamster ovary (CHO) cells and produced in vitro using standard mammalian cell culture methods. Sutimlimab-jome is composed of two heterodimers. Each heterodimer is composed of a heavy and a light polypeptide chain. Each heavy chain (H-chain) is composed of 445 amino acids and each light chain (L-chain) contains 216 amino acids. Sutimlimab-jome has a molecular weight of approximately 147 kDa.

ENJAYMO (sutimlimab-jome) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free solution for intravenous use. Each single-dose vial contains 1,100 mg sutimlimab-jome at a concentration of 50 mg/mL with a pH of 6.1. Each mL contains 50 mg of sutimlimab-jome and also contains polysorbate 80 (0.2 mg), sodium chloride (8.18 mg), sodium phosphate dibasic heptahydrate (0.48 mg), sodium phosphate monobasic monohydrate (1.13 mg), and Water for Injection, USP.  https://www.rxlist.com/enjaymo-drug.htm#clinpharm

Medical uses

Sutimlimab is indicated to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease (CAD).[1][2]

History

The effectiveness of sutimlimab was assessed in a study of 24 adults with cold agglutinin disease who had a blood transfusion within the past six months.[2] All participants received sutimlimab for up to six months and could choose to continue therapy in a second part of the trial.[2] Based on body weight, participants received either a 6.5g or 7.5g infusion of sutimlimab into their vein on day 0, day 7, and every 14 days through week 25.[2]

In total, 54% of participants responded to sutimlimab.[2] The response was defined in the study as an increase in hemoglobin (an indirect measurement of the amount of red blood cells that are not destroyed) of 2 g/dL or greater (or to 12 g/dL or greater), and no red blood cell transfusions after the first five weeks of treatment; and no other therapies for cold agglutinin disease as defined in the study.[2]

The application for sutimlimab received orphan drug,[2][7] breakthrough therapy,[2] and priority review designations.[2]

Society and culture

Names

Sutimlimab is the International nonproprietary name (INN).[8]

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https://www.sanofi.com/en/media-room/press-releases/2022/2022-02-04-23-00-00-2379517

FDA approves Enjaymo™ (sutimlimab-jome), first treatment for use in patients with cold agglutinin disease

  • Enjaymo is the only approved treatment to decrease the need for red blood cell transfusion due to hemolysis, the destruction of red blood cells, in adults with cold agglutinin disease (CAD)
  • Enjaymo addresses a serious and chronic unmet medical need for adults living with CAD, a rare blood disorder

Paris, February 4, 2022. The U.S. Food and Drug Administration (FDA) has approved Enjaymo™ (sutimlimab-jome) to decrease the need for red blood cell transfusion due to hemolysis in adults with cold agglutinin disease (CAD). Enjaymo is the first and only approved treatment for people with CAD and works by inhibiting the destruction of red blood cells (hemolysis).

Bill Sibold
Executive Vice President, Head of Specialty Care
“Until now, people living with cold agglutinin disease haven’t had an approved treatment option to manage the constant destruction of red blood cells. Without healthy, viable red blood cells, a chain reaction of debilitating signs and symptoms can be triggered, starting with severe anemia. Enjaymo is the only approved treatment to inhibit red blood cell destruction in CAD and help stop the chain reaction from the start.”

CAD, a rare autoimmune hemolytic anemia, is caused by antibodies called cold agglutinins binding to the surface of red blood cells, which starts a process that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their rupture (hemolysis). As red blood cells have the vital job of carrying oxygen throughout the body, patients with CAD may experience severe anemia, which can result in fatigue, weakness, shortness of breath, light-headedness, chest pain, irregular heartbeat, and other potential complications. CAD is a chronic and rare blood disorder that impacts the lives of an estimated 5,000 people in the U.S.

Enjaymo, targeting C1s in the classical complement pathway

Enjaymo is a humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, Enjaymo inhibits the activation of the complement cascade in the immune system and inhibits C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. Enjaymo does not inhibit the lectin and alternative pathways.

Enjaymo Phase 3 pivotal CARDINAL study results supporting approval

The approval of Enjaymo in the U.S. is based on positive results from the 26-week open label, single arm pivotal Phase 3 study in patients with CAD (n=24) who have a recent history of blood transfusion, also known as the CARDINAL study.

Catherine Broome, MD
Associate professor of medicine at Georgetown University Lombardi Comprehensive Cancer Center, and a principal investigator in the CARDINAL study
“For people living with cold agglutinin disease, it is as if their body’s immune system is waging a war on itself. The relentless destruction of healthy red blood cells is a daily, silent reality for people with CAD. For the first time, we have a treatment that targets complement-mediated hemolysis, which is the underlying cause of the red blood cell destruction in many CAD patients. In the pivotal study, patients treated with sutimlimab had an improvement in anemia as measured by hemoglobin and bilirubin levels during the 26-week study.”

In the study, Enjaymo met its primary efficacy endpoint, which was a composite endpoint defined as the proportion of patients who achieved normalization of hemoglobin (Hgb) level ≥12 g/dL or demonstrated an increase from baseline in Hgb level ≥2 g/dL at the treatment assessment time point (mean value from weeks 23, 25, and 26) and no blood transfusion from weeks 5 through 26 or medications prohibited per the protocol from weeks 5 through 26. Secondary endpoints were also met, including improvements in hemoglobin and normalization of bilirubin.

  • The majority of patients (54%; n=13) met the composite primary endpoint criteria with 63% (n=15) of patients achieving a hemoglobin ≥ 12 g/dL or an increase of at least 2 g/dL; 71% (n=17) of patients remaining transfusion-free after week five; and 92% (n=22) of patients did not use other CAD-related treatments.
  • For the secondary measures on disease process, patients enrolled experienced a mean increase in hemoglobin level of 2.29 g/dL (SE: 0.308) at week 3 and 3.18 g/dL (SE: 0.476) at the 26-week treatment assessment timepoint from the mean baseline level of 8.6 g/dL. The mean reduction in bilirubin levels (n=14) was by -2.23 mg/dL (95% CI: -2.49 to -1.98) from a mean baseline level of 3.23 mg/dL (2.7-fold ULN).

In the CARDINAL study, the most common adverse reactions occurring in 10 percent or more of patients were respiratory tract infection, viral infection, diarrhea, dyspepsia, cough, arthralgia, arthritis, and peripheral edema. Serious adverse reactions were reported in 13 percent (3/24) of patients who received Enjaymo. These serious adverse reactions were streptococcal sepsis and staphylococcal wound infection (n=1), arthralgia (n=1), and respiratory tract infection (n=1). None of the adverse reactions led to discontinuation of Enjaymo in the study. Dosage interruptions due to an adverse reaction occurred in 17 percent (4/24) of patients who received Enjaymo.

Following the completion of the 26-week treatment period of CARDINAL (Part A), eligible patients continued to receive Enjaymo in an extension study.

The recommended dose of Enjaymo is based on body weight (6,500 mg for people 39-75 kg and 7,500 mg for people >75 kg). Enjaymo is administered intravenously weekly for the first two weeks with administration every two weeks thereafter.

Enjaymo is expected to be available in the U.S. in the coming weeks. The U.S. list price, or wholesale acquisition cost, of Enjaymo is $1,800 per vial. Actual costs to patients are generally anticipated to be lower as the list price does not reflect insurance coverage, co-pay support, or financial assistance from patient support programs. As part of our commitment to ensure treatment access and affordability for innovative therapies, Enjaymo Patient Solutions provides disease education, financial and co-pay assistance programs and other support services to eligible patients. For more information, please call 1-833-223-2428.

Enjaymo received FDA Breakthrough Therapy and Orphan Drug designation, and priority review, which is reserved for medicines that, if approved, would represent significant improvements in safety or efficacy in treating serious conditions. Outside of the U.S., sutimlimab has been submitted to regulatory authorities in Europe and Japan and reviews are ongoing.

About Sanofi
We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions.
Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY

References

  1. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761164s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l “FDA approves treatment for adults with rare type of anemia”U.S. Food and Drug Administration. 4 February 2022. Retrieved 6 February 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ Tvedt TH, Steien E, Øvrebø B, Haaverstad R, Hobbs W, Wardęcki M, et al. (February 2022). “Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery”. American Journal of Hematology97 (2): E51–E54. doi:10.1002/ajh.26409PMID 34778998S2CID 244116614.
  4. ^ Nikitin PA, Rose EL, Byun TS, Parry GC, Panicker S (February 2019). “C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro”Journal of Immunology202 (4): 1200–1209. doi:10.4049/jimmunol.1800998PMC 6360260PMID 30635392.
  5. ^ “Sutimlimab FDA Approval Status”. FDA. 19 May 2020.
  6. ^ “FDA approves Enjaymo (sutimlimab-jome), first treatment for use in patients with cold agglutinin disease”Sanofi (Press release). 4 February 2022. Retrieved 6 February 2022.
  7. ^ “Sutimlimab Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 27 July 2016. Retrieved 6 February 2022.
  8. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information32 (3). hdl:10665/330907.
  • “Sutimlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03347396 for “A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion (Cardinal Study)” at ClinicalTrials.gov

//////////////Sutimlimab-jome, Enjaymo, FDA 2022, APPROVALS 2022, agglutinin disease, BIVV009, TNT009, UNII-GNWE7KJ995, WHO 10757, PEPTIDE, MONOCLONAL ANTIBODY, スチムリマブ (遺伝子組換え), 

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