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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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Darinaparsin


69819-86-9.png
img
2D chemical structure of 69819-86-9
SVG Image
IUPAC CondensedH-gGlu-Cys(Unk)-Gly-OH
SequenceXXG

Darinaparsin

ダリナパルシン , Darvias

JAPAN 2022 APPROVED, PMDA 2022/6/20

(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-dimethylarsanylsulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid

(S)-2-amino-5-(((R)-1-((carboxymethyl)amino)-3-((dimethylarsino)thio)-1-oxopropan-2-yl)amino)-5-oxopentanoic acid

Glycine, L-gamma-glutaMyl-S-(diMethylarsino)-L-cysteinyl-

FormulaC12H22AsN3O6S
CAS69819-86-9
Mol weight411.3062
EfficacyAntineoplastic
Commentorganic arsenical

Zinapar, ZIO-101, DMAs(III)G, clarinaparsinUNII-9XX54M675GSP-02L

  • OriginatorTexas A&M University; University of Texas M. D. Anderson Cancer Center
  • DeveloperSolasia Pharma; ZIOPHARM Oncology
  • ClassAmines; Antineoplastics; Arsenicals; Oligopeptides; Pentanoic acids; Small molecules; Sulfides
  • Mechanism of ActionApoptosis stimulants; Cell cycle inhibitors; Reactive oxygen species stimulants
  • Orphan Drug StatusYes – Peripheral T-cell lymphoma
  • PreregistrationPeripheral T-cell lymphoma
  • DiscontinuedLiver cancer; Lymphoma; Multiple myeloma; Non-Hodgkin’s lymphoma; Solid tumours
  • 28 Mar 2022No recent reports of development identified for phase-I development in Peripheral-T-cell-lymphoma in China (IV, Injection)
  • 26 Jan 2022ZIOPHARM Oncology is now called Alaunos Therapeutics
  • 11 Dec 2021Safety and efficacy data from a phase II trial in Peripheral T-cell lymphoma presented at the 63rd American Society of Hematology Annual Meeting and Exposition (ASH-2021)

Darinaparsin is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects. Compared to inorganic arsenic compounds such as arsenic trioxide (As2O3), darinaparsin appears to exhibit a wide therapeutic window.

Darinaparsin, also know as ZIO-101 and SP-02, is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects.

Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity.

PAPER

 Biochemical Pharmacology (Amsterdam, Netherlands), 126, 79-86; 2017

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PATENT

WO 2015085208

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015085208

Preparation of Darinaparsin

[0071] Sterile water (15.5 L) and ethyl alcohol (200 proof, 15.5 L) were charged in a reaction flask prior to the addition of L-glutathione (3.10 kg). While being stirred, the reaction mixture was cooled to 0-5 °C prior to the addition of triethylamine (1.71 L). Stirring was continued until most of the solids were dissolved and the solution was filtered. After filtration, the reaction mixture was cooled to 0-5 °C prior to the addition of chlorodimethylarsine (1.89 kg) over 115 minutes while maintaining the temperature at 0-5 °C. Stirring continued at 0-5 °C for 4 hours before acetone (30.6 L) was added over 54 minutes while maintaining the temperature at 0-5 °C. The suspension was stored at 0-5°C overnight prior to filtration. The solid was collected in a filter funnel, washed successively with ethyl alcohol (200 proof, 13.5 L) and acetone (13.5 L) and dried in suction for 23 minutes. A second similar run was performed and the collected solids from both runs were combined. Ethyl alcohol (200 proof, 124 L) and the combined solids (11.08 kg) were charged in a vessel. The slurry was stirred at ambient temperature for 2 hours before filtration, washing successively with ethyl alcohol (200 proof, 27 L) and acetone (27 L) and dried in suction for 60 minutes. The resulting solid was transferred to drying trays and dried in a vacuum oven at ambient temperature for 66 hours to provide darinaparsin as a solid with the differential scanning calorimetry (DSC) thermogram of Figure 1, with an extrapolated onset temperature at about 191.36° C and a peak temperature at about 195.65° C.

PATENT

WO 2010021928

Step 1

Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109°C was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.

Step 2

SGLU-1: Glutathione (14.0 g, 45.6 mmol) was stirred rapidly in glyme while dimethylchoroarsine (6.5 g, 45.6 mmol) was added dropwise. Pyridine (6.9 g, 91.2 mmol) was then added to the slurry and the mixture was subsequently heated to reflux. The heat was removed immediately and the mixture stirred at room temperature for 4 h. Isolation of the resultant insoluble solid and recrystallization from ethanol afforded 4 as the pyridine hydrochloride complex (75% yield). mp 115-118°C; NMR (D20) δ1.35 (s, 6H), 1.9-4.1 (m’s, 10H), 7.8-9.0 (m, 5H); mass spectrum (m/e) 140, 125, 110, 105, 79, 52, 45, 36.

PATENT

WO 2009075870

Step 1

Example 1. Preparation of Dimethylchloroarsine (DMCA). A 3-neck round-bottom flask (500 mL) equipped with mechanical stirrer, inlet for nitrogen, thermometer, and an ice bath was charged with cacodylic acid (33 g, 0.23 mol) and cone. hydrochloric acid (67 mL). In a separate flask, a solution of SnCl2·2H2O (54 g, 0.239 mol) in cone. hydrochloric acid (10 mL) was prepared. The SnCl2·2 H2O solution was added to the cacodylic acid in HCl solution under nitrogen while maintaining the temperature between 5 °C and 10 °C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was transferred to a separatory funnel and the upper layer (organic) collected. The bottom layer was extracted with dichloromethane (DCM) (2 × 25 mL). The combined organic extract was washed with 1 N HCl (2 × 10 mL) and water (2 × 20 mL). The organic extract was dried over MgSO4 and DCM was removed by rotary evaporation (bath temperature 80 °C, under nitrogen, atmospheric pressure). The residue was further distilled under nitrogen. Two tractions of DMCA were collected. The first fraction contained some DCM and the second fraction was of suitable quality (8.5 g, 26% yield). The GC analysis confirmed the identity and purity of the product.

Step 2

Example 3. Preparation of S-Dimethylarsinoglutathione (SGLU-1). In a 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel and thermometer under an inert atmosphere was prepared a suspension of glutathione (114.5 g, 0.37 mol) in a 1:1 (v/v) mixture of water/ethanol (1140 mL) and cooled to below 5 °C. The mixture was treated slowly (over 15 min) with triethylamine (63.6 mL, 0.46 mol) while maintaining the temperature below 20 °C. The mixture was cooled to 4 °C and stirred for 15 min and then the traces of undissolved material removed by filtration. The filtrate was transferred in a clean 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel, nitrogen inlet, and thermometer and DMCA (70 g, 0.49 mol) (lot # 543-07-01-44) was added slowly while maintaining the temperature at 3-4°C. The reaction mixture was stirred at 1-4°C for 4 h, and acetone (1.2 L) was added over a period of 1 h. The mixture was stirred for 90 min between 2 and 3°C and the resulting solid was isolated by filtration. The product was washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and the wet solids were suspended in ethanol 200 Proof (2000 mL). The product was isolated by filtration, washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and dried in vacuum for 2 days at RT to give 115 g (75%) of SGLU-1, HPLC purity > 99.5% (in process testing).

PATENT

WO 2007027344

Example 2 Preparation of S-Dimethylarsinoglutathione A 5 L, three necked round bottom flask was equipped with a mechanical stirrer assembly, thermometer, addition funnel, nitrogen inlet, and a drying tube was placed in a cooling bath. A polyethylene crock was charged with glutathione-reduced (200 g) and deionized water (2 L) and stirred under a nitrogen atmosphere to dissolve all solids. The mixture was filtered to remove any insoluble material and the filtrate was transferred to the 5 L flask. While stirring, ethanol, 200 proof (2 L) was added and the clear solution was cooled to 0-5° C. using an ice/methanol bath. Pyridine (120 g) was added followed by a dropwise addition of Me2AsCl (120 g) over a minimum of 1 hour. The reaction mixture was stirred at 0-5° C. for a minimum of 2 hours prior to removal of the cooling bath and allowing the mixture to warm to room temperature under a nitrogen atmosphere with stirring. The reaction mixture was stirred overnight (>15 hrs) at room temperature under a nitrogen atmosphere at which time a white solid may precipitate. The reaction mixture was concentrated to a slurry (liquid and solid) at 35-45° C. using oil pump vacuum to provide a white solid residue. As much water as possible is removed, followed by two coevaporations with ethanol to azeotrope the last traces of water. The white solid residue was slurried in ethanol, 200 pf. (5 L) under a nitrogen atmosphere at room temperature overnight. The white solid was filtered and washed with ethanol, 200 pf. (2×500 mL) followed by acetone, ACS (2×500 mL). The resulting solid was transferred to drying trays and vacuum oven dried overnight at 25-35° C. using oil pump vacuum to provide pyridinium hydrochloride-free S-dimethylarsinoglutathione as a white solid. melting point of 189-190° C.

PATENT

WO 20060128682

Step 1

Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109° C. was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.

Step 2

Pyridine Hydrochloride Free Synthesis of S-Dimethylarsinoglutathione (GLU) Dimethylarsinoglutathione is made using an adapted of Chen (Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the contents of which are hereby incorporated by reference in their entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved in dichloromethane under nitrogen. Tetramethyldiarsine is added dropwise to the solution and the reaction is stirred overnight at room temperature under nitrogen and then exposed to air for 1 h. The mixture is then evaporated to dryness and the residue is washed with water and dried to give a crude solid that is recrystallized from methanol to give S-dimethylarsinoglutathione.

//////////

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Solasia Announces Submission of New Drug Application for Anti-cancer Drug DARINAPARSIN for Peripheral T-Cell Lymphoma in Japan

Solasia Pharma K.K. (TSE: 4597, Headquarters: Tokyo, Japan, President & CEO: Yoshihiro Arai, hereinafter “Solasia”) today announced submission of a New Drug Application (NDA) for its new anti-cancer drug darinaparsin (generic name, development code: SP-02) as a treatment for relapsed or refractory peripheral T-cell lymphoma to the Ministry of Health, Labour and Welfare (MHLW). Based on positive results of R&D on darinaparsin, centered primarily on the results of the Asian Multinational Phase 2 Study (study results released in June 2020), Solasia filed an NDA for the drug with the regulatory authority in Japan ahead of anywhere else in the world.

Solasia expects to obtain regulatory approval in 2022 and to also launch in the same year. If approved and launched, darinaparsin would be the third drug Solasia successfully developed and brought to market since its founding and is expected to contribute to the treatment of PTCL.

Mr. Yoshihiro Arai, President and CEO of Solasia, commented as follows:
“No standard treatment has been established for relapsed or refractory PTCL as of yet. I firmly believe that darinaparsin, with its novel mechanism of action that differs from those of already approved drugs, will contribute to patients and healthcare providers at clinical sites as a new treatment option for relapsed or refractory PTCL. Since founding, Solasia has conducted R&D on five pipeline drugs. Of the five, we have successfully developed and brought to market two drugs, i.e., began providing them to patients, and today, we submitted an NDA for our first anti-cancer drug. Under our mission to provide patients with ‘Better Medicine for a Brighter Tomorrow’, we will continue aiming to contribute to patients’ treatment and enhanced quality of life. ”

About darinaparsin (SP-02)
Darinaparsin, an organoarsenic compound with anticancer activity, is a novel mitochondrial-targeted agent being developed for the treatment of various hematologic and solid tumors. The proposed mechanism of action of the drug involves the disruption of mitochondrial function, increased production of reactive oxygen species, and modulation of intracellular signal transduction pathways. Darinaparsin is believed to exert anticancer effect by inducing cell cycle arrest and apoptosis. Darinaparsin has been granted orphan drug designation in the US and EU.
For more information, please visit at https://solasia.co.jp/en/pipeline/sp-02.html

About Asian Multinational Phase 2 Study
The Asian Multinational Phase 2 Study was a multinational, multicenter, single-arm, open-label, non-randomized study to evaluate the efficacy and safety of darinaparsin monotherapy in patients with relapsed or refractory PTCL conducted in Japan, Korea, Taiwan, and Hong Kong. (CT.gov Identifier: NCT02653976).
Solasia plans to present the results of the study at an international academic conference to be held in the near future.

About peripheral T-cell lymphoma (PTCL)
Please visit at https://solasia.co.jp/en/pipeline/sp-02.html

About Solasia
Please visit at https://solasia.co.jp/en/

/////////////Darinaparsin, Darvias, JAPAN 2022,  APPROVALS 2022, PMDA, ダリナパルシン  , Zinapar, ZIO-101, DMAs(III)G, clarinaparsinUNII-9XX54M675GSP-02LOrphan Drug

C[As](C)SCC(C(=O)NCC(=O)O)NC(=O)CCC(C(=O)O)N

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

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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

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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

Olipudase alfa


HPLSPQGHPA RLHRIVPRLR DVFGWGNLTC PICKGLFTAI NLGLKKEPNV ARVGSVAIKL
CNLLKIAPPA VCQSIVHLFE DDMVEVWRRS VLSPSEACGL LLGSTCGHWD IFSSWNISLP
TVPKPPPKPP SPPAPGAPVS RILFLTDLHW DHDYLEGTDP DCADPLCCRR GSGLPPASRP
GAGYWGEYSK CDLPLRTLES LLSGLGPAGP FDMVYWTGDI PAHDVWHQTR QDQLRALTTV
TALVRKFLGP VPVYPAVGNH ESTPVNSFPP PFIEGNHSSR WLYEAMAKAW EPWLPAEALR
TLRIGGFYAL SPYPGLRLIS LNMNFCSREN FWLLINSTDP AGQLQWLVGE LQAAEDRGDK
VHIIGHIPPG HCLKSWSWNY YRIVARYENT LAAQFFGHTH VDEFEVFYDE ETLSRPLAVA
FLAPSATTYI GLNPGYRVYQ IDGNYSGSSH VVLDHETYIL NLTQANIPGA IPHWQLLYRA
RETYGLPNTL PTAWHNLVYR MRGDMQLFQT FWFLYHKGHP PSEPCGTPCR LATLCAQLSA
RADSPALCRH LMPDGSLPEA QSLWPRPLFC
(Disulfide bridge: 43-119, 46-111, 74-85, 175-180, 181-204, 339-385, 538-542, 548-561)

Olipudase alfa

Xenpozyme, Japan 2022, APPROVALS 2022, 2022/3/28

PEPTIDE, オリプダーゼアルファ (遺伝子組換え)

Alternative Names: Acid sphingomyelinase Niemann Pick disease type B – Sanofi; Acid-sphingomyelinase – Sanofi; GZ-402665; Recombinant human acid sphingomyelinase – Sanofi; rhASM – Sanofi; Sphingomyelinase-C (synthetic human) – Sanofi; Synthetic human sphingomyelinase-C – Sanofi; Xenpozyme

FormulaC2900H4373N783O791S24
CAS927883-84-9
Mol weight63631.0831
EfficacyLysosomal storage disease treatment, Enzyme replacement (acid sphingomyelinase)
CommentEnzyme replacement therapy product
Treatment of Niemann-Pick disease type A/B
  • OriginatorGenzyme Corporation
  • DeveloperSanofi
  • ClassRecombinant proteins; Sphingomyelin phosphodiesterases
  • Mechanism of ActionSphingomyelin-phosphodiesterase replacements
  • Orphan Drug StatusYes – Niemann-Pick diseases
  • RegisteredNiemann-Pick diseases
  • 28 Mar 2022Registered for Niemann-Pick diseases (In adolescents, In children, In adults) in Japan (IV) – First global approval
  • 09 Feb 2022FDA assigns PDUFA action date of (03/07/2022) for Olipudase alfa (In children, In adults) for Niemann-Pick diseases
  • 09 Feb 2022Adverse e

//////////

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Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

https://www.empr.com/home/mpr-first-report/worldsymposium-2021/olipudase-alfa-chronic-visceral-acid-sphingomyelinase-efficacy/embed/#?secret=x9Jl0tjBl4#?secret=4RmoWVLWaQ

Olipudase alfa was associated with significant improvements in clinically relevant disease end points among patients with chronic visceral acid sphingomyelinase (ASM) deficiency (ASMD), according to results from the phase 2/3 ASCEND trial presented at the 17th Annual WORLDSymposium.

ASMD is a rare, debilitating lysosomal storage disease characterized by a deficiency of the enzyme acid sphingomyelinase, which results in the accumulation of sphingomyelin in various tissues of the body. Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM.

The multicenter, randomized, double-blind, placebo-controlled ASCEND trial evaluated the efficacy and safety of olipudase alfa in 36 adults with chronic visceral ASMD. Patients were randomly assigned 1:1 to receive olipudase alfa 3mg/kg intravenously every 2 weeks or placebo for 52 weeks. The coprimary end points were the percent change in spleen volume and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO).

At week 52, treatment with olipudase alfa resulted in a 39.45% reduction in spleen volume, compared with a 0.5% increase for placebo (P <.0001). A decrease in spleen volume of at least 30% was observed in 17 patients (94%) treated with olipudase afla compared with no patients treated with placebo. Additionally, olipudase alfa significantly improved lung function by 22% from baseline compared with 3% for patients receiving placebo (P =.0004), as measured by percent predicted DLCO.

Olipudase alfa also met key secondary end points including a 31.7% reduction in liver volume (vs a 1.4% reduction for placebo; P <.0001) and a 16.8% improvement in mean platelet counts (vs 2.5% with placebo; P =.019) at week 52. Significant improvements in HDL, LDL, AST, ALT, chitotriosidase (54% vs 12% with placebo; P =.0003), and lyso-sphingomyelin (78% vs 6% with placebo) were also observed in the olipudase alfa group at week 52.

With regard to Splenomegaly Related Score, a patient-reported outcome measurement that evaluates patient symptoms associated with an enlarged spleen, findings showed no meaningful difference between olipudase alfa and placebo (-8 point vs -9.3 points, respectively).

As for safety, olipudase alfa was well tolerated with most adverse events being mild to moderate in severity. There were no treatment-related serious adverse events and no adverse event-related discontinuations.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Wasserstein M, Arash-Kaps L, Barbato A, et al. Adults with chronic acid sphingomyelinase deficiency show significant visceral, pulmonary, and hematologic improvements after enzyme replacement therapy with olipudase-alfa: 1-year results of the ASCEND placebo-controlled trial. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 265.

CLIP

https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-06-14-00-00-2346501

EMA accepts regulatory submission for olipudase alfa, the first potential therapy for ASMD

  • Olipudase alfa has been granted PRIority MEdicines (PRIME) designation in Europe, Breakthrough Therapy designation in the United States, and SAKIGAKE designation in Japan
  • European regulatory decision anticipated second half of 2022

DECEMBER 6, 2021

The European Medicines Agency (EMA) has accepted for review under an accelerated assessment procedure the Marketing Authorization Application (MAA) for olipudase alfa, Sanofi’s investigational enzyme replacement therapy which is being evaluated for the treatment of acid sphingomyelinase deficiency (ASMD). Historically referred to as Niemann-Pick disease (NPD) type A and type B, ASMD is a rare, progressive, and potentially life-threatening disease for which no treatments are currently approved. The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan. If approved, olipudase alfa will become the first and only therapy for the treatment of ASMD.

Today’s milestone has been decades in the making and our gratitude goes to the ASMD community who has stood by us with endless patience while olipudase alfa advanced through clinical development,” said Alaa Hamed, MD, MPH, MBA, Global Head of Medical Affairs, Rare Diseases, Sanofi. “Olipudase alfa represents the kind of potentially life-changing innovation that is possible when industry, medical professionals and the patient community work together toward a common goal.”

The MAA is based on positive results from two separate clinical trials (ASCEND and ASCEND-Peds) evaluating olipudase alfa in adult and pediatric patients with non-central nervous system (CNS) manifestations of ASMD type A/B and ASMD type B.

Olipudase alfa has received special designations from regulatory agencies worldwide, recognizing the innovation potential of the investigational therapy.

“Scientific innovation is the greatest source of hope for people living with diseases like ASMD where there are no approved treatments and is a critical component for ensuring a viable healthcare ecosystem,” said Bill Sibold, Executive Vice President of Sanofi GenzymeAt Sanofi, we have a long history of pioneering scientific innovation, and we remain committed to finding solutions to address unmet medical needs, including those of the rare disease community.”

The EMA awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

In Japan, olipudase alfa was awarded the SAKIGAKE designation, which is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication. In September, Sanofi filed the J-NDA submission for olipudase alfa.

About ASMD

ASMD results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan.

ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. ASMD type B is a serious and potentially life-threatening disease that predominantly impacts the lungs, liver, and spleen, as well as other organs. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.

About olipudase alfa

Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients. Olipudase alfa is an investigational agent and the safety and efficacy have not been evaluated by the FDA, EMA, or any other regulatory authority worldwide.

About Sanofi

Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

///////Olipudase alfa,  japan 2022, APPROVALS 2022, Xenpozyme, PEPTIDE, オリプダーゼアルファ (遺伝子組換え) , ORPHAN DRUG, GZ-402665 , GZ 402665

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Andexanet alfa



(heavy chain)
IVGGQECKDG ECPWQALLIN EENEGFCGGT ILSEFYILTA AHCLYQAKRF KVRVGDRNTE
QEEGGEAVHE VEVVIKHNRF TKETYDFDIA VLRLKTPITF RMNVAPACLP ERDWAESTLM
TQKTGIVSGF GRTHEKGRQS TRLKMLEVPY VDRNSCKLSS SFIITQNMFC AGYDTKQEDA
CQGDAGGPHV TRFKDTYFVT GIVSWGEGCA RKGKYGIYTK VTAFLKWIDR SMKTRGLPKA
KSHAPEVITS SPLK
(light chan)
ANSFLFWNKY KDGDQCETSP CQNQGKCKDG LGEYTCTCLE GFEGKNCELF TRKLCSLDNG
DCDQFCHEEQ NSVVCSCARG YTLADNGKAC IPTGPYPCGK QTLER
(Disulfide bridge: H7-H12, H27-H43, H108-L98, H156-H170, H181-H209, L16-L27, L21-L36, L38-L47, L55-L66, L62-L75, L77-L90)

Andexanet alfa

JAPAN 2022, PEPTIDE

Ondexxya
2022/3/28
Anticoagulant reversal (factor Xa inhibitors)

CAS: 1262449-58-0

アンデキサネットアルファ (遺伝子組換え)

  • Andexanet alfa
  • r-Antidote
  • rfXa Inhibitor Antidote
  • PRT-4445
  • PRT064445

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clotsheart attacksstrokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]

It was approved for medical use in the United States in May 2018.[1] It was developed by Portola Pharmaceuticals.[3]

ndexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan 1.

Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban 1. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited 7. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors 1. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways 5 and remains catalytically inactive due to structural modification 1. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex 5. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex 5. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin 5.

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Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Medical uses

Andexanet alfa is used to stop life threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]

There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[4] The only published clinical trial is a prospective, open label, single group study.[5] This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[6] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[7]

Adverse effects

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[8] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa’s procoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[9] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[3][10] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[11]

History[edit]

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[4] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents (“usual care”).[5][12]

Society and culture

Economics

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[13]

References

  1. Jump up to:a b c d e “Andexxa- andexanet alfa injection, powder, lyophilized, for solution”DailyMed. 21 September 2020. Retrieved 12 November 2020.
  2. Jump up to:a b c d e f g “Andexxa Monograph for Professionals”Drugs.com. Retrieved 19 December 2018.
  3. Jump up to:a b Dolgin E (March 2013). “Antidotes edge closer to reversing effects of new blood thinners”Nature Medicine19 (3): 251. doi:10.1038/nm0313-251PMID 23467222S2CID 13340319.
  4. Jump up to:a b Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (December 2015). “Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”New England Journal of Medicine373 (25): 2413–24. doi:10.1056/NEJMoa1510991PMID 26559317.
  5. Jump up to:a b Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). “Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”New England Journal of Medicine380 (14): 1326–1335. doi:10.1056/NEJMoa1814051PMC 6699827PMID 30730782.
  6. ^ Justin Morgenstern, “Andexanet Alfa: More garbage science in the New England Journal of Medicine”, First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  7. ^ “A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor”. 11 January 2022.
  8. ^ Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). “Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors”. Blood112 (11): 983. doi:10.1182/blood.V112.11.983.983ISSN 0006-4971.
  9. ^ Kaatz, Scott; Bhansali, Hardik; Gibbs, Joseph; Lavender, Robert; Mahan, Charles E.; Paje, David G. (2017-09-13). “Reversing factor Xa inhibitors – clinical utility of andexanet alfa”Journal of Blood Medicine8: 141–149. doi:10.2147/JBM.S121550PMC 5602457PMID 28979172.
  10. ^ Lu G, Deguzman FR, Hollenbach SJ, et al. (March 2013). “A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa”. Nature Medicine19 (4): 446–51. doi:10.1038/nm.3102PMID 23455714S2CID 11235887.
  11. ^ H. Spreitzer (23 December 2013). “Neue Wirkstoffe – Andexanet Alfa”. Österreichische Apothekerzeitung (in German) (26/2013): 40.
  12. ^ “Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor”ClinicalTrials.gov. 11 January 2022.
  13. ^ “Lexi Comp Drug Information Online”. 24 May 2018.

Further reading

External links

Clinical data
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.comMonograph
License dataUS DailyMedAndexanet_alfa
Routes of
administration
Intravenous injection
ATC codeV03AB38 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only [1]EU: Rx-only
Pharmacokinetic data
MetabolismNot studied
Elimination half-life5 h to 7 h
Identifiers
showIUPAC name
CAS Number1262449-58-0
IUPHAR/BPS7576
DrugBankDB14562
ChemSpidernone
UNIIBI009E452R
KEGGD11029
ChEMBLChEMBL3301583

//////////Andexanet alfa, JAPAN 2022, APPROVALS 2022, アンデキサネットアルファ (遺伝子組換え) , Ondexxya , PRT-4445, PRT064445

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Carotegrast methyl


ChemSpider 2D Image | CAROTEGRAST METHYL | C28H26Cl2N4O5
Carotegrast methyl (JAN).png
2D chemical structure of 401905-67-7

Carotegrast methyl

FormulaC28H26Cl2N4O5
CAS401905-67-7
Mol weight569.4358

PMDA APROVED, CAROGRA, カロテグラストメチル

ON 2022/3/28

Antiasthmatic, Integrin alpha 4 inhibitor

  • An alpha4 integrin antagonist.

401905-67-7[RN]

L-Phenylalanine, N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1,4-dihydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-, methyl ester

methyl (2S)-2-[(2,6-dichlorophenyl)formamido]-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]phenyl}propanoate

Methyl N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-L-phenylalaninate

Carotegrast Methyl

Methyl (2S)-2-(2,6-dichlorobenzamido)-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}propanoate

C28H26Cl2N4O5 : 569.44
[401905-67-7]

PATENT

WO 2008062859

https://patents.google.com/patent/WO2008062859A1/en

Step 1

(Method 2): The title compound was prepared starting from 2-amino-5-dimethylamino- benzoic acid methyl ester dihydrochloride through the hydrolysis under basic condition To 5.0 g of 2-amino-5-dimethylamino-benzoic acid methyl ester di-hydrochloride, there were added 15 mL of water and 15.6 mL of a 6M aqueous solution of sodium hydroxide and the resulting mixture was heated to 40°C for 2 hours. After the confirmation of the progress of the reaction according to HPLC, the reaction system was cooled to room temperature, a 6M hydrochloric acid aqueous solution was dropwise added to the reaction system to thus neutralize the same and to separate out crystals (pH 4.9) and then the reaction system was stirred at 10°C for 2 hours. The solid thus obtained was isolated through the filtration under reduced pressure, washed with 30 mL of water and then dried under reduced pressure at 60°C for 14 hours. Title compound 3.14 g was obtained as gray-colored solid. The physical properties determined were almost identical to those observed for the same compound prepared in the above-mentioned synthesis example. H-NMR (400MHz, DMSO-d6): δ 8.21 (bs, 3H), 7.10 (d, 1H, J=2.8Hz), 6.97 (dd, 1H, J=9.1, 2.8Hz), 6.70 (d, 1H, J=9.1 Hz), 2.72 (s, 6H); 13C-NMR (100MHz, DMSO-d6): δ168.89, 144.55, 141.61, 123.29, 117.90, 114.78, 110.11,41.95; MS (ESI+): m/z 181.3 (MH+), (ESI-): m/z 179.2 (M-H).

Step 2

Step 1: Synthesis of Nα-(2,6-dichlorobenzoyl) -4-{2-ethoxycarbonylamino-5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester To 1.96 g of 2-amino-5-dimethylaminobenzoic acid, there were added 12 mL of acetonitrile and 5.29 mL of pyridine to form a suspension and then the resulting suspension was cooled to 4°C. To this suspension there was dropwise added 4.17 mL of ethyl chloroformate over 5 minutes and then the mixture was stirred at 25°C for one hour. After confirming the disappearance of the starting material by HPLC, 0.7 mL of ethanol was added to the mixture to thus decompose the excess ethyl chloroformate and the mixture was further stirred for additional one hour. To this reaction solution there were added 4.0 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester and 12 mL of N,Ndimethylformamide, and the resulting mixture was stirred overnight. Subsequently, 48 mL of methanol was drop-wise added, the resulting mixture was stirred at 10°C overnight and then the solid separated from the mixture was isolated through filtration under reduced pressure. The solid was then washed with 8 mL of methanol and dried at 70°C for 5 hours under reduced pressure. Title compound 5.50 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 10.29 (s, 1H), 9.42 (bs, 1H), 9.24 (d, 1H, J=7.9Hz), 7.73 (bs, 1H), 7.62 (d, 2H, J=8.4Hz), 7.48-7.44 (m, 2H), 7.41 (dd, 1H, J=9.5, 6.2Hz), 7.27 (d, 2H,J=8.4Hz), 7.01 (d, 1H, J=2.7Hz), 6.93 (dd, 1H, J=9.1, 2.9Hz), 4.71 (ddd, 1H, J=9.2, 8.1, 5.7Hz), 4.05 (q, 2H, J=7.0Hz), 3.66 (s, 3H), 3.10 (dd, 1H, J=14.0, 5.6Hz), 2.96 (dd, 1H, J=14.0, 9.2Hz), 2.93 (s, 6H), 1.18 (t, 3H, J=7.2Hz); MS (ESI+): m/z 601.2 (MH+) and 623.2 (M+Na), (ESI): m/z 599.1 (M-H).

Step 3

Step2: Synthesis of Na-(2,6-dichlorobenzoyl)-4-{6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine methyl ester To 2.0 g of Na-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonylamino -5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester prepared in above-mentioned step 1, were added 16 mL of N,N-dimethylfbrmamide, 0.8 mL of methanol and 0.91 g of potassium carbonate, followed by the stirring of the resulting mixture at 25°C overnight. To this reaction solution, there was added 0.75 mL of methyl p-toluenesulfonate for subjecting the methyl ester to alkylation at 25~40°C. After confirming the disappearance of the starting material by HPLC, 0.75 mL of acetic acid was added to quench the reaction, 16 mL of water was dropped and the solid was separated. Further, 8 mLof N,N-dimethylformamide/water = 1/1 mixed liquid was added to the resulting mixture, followed by the stirring of the mixture at 25°C. Then the solid thus separated was isolated through filtration under reduced pressure and then washed with 8 mL of water. Thereafter, the isolated solid was dried at 70°C for 4 hours under reduced pressure. Desired compound 1.77 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 9.28 (d, 1H, J=8.1 Hz), 7.48-7.36 (m, 6H), 7.31 (dd, 1H, J=3.0, 9.0Hz), 7.24 (d, 1H, J=3.0Hz), 7.20-7.15 (m, 2H), 4.18 (ddd, 1H, J=10.2, 8.1,4.8Hz), 3.69 (s, 3H), 3.49 (s, 3H), 3.22 (dd, 1H, J=14.1, 4.8Hz), 3.02 (dd, 1H, J=14.2, 10.5Hz), 2.94 (s, 6H); MS (ESI+): m/z 569.2 (MH+) and 591.1 (M+Na), (ESI-): m/z 567.2 (M-H).

PATENT

https://patents.google.com/patent/WO2004074264A1/en

PATENT’ WO 2003070709

https://patents.google.com/patent/WO2003070709A1/en

PATENT

WO 2002016329

///////////

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/////////////////////////////////////////////////////////////////////////////

 

/////////////Carotegrast methyl, CAROGRA, カロテグラストメチル , JAPAN 2022, APPROVALS 2022,

COC(=O)[C@H](Cc1ccc(cc1)N2C(=O)N(C)c3ccc(cc3C2=O)N(C)C)NC(=O)c4c(Cl)cccc4Cl

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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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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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Faricimab-svoa


(A chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQGLEWMGW INPNSGGTNY
AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARSP NPYYYDSSGY YYPGAFDIWG
QGTMVTVSSA SVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN
SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGECDKTH
TCPPCPAPEA AGGPSVFLFP PKPKDTLMAS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV
HNAKTKPREE QYNSTYRVVS VLTVLAQDWL NGKEYKCKVS NKALGAPIEK TISKAKGQPR
EPQVCTLPPS RDELTKNQVS LSCAVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF
FLVSKLTVDK SRWQQGNVFS CSVMHEALHN AYTQKSLSLS PGK
(B chain)
EVQLVESGGG LVQPGGSLRL SCAASGYDFT HYGMNWVRQA PGKGLEWVGW INTYTGEPTY
AADFKRRFTF SLDTSKSTAY LQMNSLRAED TAVYYCAKYP YYYGTSHWYF DVWGQGTLVT
VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL
QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEA
AGGPSVFLFP PKPKDTLMAS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLAQDWL NGKEYKCKVS NKALGAPIEK TISKAKGQPR EPQVYTLPPC
RDELTKNQVS LWCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK
SRWQQGNVFS CSVMHEALHN AYTQKSLSLS PGK
(C chain)
DIQLTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP GKAPKVLIYF TSSLHSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSTVPWTFGQ GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(D chain)
SYVLTQPPSV SVAPGQTARI TCGGNNIGSK SVHWYQQKPG QAPVLVVYDD SDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DSSSDHWVFG GGTKLTVLSS ASTKGPSVFP
LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT
VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSC
(Disulfide bridge: A22-A96, A156-A216, A236-D213, A242-B232, A245-B235, A277-A337, A365-A441, B22-B96, B150-B206, B226-C214, B267-B327, B360-B431, B23-B88, B134-B194, D22-D87, D137-D193)

Faricimab

FormulaC6506H9968N1724O1026S45
CAS1607793-29-2
Mol weight130194.6203

Faricimab-svoa

FDA APPROVED 1/28/2022, Vabysmo

To treat neovascular (wet) aged-related macular degeneration and diabetic macular edema

RO6867461

  • Faricimab
  • Faricimab [INN]
  • RG-7716
  • RG7716
  • RO-6867461
  • RO6867461
  • UNII-QC4F7FKK7I
  • WHO 10563
FDA Approves Faricimab for nAMD and Diabetic Macular Edema
EfficacyAngiogenesis inhibitor, Anti-angiopoietin 2 antibody, Anti-VEGF antibody
CommentAntibody
Opthamology indications in patients susceptible to blocking of vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2)

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).[1] Faricimab is a bispecific monoclonal antibody.[2]

Faricimab was developed by Roche. Faricimab completed Phase III trials[3] and was approved for use in the United States by the Food and Drug Administration in January 2022.[1][4]

FDA Approves Faricimab to Treat Wet AMD and DME\

FDA Approves Faricimab to Treat Wet AMD and DMEFebruary 1, 2022

Laura Joszt, MA

This represents the approval of the first bispecific antibody to treat wet age-related macular degeneration (AMD) and diabetic macular edema (DME).

https://www.ajmc.com/view/fda-approves-fariximab-to-treat-wet-amd-and-dme

The FDA has approved faricimab-svoa (Vabysmo; Genentech) to treat 2 leading causes of vision loss: wet, or neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME).

After 4 initial monthly doses, faricimab is delivered as injections from 1 to 4 months apart in the first year while the current standard of care for wet AMD and DME requires injections every 1 to 2 months. In wet AMD, patients receive the 4 monthly injections first and then based on outcomes may receive their subsequent treatments every 2, 3, or 4 months. For DME, after the 4 initial monthly injections, treatment is extended or reduced based on outcomes, with a range of 1 to 4 months between doses.

The treatment targets and inhibits pathways involving angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), which are thought to contribute to vision loss by destabilizing blood vessels.

“Vabysmo represents an important step forward for ophthalmology. It is the first bispecific antibody approved for the eye and a major advance in treating retinal conditions such as wet AMD and diabetic macular edema,” Charles Wykoff, MD, PhD, director of research at Retina Consultants of Texas in Houston and a Vabysmo phase 3 investigator, said in a statement. “With Vabysmo, we now have the opportunity to offer patients a medicine that could improve their vision, potentially lowering treatment burden with fewer injections over time.”

The FDA approved faricimab on the results from 4 phase 3 studies: TENAYA and LUCERNE for wet AMD and YOSEMITE and RHINE for DME. All 4 studies were randomized, multicenter, double-masked, global trials.

TENAYA and LUCERNE were identical: 1329 treatment-naive patients with wet AMD, aged 50 and older, were assigned 1:1 to faricimab up to every 16 weeks or aflibercept every 8 weeks. YOSEMITE and RHINE were also identical: 1891 patients with vision loss due to DME were randomly assigned 1:1:1 to faricimab every 8 weeks, faricimab per personalized treatment interval, or aflibercept every 8 weeks.

For all trials, faricimab was noninferior to aflibercept and the incidence of ocular adverse events was comparable. The researchers determined that the longer time between dosing intervals combined with the visual benefits of faricimab reduced the burden in patients.

The 1-year results from these studies were published January 24 in The Lancet.1,2

“These data published in The Lancet reinforce the potential of faricimab as an important treatment option that may help improve and maintain vision while extending the time between treatments up to 4 months,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, said in a statement. “We remain deeply committed to developing new medicines such as faricimab that may help preserve sight in many people living with serious retinal conditions.”

Now that faricimab is approved, Genentech expects it to become available in the United States within weeks. Meanwhile, the European Medicines Agency is currently evaluating a Marketing Authorization Application for faricimab to treat wet AMD and DME.

There are additional trials—COMINO and BALATON—underway to evaluate the efficacy and safety of faricimab in people with macular edema following retinal vein occlusion. In addition, 2-year results for faricimab in DME will be presented at the Angiogeneisis, Exudation, and Degeneration 2022 meeting in February.

References

1. Heier JS, Khanani AM, Quezada Ruiz C, et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. Published January 24, 2022. doi:10.1016/S0140-6736(22)00010-1

2. Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. Published online January 24, 2022. doi:10.1016/S0140-6736(22)00018-6

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Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetVEGF-Aangiopoietin 2
Clinical data
Trade namesVabysmo
Other namesRO6867461; faricimab-svoa
License dataUS DailyMedFaricimab
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
CAS Number1607793-29-2
UNIIQC4F7FKK7I
KEGGD11516
Chemical and physical data
FormulaC6506H9968N1724O1026S45
Molar mass130197.05 g·mol−1

Society and culture

Names

Faricimab is the International Nonproprietary Name (INN).[5]

References

  1. Jump up to:a b “FDA approves Roche’s Vabysmo, the first bispecific antibody for the eye, to treat two leading causes of vision loss”Roche (Press release). 31 January 2022. Retrieved 31 January 2022.
  2. ^ Nicolò M, Ferro Desideri L, Vagge A, Traverso CE (March 2021). “Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases”. Expert Opinion on Investigational Drugs30 (3): 193–200. doi:10.1080/13543784.2021.1879791PMID 33471572S2CID 231665201.
  3. ^ Khan M, Aziz AA, Shafi NA, Abbas T, Khanani AM (August 2020). “Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab”Cells9 (8): 1869. doi:10.3390/cells9081869PMC 7464130PMID 32785136.
  4. ^ “FDA approves faricimab for treatment of wet AMD, DME”. Ophthalmology Times. 28 January 2022.
  5. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information32 (3). hdl:10665/330907.
  • “Faricimab”Drug Information Portal. U.S. National Library of Medicine.

////////////Faricimab-svoa, APPROVALS 2022, FDA 2022, RO6867461, RO 6867461, PEPTIDE, MONOCLONAL ANTIBODY, RG 7716, WHO 10563, peptide

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Somatrogon


>Somatrogon amino acid sequence
SSSSKAPPPSLPSPSRLPGPSDTPILPQFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFE
EAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQF
LRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHN
DDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGFSSSSKAPPPSLPSPSRLPGPS
DTPILPQSSSSKAPPPSLPSPSRLPGPSDTPILPQ

Somatrogon

CAS: 1663481-09-1

Protein Chemical FormulaC1359H2125N361O420S7

Protein Average Weight30465.1 Da (Aglycosylated)

NGENLA, JAPAN PMDA APPROVED 2022/1/20

ソマトロゴン;

  • MOD-4023

Replenisher (somatotoropin)

  • OriginatorModigene
  • DeveloperOPKO Health; Pfizer
  • ClassBiological proteins; Growth hormones; Hormonal replacements; Recombinant proteins
  • Mechanism of ActionHuman growth hormone replacements
  • Orphan Drug StatusYes – Somatotropin deficiency
  • RegisteredSomatotropin deficiency
  • 21 Jan 2022Pfizer and OPKO health receives complete response letter from the US FDA for somatrogon in Somatotropin deficiency (In children)
  • 20 Jan 2022Registered for Somatotropin deficiency (In children) in Japan (SC)
  • 01 Dec 2021CHMP issues a positive opinion and recommends approval of somatrogon for Somatotropin deficiency in the European Union

Somatrogon, sold under the brand name Ngenla, is a medication for the treatment of growth hormone deficiency.[1][2] Somatrogon is a glycosylated protein constructed from human growth hormone and a small part of human chorionic gonadotropin which is appended to both the N-terminal and C-terminal.[2]

Somatrogon is a long-acting recombinant human growth hormone used as the long-term treatment of pediatric patients who have growth failure due to growth hormone deficiency.

omatrogon is a long-acting recombinant human growth hormone. Growth hormone is a peptide hormone secreted by the pituitary gland that plays a crucial role in promoting longitudinal growth during childhood and adolescence and regulating metabolic function in adulthood.2 Recombinant growth hormone therapy for growth hormone deficiency and other conditions has been available since 1985, with daily administration being the standard treatment for many years. More recently, longer-acting forms of growth hormone were developed to improve patient adherence and thus, improve the therapeutic efficacy of treatment.1 Somatrogon was produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. It is a chimeric product generated by fusing three copies of the C-terminal peptide (CTP), or 28 carboxy-terminal residues, from the beta chain of human chorionic gonadotropin (hCG) to the N-terminus and C-terminus of human growth hormone.2,6 The glycosylation and the presence of CTPs in the protein sequence prolongs the half-life of somatrogon and allows its once-weekly dosing.6

In October 2021, Health Canada approved somatrogon under the market name NGENLA as the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone caused by growth hormone deficiency, marking Canada as the first country to approve this drug.4 It is available as a once-weekly subcutaneous injection.5

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About Somatrogon©

Somatrogon©, a long-acting human growth hormone (hGH) molecule, is a once-weekly injectable, created using recombinant technology, for the treatment of pediatric and adult growth hormone deficiency (GHD). The molecule consists of the natural peptide sequence of native growth hormone and the 28 amino acids of the C-Terminus Peptide (CTP) of the human chorionic gonadotropin hormone. This molecule, as compared to current GH replacement therapies, is intended to reduce the injection frequency from a daily to once a week in adults and children with GHD.

Clinical data
Trade namesNgenla
Other namesMOD-4023
Pregnancy
category
AU: B1[1]
Routes of
administration
Subcutaneous injection
ATC codeH01AC08 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]
Identifiers
CAS Number1663481-09-1
DrugBankDB14960
UNII6D848RA61B

Somatrogon© COMPETITIVE ADVANTAGES

In 2014, Pfizer and OPKO entered into a worldwide agreement for the development and commercialization of Somatrogon©. Under the agreement, OPKO is responsible for conducting the clinical program and Pfizer is responsible for registering and commercializing the product.

  • New molecular entity (NME) that maintains natural native sequence of growth hormone
  • Once weekly injection vs. current products requiring daily injections
  • Human growth hormone is used for:
    • Growth hormone deficient children and adults
    • SGA, PWS, ISS
  • Final presentation:
    • Refrigerated, liquid, non-viscous formulation
    • Disposable easy to handle pen injection device with thin needle and small injection volume
  • Orphan drug designation in the U.S. and the EU for children and adults

Somatrogon© PROGRAM STATUS

Phase 3 Pediatric Somatrogon©

  • Phase 3 study in naive growth hormone deficiency pediatric population was completed.

The study was conducted in over 20 countries. This study enrolled and treated 224 pre-pubertal, treatment-naive children with growth hormone deficiency.

  • OPKO and Pfizer Announce Positive Phase 3 Top-Line Results for Somatrogon© during Oct 2019.
  • Achieved Primary Endpoint
    • Somatrogon© was proven non-inferior to daily Genotropin® (somatropin) with respect to height velocity after 12 months
    • Height velocity at 12 months of treatment was higher in the Somatrogon© group (10.12 cm/year) than in the somatropin group (9.78 cm/year)
  • Secondary Endpoints Achieved
    • Change in height standard deviation scores at six and 12 months were higher with Somatrogon© in comparison to somatropin
    • At six months, change in height velocity was higher with Somatrogon© in comparison to somatropin
    • Somatrogon© was generally well tolerated in the study and comparable to that of somatropin dosed once-daily with respect to the types, numbers and severity of the adverse events observed between the treatment arms
  • Children completing this study had the opportunity to enroll in a global, open-label, multicenter, long-term extension study, in which they were able to either continue receiving or switch to Somatrogon© Approximately 95% of the patients switched into the open-label extension study and received Somatrogon© treatment

Phase 3 adults Somatrogon© completed

  • Primary endpoint of change in trunk fat mass from baseline to 26 weeks did not demonstrate a statistical significance between the Somatrogon© treated group and placebo
  • Completed post hoc outlier analysis in June 2017 to assess the influence of outliers on the primary endpoint results
  • Analyses which excluded outliers showed a statistically significant difference between Somatrogon© and placebo on the change in trunk fat mass: additional analyses that did not exclude outliers showed mixed results
  • No safety concerns
  • OPKO and Pfizer have agreed that OPKO may proceed with a pre-BLA meeting with FDA to discuss a submission plan
  • OPKO plans to carry out an additional study in adults using a pen device

Pediatric Somatrogon© registration study in Japan- expected to be completed in Q1 2020

  • 44 patients, comparison of weekly Somatrogon to daily growth hormone.
  • Same pen device, dosage and formulation used in global study.

Somatrogon© Path to Approval

  • BLA submission in US anticipated second half of 2020
    • Completion of analysis of immunogenicity and safety data from pivotal Phase 3 study and open label extension study
  • Two abstracts accepted for oral presentation of data set at the Endo Society’s Annual Meeting in March 2020
    • “Somatrogon© Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Phase 3”
    • “Interpretation of Insulin-like Growth Factor (IGF-1) Levels Following Administration of Somatrogon© (a long acting Growth Hormone-hGH-CTP)”
  • MAA submission in Europe to follow upon completion of open label study demonstrating benefit and compliance with reduced treatment burden
    • Study expected to be completed in Q3 2020

References

Hershkovitz O, Bar-Ilan A, Guy R, et al. In vitro and in vivo characterization of MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone. Mol Pharm. 2016; 13:631–639 [PDF]

Strasburger CJ, Vanuga P, Payer J, et al. MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. 2017;176:283–294 [PDF]

Zelinska N, Iotova V, Skorodok J, et al. Long-acting CTP-modified hGH (MOD-4023): results of a safety and dose-finding study in GHD children. J Clin Endocrinol Metab. 2017;102:1578–1587 [PDF]

Fisher DM, Rosenfeld RG, Jaron-Mendelson M, et al. Pharmacokinetic and pharmacodynamic modeling of MOD-4023, a long-acting human growth hormone, in GHD Children. Horm Res Paediatr. 2017;87:324–332 [PDF]

Kramer W, Jaron-Mendelson M, Koren R, et al. Pharmacokinetics, Pharmacodynamics and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults. Clin Pharmacol Drug Dev. 2017 [in press]

Society and culture

On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ngenla, intended for the treatment of growth hormone deficiency (GHD) in children and adolescents from 3 years of age.[3] The applicant for this medicinal product is Pfizer Europe MA EEIG.[3]

Somatrogon was approved for medical use in Australia in November 2021.[1]

References

  1. Jump up to:a b c d “Ngenla”Therapeutic Goods Administration (TGA). 13 December 2021. Retrieved 28 December 2021.
  2. Jump up to:a b “Pfizer and OPKO Announce Extension of U.S. FDA Review of Biologics License Application of Somatrogon for Pediatric Growth Hormone Deficiency” (Press release). Opko Health. 24 September 2021. Retrieved 18 December 2021 – via GlobeNewswire.
  3. Jump up to:a b “Ngenla: Pending EC decision”European Medicines Agency (EMA). 16 December 2021. Retrieved 18 December 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Further reading

///////////Somatrogon, NGENLA, APPROVALS 2022, JAPAN 2022, ソマトロゴン , MOD-4023, Modigene, OPKO Health,  Pfizer

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