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ORGANIC SPECTROSCOPY

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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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Difamilast


img

Difamilast (JAN/USAN).png

2D chemical structure of 937782-05-3

Difamilast

PMDA Moizerto, JAPAN APPROVED 2021/9/27

ジファミラスト

ディファミラスト;

地法米司特

N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3- oxazol-4-yl}methyl)-2-ethoxybenzamide

OPA-15406

Formula
C23H24F2N2O5
CAS
937782-05-3
Mol weight
446.4439

MM 36; MM-36-Medimetriks-Pharmaceuticals; Moizerto; OPA-15406

Efficacy
Anti-inflammatory, Phosphodiesterase IV inhibitor
Comment
Treatment of atopic dermatitis

  • Originator
    Otsuka Pharmaceutical Development & Commercialization
  • DeveloperMedimetriks Pharmaceuticals; Otsuka Pharmaceutical Development & Commercialization
  • ClassBenzamides; Nonsteroidal anti-inflammatories; Oxazoles; Skin disorder therapies
  • Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
  • RegisteredAtopic dermatitis
  • 27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
  • 11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
  • 28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)

Fig. 1

Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).

PATENT

JP 2021059538

https://patentscope.wipo.int/search/en/detail.jsf?docId=JP322244172&_cid=P20-L1WXG6-04592-1

Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.

patcit 1 : International Publication No. 2007/058338 (Japanese Publication No. 2009-515872 )
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780

[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).

[0060]
化合物(5)データ
N−({2−[4−(difluoromethoxy)−3−isopropoxyphenyl]oxazol−4−yl}methyl)−2−ethoxybenzamide
: white powder.
H NMR (400 MHz, CDCl3): δ = 8.56 (br s,
1H, NH), 8.23 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.63 (d, J = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 8.4 Hz, 2.0 Hz, 1H, ArH), 7.44−7.39 (m, 1H, ArH), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.08−7.04 (m, 1H, ArH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.61 (t, J = 75.2 Hz, 1H, CHF ), 4.68 (sept, J = 6.0 Hz, 1H, CH), 4.62
(d, J = 6.0 Hz, 2H, CH ), 4.17 (q, J = 6.93, 2H, CH ), 1.48 (t, J = 7.2 Hz, 3H,
CH ), 1.39 (d, J = 5.6 Hz, 6H, 2CH ).
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).

[0072]
[Chem. 6]

[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).

[0074]
[Chem. 7]

[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).

[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017115780

Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0146]
[Chem. 11]

[0147]
10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 ml of N,N-dimethylformamide and 6 ml of water, and the mixture was stirred until exotherm subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was added thereto, and the mixture was reacted at 95 to 110°C for 3 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the solution was partitioned. 80 ml of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of 20°C or below, followed by pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder.

[0148]

1H-NMR (CDCl 3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).

Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.

[0149]
[Chem. 12]

[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.

[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.

[0152]
[Chem. 13]
Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.

[0160]
[Chem. 14]

[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.

[0162]
1H-NMR (DMSO-d 6) δ: 8.22 (1H,s),7.94-7.86 (4H,m),7.58 (1H,d,J = 2.0 Hz),7.52 (1H,dd,J = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 Hz),7.14 (1H,t,J = 74.2 Hz),4.78-4.69 (3H,m),1.30 (6H,d,J = 6.0 Hz).

[0163]
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.

[0164]
1H-NMR (DMSO-d 6) δ: 8.51 (3H,br-s),8.29 (1H,s),7.64 (1H,d,J = 2 Hz),7.59 (1H,dd,J = 8.0 Hz,1.6 Hz),7.37 (1H,d,J = 8.4 Hz),7.18 (1H,t,J = 74.0 Hz),4.72 (1H,sept,J = 6.1 Hz),4.03 (2H,s),1.33 (6H,d,J = 6.4 Hz).

[0165]
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.

[0166]
1H-NMR (CDCl 3) δ: 8.56 (1H,br-s),8.23 (1H,dd,J = 7.6 Hz,1.6 Hz),7.66 (1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 (1H,dd,J = 8.4 Hz,2.0 Hz),7.44-7.39 (1H,m),7.21 (1H,d,J = 8.0 Hz),7.08-7.04 (1H,mH),6.94 (1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.68 (1H,sept,J = 6.0 Hz),4.62 (2H,d,J = 6.0 Hz),4.17 (2H,q,J = 6.93),1.48 (3H,t,J = 7.2 Hz),1.39 (6H,d,J = 5.6 Hz).

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211


*DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether,
DMF: N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid,
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).

[0072]

[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).

[0074]

[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.

[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).

PATENT

WO2014034958A1

WO2007058338A2

WO2007058338A9

WO2007058338A3

US9181205B2

US2015239855A1

USRE46792E

US2020078340A1

US2017216260A1

US2019070151A1

US2009221586A1

US8637559B2

US2014100226A1

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/////////////Difamilast, JAPAN 2021, APPROVALS 2021, ジファミラスト ,  MM 36,  MM-36-Medimetriks-Pharmaceuticals,  Moizerto, OPA-15406, OPA 15406, 地法米司特

O=C(NCC1=COC(C2=CC=C(OC(F)F)C(OC(C)C)=C2)=N1)C3=CC=CC=C3OCC

INTrmediate No.CAS No.DIFAM-001177429-27-5DIFAM-00293652-48-3DIFAM-0031574285-26-9DIFAM-00470-23-5DIFAM-0051574285-28-1DIFAM-0061574285-30-5DIFAM-0071574285-32-7DIFAM-0081574285-36-1DIFAM-0091574285-38-3DIFAM-010DIFAM-0111574285-40-7DIFAM-0121574285-43-0DIFAM-013134-11-2Difamilast937782-05-3

Tixagevimab


(Heavy chain)
QMQLVQSGPE VKKPGTSVKV SCKASGFTFM SSAVQWVRQA RGQRLEWIGW IVIGSGNTNY
AQKFQERVTI TRDMSTSTAY MELSSLRSED TAVYYCAAPY CSSISCNDGF DIWGQGTMVT
VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL
QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEF
EGGPSVFLFP PKPKDTLYIT REPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPASIEK TISKAKGQPR EPQVYTLPPS
REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK
SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK
(Light chain)
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP
DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ HYGSSRGWTF GQGTKVEIKR TVAAPSVFIF
PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST
LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC
(Disulfide bridge: H22-H96, H101-H106, H150-H206, H216-L216, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’101-H’106, H’150-H’206, H’226-L’216, H’267-H’327, H’373-H’431, L23-L89, L136-L196, L’23-L’89, L’136-L’196)

Tixagevimab

FDA 2021, 2021/12/8

ANTI VIRAL, CORONA VIRUS, PEPTIDE

Monoclonal antibody
Treatment and prevention of SARS-CoV-2 infection

FormulaC6488H10034N1746O2038S50
CAS2420564-02-7
Mol weight146704.817
  • 2196
  • AZD-8895
  • AZD8895
  • COV2-2196
  • Tixagevimab
  • Tixagevimab [INN]
  • UNII-F0LZ415Z3B
  • WHO 11776
  • OriginatorVanderbilt University
  • DeveloperAstraZeneca; INSERM; National Institute of Allergy and Infectious Diseases
  • ClassAntivirals; Monoclonal antibodies
  • Mechanism of ActionVirus internalisation inhibitors
  • RegisteredCOVID 2019 infections
  • 24 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 16 Dec 2021Pharmacodynamics data from a preclinical trial in COVID-2019 infections released by AstraZeneca
  • 10 Dec 2021Registered for COVID-2019 infections (In the elderly, Prevention, In adults) in USA (IM) – Emergency Use Authorization

Tixagevimab/cilgavimab is a combination of two human monoclonal antibodiestixagevimab (AZD8895) and cilgavimab (AZD1061) targeted against the surface spike protein of SARS-CoV-2[4][5] used to prevent COVID-19. It is being developed by British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca.[6][7] It is co-packaged and given as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession).[2]

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Development

In 2020, researchers at Vanderbilt University Medical Center discovered particularly potent monoclonal antibodies, isolated from COVID-19 patients infected with a SARS-CoV-2 circulating at that time. Initially designated COV2-2196 and COV2-2130, antibody engineering was used to transfer their SARS-CoV-2 binding specificity to IgG scaffolds that would last longer in the body, and these engineered antibodies were named AZD8895 and AZD1061, respectively (and the combination was called AZD7442).[8]

To evaluate the antibodies’ potential as monoclonal antibody based prophylaxis (prevention), the ‘Provent’ clinical trial enrolled 5,000 high risk but not yet infected individuals and monitored them for 15 months.[9][10] The trial reported that those receiving the cocktail showed a 77% reduction in symptomatic COVID-19 and that there were no severe cases or deaths. AstraZeneca also found that the antibody cocktail “neutralizes recent emergent SARS-CoV-2 viral variants, including the Delta variant“.[7]

In contrast to pre-exposure prophylaxis, the Storm Chaser study of already-exposed people (post-exposure prophylaxis) did not meet its primary endpoint, which was prevention of symptomatic COVID-19 in people already exposed. AZD7442 was administered to 1,000 volunteers who had recently been exposed to COVID.[9]

Regulatory review

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of tixagevimab/cilgavimab, which is being developed by AstraZeneca AB, for the prevention of COVID-19 in adults.[11]

Also in October 2021, AstraZeneca requested Emergency Use Authorization for tixagevimab/cilgavimab to prevent COVID-19 from the U.S. Food and Drug Administration (FDA).[12][13]

Emergency use authorization

On 14 November 2021, Bahrain granted emergency use authorization.[14]

On 8 December 2021, the U.S. Food and Drug Administration (FDA) granted emergency use authorization of this combination to prevent COVID-19 (before exposure) in people with weakened immunity or who cannot be fully vaccinated due to a history of severe reaction to coronavirus vaccines.[15] The FDA issued an emergency use authorization (EUA) for AstraZeneca’s Evusheld (tixagevimab co-packaged with cilgavimab and administered together) for the pre-exposure prophylaxis (prevention) of COVID-19 in certain people aged 12 years of age and older weighing at least 40 kilograms (88 lb).[2] The product is only authorized for those individuals who are not currently infected with the SARS-CoV-2 virus and who have not recently been exposed to an individual infected with SARS-CoV-2.[2]

References

  1. ^ “Evusheld- azd7442 kit”DailyMed. Retrieved 4 January 2022.
  2. Jump up to:a b c d “Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals”U.S. Food and Drug Administration (FDA) (Press release). 8 December 2021. Retrieved 9 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ O’Shaughnessy, Jacqueline A. (20 December 2021). “Re: Emergency Use Authorization 104” (PDF). Food and Drug Administration. Letter to AstraZeneca Pharmaceuticals LP | Attention: Stacey Cromer Berman, PhD. Archived from the original on 29 December 2021. Retrieved 18 January 2022.
  4. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  5. ^ “IUPHAR/BPS Guide to PHARMACOLOGY”IUPHAR. 27 December 2021. Retrieved 27 December 2021.
  6. ^ Ray, Siladitya (21 August 2021). “AstraZeneca’s Covid-19 Antibody Therapy Effective In Preventing Symptoms Among High-Risk Groups, Trial Finds”ForbesISSN 0015-6914Archived from the original on 21 August 2021. Retrieved 18 January 2022.
  7. Jump up to:a b Goriainoff, Anthony O. (20 August 2021). “AstraZeneca Says AZD7442 Antibody Phase 3 Trial Met Primary Endpoint in Preventing Covid-19”MarketWatchArchived from the original on 21 August 2021. Retrieved 18 January 2022.
  8. ^ Dong J, Zost SJ, Greaney AJ, Starr TN, Dingens AS, Chen EC, et al. (October 2021). “Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail”. Nature Microbiology6 (10): 1233–1244. doi:10.1038/s41564-021-00972-2ISSN 2058-5276PMC 8543371. PMID 34548634.
  9. Jump up to:a b Haridy, Rich (23 August 2021). “”Game-changing” antibody cocktail prevents COVID-19 in the chronically ill”New Atlas. Retrieved 23 August 2021.
  10. ^ “AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19”AstraZeneca (Press release). 20 August 2021. Retrieved 15 October 2021.
  11. ^ “EMA starts rolling review of Evusheld (tixagevimab and cilgavimab)”European Medicines Agency. 14 October 2021. Retrieved 15 October 2021.
  12. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca US (Press release). 5 October 2021. Retrieved 15 October 2021.
  13. ^ “AZD7442 request for Emergency Use Authorization for COVID-19 prophylaxis filed in US”AstraZeneca (Press release). 5 October 2021. Retrieved 15 October 2021.
  14. ^ Abd-Alaziz, Moaz; Elhamy, Ahmad (14 November 2021). Macfie, Nick (ed.). “Bahrain authorizes AstraZeneca’s anti-COVID drug for emergency use”ReutersArchived from the original on 23 November 2021. Retrieved 18 January 2022.
  15. ^ Mishra, Manas; Satija, Bhanvi (8 December 2021). Dasgupta, Shounak (ed.). “U.S. FDA authorizes use of AstraZeneca COVID-19 antibody cocktail”ReutersArchived from the original on 13 January 2022. Retrieved 18 January 2022.

“Tixagevimab”Drug Information Portal. U.S. National Library of Medicine.

  • “Cilgavimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT04625972 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)” at ClinicalTrials.gov
  • Clinical trial number NCT04625725 for “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult. (PROVENT)” at ClinicalTrials.gov
Tixagevimab (teal, right) and cilgavimab (purple, left) binding the spike protein RBD. From PDB7L7E.
Combination of
TixagevimabMonoclonal antibody
CilgavimabMonoclonal antibody
Clinical data
Trade namesEvusheld
Other namesAZD7442
License dataUS DailyMedTixagevimab
Routes of
administration
Intramuscular
ATC codeJ06BD03 (WHO)
Legal status
Legal statusUS: ℞-only via emergency use authorization[1][2][3]
Identifiers
KEGGD12262
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420564-02-7
DrugBankDB16394
UNIIF0LZ415Z3B
KEGGD11993
Chemical and physical data
FormulaC6488H10034N1746O2038S50
Molar mass146706.82 g·mol−1
Clinical data
Drug classAntiviral
ATC codeNone
Identifiers
CAS Number2420563-99-9
DrugBankDB16393
UNII1KUR4BN70F
KEGGD11994
Chemical and physical data
FormulaC6626H10218N1750O2078S44
Molar mass149053.44 g·mol−1

/////////////////Tixagevimab, ANTI VIRAL, CORONA VIRUS, PEPTIDE, Monoclonal antibody,  SARS-CoV-2 , WHO 11776, 2196, AZD-8895, AZD 8895, COV2-2196, COVID 19

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Tezepelumab-ekko


Structural basis for inhibition of TSLP-signaling by Tezepelumab.png

(Heavy chain)
QMQLVESGGG VVQPGRSLRL SCAASGFTFR TYGMHWVRQA PGKGLEWVAV IWYDGSNKHY
ADSVKGRFTI TRDNSKNTLN LQMNSLRAED TAVYYCARAP QWELVHEAFD IWGQGTMVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS
VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVQFNWYV DGVEVHNAKT KPREEQFNST
FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP APIEKTISKT KGQPREPQVY TLPPSREEMT
KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD SDGSFFLYSK LTVDKSRWQQ
GNVFSCSVMH EALHNHYTQK SLSLSPGK
(Light chain)
SYVLTQPPSV SVAPGQTARI TCGGNNLGSK SVHWYQQKPG QAPVLVVYDD SDRPSWIPER
FSGSNSGNTA TLTISRGEAG DEADYYCQVW DSSSDHVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H136-L213, H149-H205, H224-H’224, H225-H’225, H228-H’228, H231-H’231, H262-H322, H368-H426, H’22-H’96, H’136-L’213, H’149-H’205, H’262-H’322, H’368-H’426, L22-L87, L136-L195, L’22-L’87, L’136-L’195)

Tezepelumab-ekko

テゼペルマブ (遺伝子組換え)

FormulaC6400H9844N1732O1992S52
CAS1572943-04-4
Mol weight144588.4306

PEPTIDE

UD FDA APPROVED, 12/17/2021, To treat severe asthma as an add-on maintenance therapy , Tezspire

Monoclonal antibody
Treatment of asthma and atopic dermatitis

Tezepelumab, sold under the brand name Tezspire, is a human monoclonal antibody used for the treatment of asthma.[4][5]

It blocks thymic stromal lymphopoietin (TSLP),[2] an epithelial cytokine that has been suggested to be critical in the initiation and persistence of airway inflammation.[6]

It was approved for medical use in the United States in December 2021.[2][3]

Medical uses

Tezepelumab is indicated for the add-on maintenance treatment of people aged twelve years and older with severe asthma.[2]

Research

In Phase III trials, tezepelumab demonstrated efficacy compared to placebo for patients with severe, uncontrolled asthma.[7][8]

Structural studies by X-ray crystallography showed that Tezepelumab competes against a critical part of the TSLPR binding site on TSLP.[1]

It is being studied for the treatment of chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria and eosinophilic esophagitis (EoE).[3]

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TEZSPIRE (tezepelumab) Approved in the US for Severe Asthma | Business Wire

References

  1. Jump up to:a b Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. (April 2017). “Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma”Nature Communications8 (1): 14937. Bibcode:2017NatCo…814937Vdoi:10.1038/ncomms14937PMC 5382266PMID 28368013.
  2. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761224s000lbl.pdf
  3. Jump up to:a b c “Tezspire (tezepelumab) approved in the US for severe asthma”AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
  4. ^ Marone G, Spadaro G, Braile M, Poto R, Criscuolo G, Pahima H, et al. (November 2019). “Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma”. Expert Opinion on Investigational Drugs28 (11): 931–940. doi:10.1080/13543784.2019.1672657PMID 31549891S2CID 202746054.
  5. ^ Matera MG, Rogliani P, Calzetta L, Cazzola M (February 2020). “TSLP Inhibitors for Asthma: Current Status and Future Prospects”. Drugs80 (5): 449–458. doi:10.1007/s40265-020-01273-4PMID 32078149S2CID 211194472.
  6. ^ “Tezepelumab granted Breakthrough Therapy Designation by US FDA”AstraZeneca (Press release). 7 September 2018.
  7. ^ “Studies found for: Tezepelumab”ClinicalTrials.Gov. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services.
  8. ^ Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, et al. (May 2021). “Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma”. New England Journal of Medicine384 (19): 1800–09. doi:10.1056/NEJMoa2034975PMID 33979488S2CID 234484931.
  • “Tezepelumab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02054130 for “Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma” at ClinicalTrials.gov
  • Clinical trial number NCT03347279 for “Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma (NAVIGATOR)” at ClinicalTrials.gov
Structural basis for inhibition of TSLP-signaling by Tezepelumab (PDB 5J13)[1]
Monoclonal antibody
TypeWhole antibody
SourceHuman
Targetthymic stromal lymphopoietin (TSLP)
Clinical data
Trade namesTezspire
Other namesMEDI9929, AMG 157, tezepelumab-ekko
License dataUS DailyMedTezepelumab
Routes of
administration
Subcutaneous
ATC codeNone
Legal status
Legal statusUS: ℞-only [2][3]
Identifiers
CAS Number1572943-04-4
DrugBankDB15090
ChemSpiderNone
UNIIRJ1IW3B4QX
KEGGD11771
Chemical and physical data
FormulaC6400H9844N1732O1992S52
Molar mass144590.40 g·mol−1

////////////Tezepelumab-ekko, Tezspire, PEPTIDE, APPROVALS 2021, FDA 2021, Monoclonal antibody
, asthma, atopic dermatitis, ANTI INFLAMATORY, テゼペルマブ (遺伝子組換え)

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Efgartigimod alfa-fcab


DKTHTCPPCP APELLGGPSV FLFPPKPKDT LYITREPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK
GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS
DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALKFHYTQKS LSLSPGK
(Disulfide bridge: 6-6′, 9-9′, 41-101, 147-205, 41′-101′, 147′-205′)

Efgartigimod alfa-fcab

FormulaC2310H3554N602O692S14
CAS1821402-21-4
Mol weight51279.464

US FDA APPROVED 12/17/2021, To treat generalized myasthenia gravis
Press ReleaseVyvgart BLA 761195

エフガルチギモドアルファ (遺伝子組換え)

PEPTIDE

Treatment of IgG-driven autoimmune diseases

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AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

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https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis

FDA Approves New Treatment for Myasthenia Gravis

Approval is the First of a New Class of Medication for this Rare, Chronic, Autoimmune, Neuromuscular DiseaseFor Immediate Release:December 17, 2021

The U.S. Food and Drug Administration today approved Vyvgart (efgartigimod) for the treatment of generalized myasthenia gravis (gMG) in adults who test positive for the anti-acetylcholine receptor (AChR) antibody.

Myasthenia gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles (also called voluntary muscles) that worsens after periods of activity and improves after periods of rest. Myasthenia gravis affects voluntary muscles, especially those that are responsible for controlling the eyes, face, mouth, throat, and limbs. In myasthenia gravis, the immune system produces AChR antibodies that interfere with communication between nerves and muscles, resulting in weakness. Severe attacks of weakness can cause breathing and swallowing problems that can be life-threatening.

“There are significant unmet medical needs for people living with myasthenia gravis, as with many other rare diseases,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is an important step in providing a novel therapy option for patients and underscores the agency’s commitment to help make new treatment options available for people living with rare diseases.”

Vyvgart is the first approval of a new class of medication. It is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing FcRn from recycling immunoglobulin G (IgG) back into the blood. The medication causes a reduction in overall levels of IgG, including the abnormal AChR antibodies that are present in myasthenia gravis.

The safety and efficacy of Vyvgart were evaluated in a 26-week clinical study of 167 patients with myasthenia gravis who were randomized to receive either Vyvgart or placebo. The study showed that more patients with myasthenia gravis with antibodies responded to treatment during the first cycle of Vyvgart (68%) compared to those who received placebo (30%) on a measure that assesses the impact of myasthenia gravis on daily function. More patients receiving Vyvgart also demonstrated response on a measure of muscle weakness compared to placebo.

The most common side effects associated with the use of Vyvgart include respiratory tract infections, headache, and urinary tract infections. As Vyvgart causes a reduction in IgG levels, the risk of infections may increase. Hypersensitivity reactions such as eyelid swelling, shortness of breath, and rash have occurred. If a hypersensitivity reaction occurs, discontinue the infusion and institute appropriate therapy. Patients using Vyvgart should monitor for signs and symptoms of infections during treatment. Health care professionals should administer appropriate treatment and consider delaying administration of Vyvgart to patients with an active infection until the infection is resolved.

The FDA granted this application Fast Track and Orphan Drug designations. The FDA granted the approval of Vyvgart to argenx BV.

///////////efgartigimod alfa-fcab, Vyvgart, FDA 2021,APPROVALS 2021, myasthenia gravis, argenx BV, Fast Track,  Orphan Drug, PEPTIDE,

エフガルチギモドアルファ (遺伝子組換え)
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Regdanvimab


Best Monoclonal Antibodies GIFs | Gfycat
Celltrion plans to expand the supply of its Covid-19 antibody drug, Regkirona (ingredient: regdanvimab), to more medical facilities treating early-stage patients.
(Heavy chain)
QITLKESGPT LVKPTQTLTL TCSFSGFSLS TSGVGVGWIR QPPGKALEWL ALIDWDDNKY
HTTSLKTRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI PGFLRYRNRY YYYGMDVWGQ
GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT
FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT
KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK
LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK
(Light chain)
ELVLTQPPSV SAAPGQKVTI SCSGSSSNIG NNYVSWYQQL PGTAPKLLIY DNNKRPSGIP
DRFSGSKSGT SATLGITGLQ TGDEADYYCG TWDSSLSAGV FGGGTELTVL GQPKAAPSVT
LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK AGVETTKPSK QSNNKYAASS
YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS
(Disulfide bridge: H22-H97, H155-H211, H231-L215, H237-H’237, H240-H’240, H272-H332, H378-H436, H’22-H’97, H’155-H’211, H’231-L’215, H’272-H’332, H’378-H’436, L22-L89, L138-L197, L’22-L’89, L’138-L’197)
>Regdanvimab light chain:
ELVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIP
DRFSGSKSGTSATLGITGLQTGDEADYYCGTWDSSLSAGVFGGGTELTVLGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS
YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
>Regdanvimab heavy chain:
QITLKESGPTLVKPTQTLTLTCSFSGFSLSTSGVGVGWIRQPPGKALEWLALIDWDDNKY
HTTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIPGFLRYRNRYYYYGMDVWGQ
GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT
FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT
KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Regdanvimab

レグダンビマブ;

EMA APPROVED, 2021/11/12, Regkirona

Treatment of adults with coronavirus disease 2019 (COVID-19)

MONOCLONAL ANTIBODY, ANTI VIRAL, PEPTIDE

CAS: 2444308-95-4, CT-P59

Regdanvimab, sold under the brand name Regkirona, is a human monoclonal antibody used for the treatment of COVID-19.[1] The antibody is directed against the spike protein of SARS-CoV-2. It is developed by Celltrion.[2][3] The medicine is given by infusion (drip) into a vein.[1][4]

The most common side effects include infusion-related reactions, including allergic reactions and anaphylaxis.[1]

Regdanvimab was approved for medical use in the European Union in November 2021.[1]

Regdanvimab is a monoclonal antibody targeted against the SARS-CoV-2 spike protein used to treat patients with COVID-19 who are at risk of progressing to severe COVID-19.

Regdanvimab (CT-P59) is a recombinant human IgG1 monoclonal antibody directed at the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.4 It blocks the interaction between viral spike proteins and angiotensin-converting enzyme 2 (ACE2) that allows for viral entry into the cell, thereby inhibiting the virus’ ability to replicate. Trials investigating the use of regdanvimab as a therapeutic candidate for the treatment of COVID-19 began in mid-2020.1,3 It received its first full approval in South Korea in September 2021,3 followed by the EU in November 2021.5

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Synthesis Reference

Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, Jeong JH, Kim M, Kim JI, Kim P, Bae JS, Shim EY, Lee MS, Kim MS, Noh H, Park GS, Park JS, Son D, An Y, Lee JN, Kwon KS, Lee JY, Lee H, Yang JS, Kim KC, Kim SS, Woo HM, Kim JW, Park MS, Yu KM, Kim SM, Kim EH, Park SJ, Jeong ST, Yu CH, Song Y, Gu SH, Oh H, Koo BS, Hong JJ, Ryu CM, Park WB, Oh MD, Choi YK, Lee SY: A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun. 2021 Jan 12;12(1):288. doi: 10.1038/s41467-020-20602-5.

Celltrion’s Monoclonal Antibody Treatment regdanvimab, Approved by the European Commission for the Treatment of COVID-19

https://www.businesswire.com/news/home/20211114005312/en/Celltrion%E2%80%99s-Monoclonal-Antibody-Treatment-regdanvimab-Approved-by-the-European-Commission-for-the-Treatment-of-COVID-19

  • The European Commission (EC) granted marketing authorisation for Celltrion’s regdanvimab following positive opinion by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) last week (11/11/2021)
  • Celltrion continues to discuss supply agreements with regulatory agencies and contractors in more than 30 countries in Europe, Asia and LATAM to accelerate global access to regdanvimab
  • The use of regdanvimab across the Republic of Korea is rapidly increasing to address the ongoing outbreaks

November 14, 2021 08:04 PM Eastern Standard Time

INCHEON, South Korea–(BUSINESS WIRE)–Celltrion Group announced today that the European Commission (EC) has approved Regkirona (regdanvimab, CT-P59), one of the first monoclonal antibody treatments granted marketing authorisation from the European Medicines Agency (EMA). The EC granted marketing authorisation for adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19. The decision from the EC follows a positive opinion by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on November 11th, 2021.1

“Today’s achievement, coupled with CHMP positive opinion for regdanvimab, underscores our ongoing commitment to addressing the world’s greatest health challenges,” said Dr. HoUng Kim, Ph.D., Head of Medical and Marketing Division at Celltrion Healthcare. “Typically, the recommendations from the CHMP are passed on to the EC for rapid legally binding decisions within a month or two, however, given the unprecedented times, we have received the EC approval within a day. As part of our global efforts to accelerate access, we have been communicating with the governments and contractors in 30 countries in Europe, Asia and LATAM. We will continue working with all key stakeholders to ensure COVID-19 patients around the world have access to safe and effective treatments.”

Monoclonal antibodies are proteins designed to attach to a specific target, in this case the spike protein of SARS-CoV-2, which works to block the path the virus uses to enter human cells. The EC approval is based on the global Phase III clinical trial involving more than 1,315 people to evaluate the efficacy and safety of regdanvimab in 13 countries including the U.S., Spain, and Romania. Data showed regdanvimab significantly reduced the risk of COVID-19 related hospitalisation or death by 72% for patients at high-risk of progressing to severe COVID-19.

Emergency use authorisations are currently in place in Indonesia and Brazil, and the monoclonal antibody treatment is fully approved in the Republic of Korea. In the U.S., regdanvimab has not yet been approved by the Food and Drug Administration (FDA), but the company is in discussion with the FDA to submit applications for an Emergency Use Authorisation (EUA).

As of November 12th, 2021, more than 22,587 people have been treated with regdanvimab in 129 hospitals in the Republic of Korea.

Notes to Editors:

About Celltrion Healthcare

Celltrion Healthcare is committed to delivering innovative and affordable medications to promote patients’ access to advanced therapies. Its products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US FDA cGMP and the EU GMP guidelines. Celltrion Healthcare endeavours to offer high-quality cost-effective solutions through an extensive global network that spans more than 110 different countries. For more information please visit: https://www.celltrionhealthcare.com/en-us.

About regdanvimab (CT-P59)

CT-P59 was identified as a potential treatment for COVID-19 through screening of antibody candidates and selecting those that showed the highest potency in neutralising the SARS-CoV-2 virus. In vitro and in vivo pre- clinical studies showed that CT-P59 strongly binds to SARS-CoV-2 RBD and significantly neutralise the wild type and mutant variants of concern. In in vivo models, CT-P59 effectively reduced the viral load of SARS-CoV-2 and inflammation in lung. Results from the global Phase I and Phase II/III clinical trials of CT-P59 demonstrated a promising safety, tolerability, antiviral effect and efficacy profile in patients with mild-to-moderate symptoms of COVID-19.2 Celltrion also has recently commenced the development of a neutralising antibody cocktail with CT-P59 against new emerging variants of SARS-CoV-2.

Medical uses

In the European Union, regdanvimab is indicated for the treatment of adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19.[1]

Society and culture

Names

Regdanvimab is the proposed international nonproprietary name (pINN).[5]

In March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on regdanvimab.[6][7] In October 2021, the EMA started evaluating an application for marketing authorization for the monoclonal antibody regdanvimab (Regkirona) to treat adults with COVID-19 who do not require supplemental oxygen therapy and who are at increased risk of progressing to severe COVID 19.[8] The applicant is Celltrion Healthcare Hungary Kft.[8] The European Medicines Agency (EMA) concluded that regdanvimab can be used for the treatment of confirmed COVID-19 in adults who do not require supplemental oxygen therapy and who are at high risk of progressing to severe COVID-19.[4]

In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a marketing authorization in the European Union for regdanvimab (Regkirona) for the treatment of COVID-19.[9][10] The company that applied for authorization of Regkirona is Celltrion Healthcare Hungary Kft.[10] Regdanvimab was approved for medical use in the European Union in November 2021.[1]

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetSpike protein of SARS-CoV-2
Clinical data
Trade namesRegkirona
Other namesCT-P59
License dataEU EMAby INN
Routes of
administration
Intravenous infusion
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number2444308-95-4
DrugBankDB16405
UNIII0BGE6P6I6
KEGGD12241
  1. Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, Maggi F, Focosi D: Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. 2020 Jan-Dec;12(1):1854149. doi: 10.1080/19420862.2020.1854149. [Article]
  2. Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, Jeong JH, Kim M, Kim JI, Kim P, Bae JS, Shim EY, Lee MS, Kim MS, Noh H, Park GS, Park JS, Son D, An Y, Lee JN, Kwon KS, Lee JY, Lee H, Yang JS, Kim KC, Kim SS, Woo HM, Kim JW, Park MS, Yu KM, Kim SM, Kim EH, Park SJ, Jeong ST, Yu CH, Song Y, Gu SH, Oh H, Koo BS, Hong JJ, Ryu CM, Park WB, Oh MD, Choi YK, Lee SY: A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun. 2021 Jan 12;12(1):288. doi: 10.1038/s41467-020-20602-5. [Article]
  3. Syed YY: Regdanvimab: First Approval. Drugs. 2021 Nov 1. pii: 10.1007/s40265-021-01626-7. doi: 10.1007/s40265-021-01626-7. [Article]
  4. EMA Summary of Product Characteristics: Regkirona (regdanvimab) concentrate for solution for intravenous infusion [Link]
  5. EMA COVID-19 News: EMA recommends authorisation of two monoclonal antibody medicines [Link]
  6. EMA CHMP Assessment Report: Celltrion use of regdanvimab for the treatment of COVID-19 [Link]
  7. Protein Data Bank: Crystal Structure of COVID-19 virus spike receptor-binding domain complexed with a neutralizing antibody CT-P59 [Link]

References

  1. Jump up to:a b c d e f g “Regkirona EPAR”European Medicines Agency. Retrieved 12 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ^ “Celltrion Develops Tailored Neutralising Antibody Cocktail Treatment with CT-P59 to Tackle COVID-19 Variant Spread Using Its Antibody Development Platform” (Press release). Celltrion. 11 February 2021. Retrieved 4 March 2021 – via Business Wire.
  3. ^ “Celltrion Group announces positive top-line efficacy and safety data from global Phase II/III clinical trial of COVID-19 treatment candidate CT-P59” (Press release). Celltrion. 13 January 2021. Retrieved 4 March 2021 – via Business Wire.
  4. Jump up to:a b “EMA issues advice on use of regdanvimab for treating COVID-19”European Medicines Agency. 26 March 2021. Retrieved 15 October 2021.
  5. ^ World Health Organization (2020). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 124 – COVID-19 (special edition)” (PDF). WHO Drug Information34 (3): 660–1.
  6. ^ “EMA starts rolling review of Celltrion antibody regdanvimab for COVID-19” (Press release). European Medicines Agency (EMA). 24 February 2021. Retrieved 4 March 2021.
  7. ^ “EMA review of regdanvimab for COVID-19 to support national decisions on early use” (Press release). European Medicines Agency (EMA). 2 March 2021. Retrieved 4 March 2021.
  8. Jump up to:a b “EMA receives application for marketing authorisation Regkirona (regdanvimab) treating patients with COVID-19”European Medicines Agency. 4 October 2021. Retrieved 15 October 2021.
  9. ^ “Regkirona: Pending EC decision”European Medicines Agency. 11 November 2021. Retrieved 11 November 2021.
  10. Jump up to:a b “COVID-19: EMA recommends authorisation of two monoclonal antibody medicines”European Medicines Agency (EMA) (Press release). 11 November 2021. Retrieved 11 November 2021.

Further reading

///////////Regdanvimab, Regkirona, MONOCLONAL ANTIBODY, ANTI VIRAL, EU 2021, APPROVALS 2021, EMA 2021, COVID 19, CORONAVIRUS, PEPTIDE, レグダンビマブ , CT-P59, CT P59

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Diroximel fumarate


Diroximel fumarate (USAN/INN).png

Diroximel fumarate.png

ChemSpider 2D Image | Diroxamel fumarate | C11H13NO6

Diroximel fumarate

ジロキシメルフマル酸エステル;

Formula
C11H13NO6
CAS  1577222-14-0
Mol weight
255.224

2021/11/15 EMA APPROVED, VUMERITY

Treatment of multiple sclerosis

10356
 
1577222-14-0 [RN]
 
2-(2,5-Dioxo-1-pyrrolidinyl)ethyl methyl (2E)-2-butenedioate
 
K0N0Z40J3W
 
RDC-5108
 
дироксимела фумарат [Russian] [INN]
ديروكسيميل فومارات [Arabic] [INN]
富马地罗昔美 [Chinese] [INN]

Diroximel fumarate, sold under the brand name Vumerity, is a medication used for the treatment of relapsing forms of multiple sclerosis (MS).[1][3][4]

Diroximel fumarate was approved for medical use in the United States in October 2019,[5] and in the European Union in November 2021.[2]

History

This drug was formulated by Alkermes in collaboration with Biogen.[6]

Society and culture

Legal status

Diroximel fumarate was approved for medical use in the United States in October 2019.[5]

On 16 September 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 Vumerity, intended for the treatment of adults with relapsing remitting multiple sclerosis.[7] The applicant for this medicinal product is Biogen Netherlands B.V.[7] It was approved for medical use in the European Union in November 2021.[2]

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PATENT

US 8669281

https://patents.google.com/patent/US8669281B1/en

PATENT

WO 2014152494

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152494

2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (14)

2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate 14 was synthesized following general procedure 1 (1.03 g, 35 %).

1H NMR (400 MHz, DMSO): δ 6.81 (2H, dd, J = 15.8 Hz); 4.36 (2H, t, J = 5.3 Hz); 3.84 (2H, t, J = 5.1 Hz); 3.80 (3H, s); 2.73 (4H, s). [M+H]+ = 256.07.

General Procedure 1

To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in DMF (25 ml per g of MMF) was added Hünigs base (2.0 equivalents). The dark brown solution was stirred for 10 minutes, where turned into a brown suspension, before addition of the alcohol (1.0 – 1.5 equivalents). The reaction was stirred for 18 hours at room temperature. Water was added and the product extracted into ethyl acetate three times. The combined organic layers were washed with water three times, dried with magnesium sulphate, filtered and concentrated in vacuo at 45 ºC to give the crude product. The crude product was purified by silica chromatography and in some cases further purified by trituration with diethyl ether to give the clean desired ester product. All alcohols were either commercially available or made following known literature procedures.

As an alternative to HBTU (N,N,N’,N’-Tetramethyl-O-(1H-benzotriazol-1 -yl)uronium hexafluorophosphate), any one of the following coupling reagents can be used: EDCI/HOBt (N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride/hydroxybenzotriazole hydrate); COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate); TBTU (O-(benzotriazol-1 -yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate); TATU (O-(7-azabenzotriazole-1-yl)-1,1 ,3,3-tetramethyluronium tetrafluoroborate); Oxyma (ethyl (hydroxyimino)cyanoacetate); PyBOP ((benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate); HOTT (5-(1-oxido-2-pyridyl)-N,N,N’,N’-tetramethylthiuronium hexafluorophosphate); FDPP (pentafluorophenyl diphenylphosphinate); T3P (propylphosphonic anhydride); DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-y1)-4-methylmorpholinium tetrafluoroborate); PyOxim ([ethyl

cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate); TSTU (N,N,N’,N’-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate); TDBTU (O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate); TPTU (O-(2-oxo-1(2H)pyridyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate); TOTU (O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N’,N’-tetramethyluronium tetrafluoroborate); IIDQ (isobutyl 1,2-dihydro-2-isobutoxy- 1-quinolinecarboxylate); or PyCIU

(chlorodipyrrolidinocarbenium hexafluorophosphate),

As an alternative to Hünig’s base (diisopropylethylamine), any one of the following amine bases can be used: triethylamine; tributylamine; triphenylamine; pyridine; lutidine (2,6-dimethylpyridine); collidine (2,4,6-trimethylpyridine); imidazole; DMAP (4-(dimethylamino)pyridine); DABCO (1 ,4-diazabicyclo[2.2.2]octane); DBU (1 ,8-

diazabicyclo[5.4.0]undec-7-ene); DBN (1,5-diazabicyclo[4.3.0]non-5-ene); or proton sponge® (N,N,N’,N’-tetramethyl-1 ,8-naphthalenediamine).

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PATENT

WO 2016124960

PATENT

WO 2017108960

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017108960

Example 3b: Synthesis of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester

Procedure A:

Distilled 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (3 g; 20.96 mmol) and maleic acid anhydride (2.26 g; 23.1 mmol) in toluene (10 mL) were heated to 60°C under stirring for 29 hours. The temperature was raised to 80°C and heated for another 19 hours. Acetyl chloride (0.3 mL; 4.2 mmol) was added and heating (80°C) was continued for 24 hours. The reaction mixture was cooled to RT. The biphasic system was separated, the upper layer was discarded. The lower layer (viscous oil) crystallized. The crystallized compound was suspended in acetone (50 mL) and stirred for 15 minutes before being filtrated off. The product was dried at 50°C for 5 hours and 8 mbar to yield the 1st crop (1.65 g). The mother liquor was evaporated and the obtained oil/solid was suspended in acetone (5 mL) and stirred overnight at RT. The product was filtrated off and dried at 50°C for 5 hours and 8 mbar to yield the 2nd crop (1.41 g). The mother liquor was evaporated and the obtained oil/solid was suspended in a mixture of diethylether/acetone (5 mL/1 mL) and stirred overnight at RT. The product was filtrated off and dried at 8mbar/50°C for 3 hours (3rd crop, 0.37 g).<a name=”

Yield: 3.43 g (68% of theory)

Purity: 1st crop 96.8 area%; 2nd crop 96.0 area-%; 3rd crop 85.4 area-% (HPLC/UV, method A, λ=200nm; tr: 3.8 min.)

1H NMR (400 MHz, DMSO-d6) δ ppm: 2.61 (s, 4 H) 3.66 (t, J=5.47 Hz, 2 H) 4.23 (t, J=5.47 Hz, 2 H) 6.51 – 6.72 (m, 2 H) 6.60 (s, 1 H) 6.63 (s, 1 H) 13.21 (br s, 1 H)

Procedure B:

Reaction performed in a reactor (Mettler Toledo, Optimax):

Distilled 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (20 g; 0.14 mol) and maleic acid anhydride (15 g; 0.15 mol) in toluene (70 mL) were heated to 80°C under stirring (150 rpm) for 29 hours. Acetyl chloride (2 mL; 0.03 mol) was added and heating (80°C) was continued overnight. Stirring speed was raised to 200 rpm) after 15.5 hours (at 80°C) (product precipitated upon raising stirring speed. The reaction mixture was cooled to 20°C within 1 hour, directly after highering stirring speed. The reaction mixture was stirred for 4 hours, before being filtrated off. The filtrated precipitate was washed with toluene (30 mL) and then with heptane (70 mL), the product was dried at 60°C and 18 mbar. The crude product (26.26 g) with -90% purity was suspended in a mixture of acetone (30 mL)/heptane (30 mL) and stirred at RT for 2 days. The product was filtrated off, washed with heptane (30 mL) and dried at 50°C and 7 mbar.

Yield: 24.12 g (72% of theory)

Purity: 97.4 area-% at 200 nm

Procedure C:

a) Ethylene carbonate (8.89 g; 0.1 mol), succinimide (10 g; 0.1 mol) and sodium carbonate (0.53 g, 5 mmol) were heated to 100°C, the temperature was hold overnight. The product was cooled down yielding a brownish solid (13.73 g) which was grinded in a mortar.

b) 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (10 g, 69.9 mmol) from sequence a) and maleic acid anhydride (6.85 g; 69.9 mmol) in toluene (33 mL) were heated to 80°C under stirring for 23 hours. Acetyl chloride (0.5 mL; 7 mmol) was added and heating<a name=”

(80°C) was continued overnight. Heating was stopped and after stirring for another 2 hours the product was filtered off. The product was dried for 2 hours at 60°C and 8 mbar, yielding 15.82 g of crude product.

purity: 63 area-% at 200nm; 80 area-% at 220 nm

Procedure D

a) Ethylene carbonate (44.43 g; 0.5 mol), succinimide (50 g; 0.5 mol) and sodium carbonate (2.67 g; 25 mmol) were heated to 100°C. The reaction mixture was stirred at 100°C for overnight. The mixture was cooled to RT, yielding 72.4 g of the raw product.

40 g of the raw product were suspended in ethylacetate (40 mL) and heated to reflux for 30 minutes. The turbid mixture was cooled to RT and left stirring O/N. The product was filtrated off and dried under vacuum at RT to yield 29.19 g.

b) 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (10 g; 69.9 mmol) from sequence a) and maleic acid anhydride (6.85 g; 69.9 mmol) in toluene (30 mL) were heated to 80°C under stirring. Acetyl chloride (0.5 mL; 7 mmol) was added after 19 hours and heating (80°C) was continued overnight. Heating was stopped and stirring was continued for 2 days. The product was filtrated off and dried at 23 mbar and 60°C.

purity: 82 area% at 200 nm; 91 area-% at 220 nm

Procedure E:

a) Succinimide (500 g; 5.0 mol), ethylene carbonate (444.34 g; 5.0 mol) and sodium carbonate (26.74 g; 0.25 mol) were mixed and slowly heated to 130°C under stirring for 7 hours. The product was distilled via vacuum distillation to yield the product as colourless substance (628.14 g; 87% of theory)

b) The distilled 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (150 g; 1.05 mol) from sequence a) and maleic acid anhydride (102.76 g; 1.05 mol) in toluene (350 mL) were heated to 80°C under stirring for 23 hours. Acetyl chloride (7 mL; 0.01 mol) was added and heating (80°C) was continued. After 6 hours, the reaction mixture was cooled to 20°C within 30 minutes. The product was filtrated off and washed with toluene (200 mL), yielding 221.8 g of a white crystalline product (crude product).

purity: 91 area% at 200 nm; 92 area-% at 220 nm<a name=”

Procedure F:

a) Ethylene carbonate (9.78 g; 0.11 mol), succinimide (10 g; 0.10 mol) and triethylamine (0.7 mL; 5mmol) were heated to 98°C. The reaction mixture was stirred at this temperature overnight. The mixture was cooled to RT, yielding a colourless liquid, which crystallizes upon standing at RT to a colorless solid (14.89 g).

b) The crude 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione from sequence a) (5 g; 35 mmol) and maleic acid anhydride (3.43 g; 35 mmol) in toluene (25 mL) were heated to 80°C under stirring for 24 hours. Acetyl chloride (0.25 mL; 3.5 mmol) was added and heating (80°C) was continued for ~4 hours. The reaction mixture was cooled to RT. The product was filtrated off washed with toluene and dried at 50°C and 8 mbar for 3 hours. Yield: 6.52 g (77%)purity: 93 area% at 200 nm; 94 area-% at 220 nm

Procedure F’

Ethylene carbonate (161.50 g, 1.834 mol) was melted at 50°C in a reactor, succinimide (173.07 g, 1.747 mol) and Et3N (12.2 mL, 87.350 mmol) were added and the reaction mixture was warmed up to 90°C and stirred for 24h. Reaction mixture was cooled to 50°C, 500 mL of acetone was added, followed by addition of maleic anhydride (164.19 g, 1.674 mol) and Et3N (10.15 mL, 72.772 mmol). Reaction mixture was stirred at 50-55°C for 4h, cooled to 0°C and stirred for 20h. Resulting white suspension was filtered off and solid was washed with cold acetone (2×50 mL) and dried for 6h at 50°C and 30 mbar to afford crystalline (Z)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid.

Yield: 274 g (65%)

Purity: 97.23 area % at 200 nm

Procedure F”

(Z)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid (250 g, 1.036 mol) was suspended in acetone (500 mL) in 1-L reactor, acetyl chloride (5.53 mL, 77.736 mmol) was added drop wise at 20-25°C and reaction mixture was warmed up to 50-55°C and stirred for 20h. Reaction mixture was cooled to 0°C and stirred for 3h. Resulting white suspension was filtered off and solid was washed with cold acetone <a name=”(2×50 mL) and dried for 6h at 50°C and 30 mbar to afford crystalline (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid (Formula II).

Yield: 231.3 g (92.5%)

Purity: 99.47 area % at 200 nm

Summary:

Procedure B and E, using distilled 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione, showed purities of -90-91 area-% of the crude product, ongoing crystallization of the target compound could improve the purity to -97% also shown in procedure A. Distillation of 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione needs harsh conditions (Ex. 3a; procedure A). Using the crude 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione, produced with Na2CO3 lead to low product purities of 63 area-% (procedure C).

Crystallization of 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (procedure D) lead to product purities comparable to procedure A, B and E with distilled 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione, but crystallization is compounded by a significant product loss of – 25%.

The raw 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione could be used without any disadvantageous impact on product quality by substituting Na2CO3 with triethylamine as shown in procedure F with a purity of 93 area-%.

Procedure G

Two experiments were performed in parallel:

Each with 1 g (7 mmol) 1-(2-hydroxy-ethyl)-pyrrolidine-2,5-dione and 0.75 g (7.7 mmol) maleic acid anhydride in 6 mL acetonitrile in screw capped vials. To one of the reaction mixtures was given 0.1 mL triethylamine. Both mixtures were stirred at RT. Samples were taken and investigated by NMR (in DMSO).

product formation after 1 hour (quantified by NMR):

mixture without triethylamine: 0%

mixture with triethylamine: 55%<a name=”

product formation after 2 hours:

mixture without triethylamine: 0%

mixture with triethylamine: 71 %

Procedure H (isolation of cis intermediate):

1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (5 g; 35 mmol) and maleic acid anhydride (3.43 g; 35 mmol) in toluene (30 mL) were heated to 80°C under stirring for -24 hours. The reaction was cooled to RT, first a biphasic layer was observed, then the product solidified (sticking to glass wall and stirrer). The product was filtrated off after 2.5 hours of stirring, washed with toluene (50 mL) and dried under vacuum. The dried product was milled and suspended again in toluene (60 mL) at RT, after 30 minutes the product was filtrated off and dried under atmospheric conditions to yield 7.24 g of the cis intermediate (86% of theory). The intermediate product was suspended in toluene (30 mL) and heated to 80°C, acetyl chloride (0.25 mL; 3.5 mmol) was added and heating (80°C) was continued for 5 hours. The reaction mixture was cooled to RT and stirred for 2 hours. The product was filtrated off, washed with toluene (30 mL) and dried at 50°C and 8 mbar O/N.

purity: 95.6 area-% at 200nm; (0.2% of Impurity I)

Procedure H (without isolation of cis intermediate):

1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione (5 g; 35 mmol) and maleic acid anhydride (3.43 g; 35 mmol) in toluene (30 mL) were heated to 80°C under stirring for 24 hours. Acetyl chloride (0.25 mL; 3.5 mmol) was added and heating (80°C) was continued for ~4 hours. The reaction mixture was cooled to RT. The product was filtrated off washed with toluene (30 mL) and dried at 50°C and 8 mbar for 3 hours.

purity: 93.2 area-% at 200nm; (1.3% of Impurity I)

Procedure I (scale-up without cis isolation)

Maleic acid (959.09 g; 9.8 mol) was added to a reactor under stirring, which was already loaded with toluene (7 L), then 1-(2-Hydroxyethyl)-pyrrolidine-2,5-dione<a name=”

(1400 g; 9.8 mol) was added. Then the mixture was heated to 76°C within ~1 h (up to ~50°C the mixture is a suspension with the tendency of conglomeration of solids, very difficult consistency) at 50°C a turbid solution resulted. Stirring was continued at 80°C for 2 days. Acetyl chloride (138 mL; 1.96 mol) was added under enhanced stirring at 80°C. After -5-10 minutes a crystalline precipitate was formed, which transformed into a pasty/syrupy solid, sticking to reactor walls (difficult handling). Heating was continued overnight (reaction completed after 5 hours as IPC showed). Mixture is still an emulsion, seeding was added and the product precipitated. Stirring at 80°C was continued for ~2 hours then the mixture was cooled to RT. The solid was filtrated off and dried at 50°C and 12 mbar overnight to yield 1818.74 g of the product.

purity: 96.34 area-% at 218 nm; (1.5% of Impurity I)

Procedure J:

2L flask (reaction volume ~1 L): Succinimide (460 g; 4.6 mol), ethylene carbonate (450 g; 5.1 mol) and triethylamine (32 mL; 0.23 mol) were heated to 85°C under stirring overnight. Temperature was raised to 95°-97C and heating was continued O/N. The mixture was cooled to 50°C. Acetonitrile (1600 mL) was charged into a 10 L reactor. To the reaction mixture was added acetonitrile (1000 mL) at 50°C and the solution was transferred to the reactor (reactor T ~22°C), triethylamine (35 mL) was added, then maleic acid anhydride (500.81 g; 5.1 mol). The mixture was heated to 55°C for 5.5 hours. A part of the solvent was distilled off (~1200 mL). Then toluene (1200 mL) was added. The mixture was heated to 90°C. The mixture was cooled to 50°C. At 60°C (clear solution), seeding was added ~300 mg, after -3 minutes a suspension resulted. The mixture was further cooled down to 20°C within 10 hours and kept on stirring O/N. The white crystalline product was filtrated off, washed with toluene (1000 mL) and dried at 55°C and 9 mbar for 2 h to yield 908.99 g (81% yield).

905 g of the isolated, crystallized product was suspended in acetonitrile (2.9 L). Acetyl chloride (23 mL) was added and the mixture was heated to 80°C (clear, colorless solution) for 4 hours. Toluene (1000 mL) was added and the mixture was cooled to RT within 2 hours (linear). The mixture was further cooled to 0°C within 60 minutes. The <a name=”product was filtrated off and washed with toluene (1000 mL). The product was dried overnight at 9 mbar and 50°C.

Yield: 742.06 g (66%)

purity: 99.9 area% at 200 nm

Summary:

Isolation of the cis intermediate leads to a significantly lower content of impurities, in particular of Impurity I. Toluene as solvent leads to disadvantageous conditions regarding consistency of the reaction mixture (procedure H). The use of acetonitrile or acetone (procedure I/F) leads to improved reaction conditions and product quality.

Example 3c

Preparation of (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid (Formula II) from ethylene carbonate and succinimide (without isolation of

intermediates)

 Procedure

Ethylene carbonate (161.50 g, 1.834 mol) was melted at 50°C in an 1-L reactor, succinimide (173.07 g, 1.747 mol) and Et3N (24.4 mL, 0.175 mol) were added and the reaction mixture was warmed up to 90-92°C and stirred for 24h. Distillation column<a name=”

was set up on the reactor and the remaining Et3N was distilled off. Reaction mixture was cooled to 40-45°C, 500 mL of acetone was added, followed by addition of maleic anhydride (184 g, 1.878 mol) and Et3N (10.96 mL, 78.615 mmol). Reaction was stirred at 40°C for 6h (precipitation occurred after 3h), cooled to 20-25°C and acetyl chloride (20.86 mL, 0.293 mol) was added drop wise. Reaction mixture was then warmed up to 50-55°C and stirred for 20h. Orange solution crystallized upon seeding. Reaction mixture was cooled to 0°C and stirred for 3h. Resulting white suspension was filtered off and solid was washed with cold acetone (2×200 mL) and dried for 6h at 50°C and 30 mbar to afford (E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid. Yield: 352.8 g (83.7%)

Purity: 99.69 area % at 200 nm

Example 4: Synthesis of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester

Procedure A:

The starting material (E)-But-2-enedioic acid mono-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl] ester (5 g; 20 mmol) was suspended in dichloromethane (60 mL) and cooled to 0°C, triethylamine (3.16 mL; 22.8 mmol) was added, resulting a clear solution. To this solution methylchloroformate (3.3 mL; 20.7 mmol) was carefully added within 30 minutes via syringe (reaction very exothermic). After 15 min of stirring at 0°C, DMAP (0.25 g; 2.1 mmol) was added into the reaction mixture at 0°C, stirring was continued for 3 hours at 0°C. The reaction mixture was poured into water (200 mL) and additional dichloromethane (100 mL) was added. The organic layer was separated and the aqueous layer was extracted once again with dichloromethane (50 mL). The combined organic layers were washed with brine (50 mL). The solvent was evaporated at 52°C. To the brown oil, which solidified, was added acetone (20 mL) and the mixture was stirred overnight. The product was filtrated off (white solid, part I) (2.73 g) and to the mother <a name=”liquor silica was added, the mixture was evaporated. Acetone (50 mL) was added and silica was filtrated off. The solvent was evaporated and diethylether (30 mL) was added to the solid, the mixture was stirred for ~1 hour. The product was filtrated off (part II) (1.6 g).

Overall yield: 4.33 g (82%)

Purity: part I 100 area-% at 200 nm; part II 97.96 area-% at 200 nm

Procedure A’

(E)-4-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-4-oxobut-2-enoic acid (Formula II) (200 g, 0.829 mol) was suspended in acetone (2000 mL) in 3-L reactor at 20-25°C and cooled to 0°C. Et3N (150.31 mL, 1.078 mol) was added drop wise at 0-5°C. Into resulting solution, methyl chloroformate (83.27 mL, 1.072 mol) was added drop wise at 0-5°C. Reaction mixture was warmed up to 45°C and stirred for 2h. Upon completion, reaction mixture was cooled to 20-25°C and water (600 mL) was added drop wise with maintaining the temperature at 20-25°C resulting with off white to yellowish solution. pH was adjusted to 7 with 1M HCl. One more volume of water was added and pH corrected if needed. Part of acetone from the reaction mixture (5 volumes or 1000 mL) was distilled off under diminished pressure and reactor walls were washed with 1 more volume of water (200 mL), thus resulting in a solution of acetone/water mixture 1:1 (total 10 volumes). Reaction mixture was gradually cooled to 0°C and stirred for 20h. Resulting white suspension was filtered off and solid was washed with cold water (2×200 mL) and dried for 6h at 50°C and 30 mbar to afford crude 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (Formula I).

Yield: 183.7 g (86.8%)

Purity: 100.00 area % at 200 nm

Crude 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (170 g) was suspended in acetone (850 mL) at 20-25°C and warmed up to 50°C resulting with colorless solution. Water (850 mL) was added in portions at 50°C and solution was cooled gradually. Crystallization started at 32°C. Reaction mixture was stirred at crystallization temperature for 30 minutes and cooled further to 0°C, stirred at 0°C for 2h and resulting <a name=”white suspension was filtered off and solid was washed with cold water (2×170 mL) and dried for 6h at 50°C and 30 mbar to afford crystalline 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate.

Yield: 152.5 g (89.7%)

Purity: 100.00 area % at 200 nm

Procedure B:

The starting material (5 g, 20 mmol) was suspended in toluene (25 mL). Acetyl chloride (0.29 mL) and methanol (2.5 mL) were added, the reaction mixture was heated to 55°C and stirred for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with ethylacetate (100 mL). The organic layer was separated and dried over sodium sulfate. The solvent was evaporated (crude product 4.7 g, main impurities dimetylfumarate (13%) and fumaric acid (1%) (HPLC at 200 nm)).

Yield: 4.7 g (88%)

Purity: 82.1 area-% at 200 nm

Procedure C:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester in polymorphic form A; short: (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form A

The starting material (without isolation of (Z)-But-2-enedioic acid mono-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl] ester) (30 g; 0.12 mol) was suspended in dichloromethane (DCM, 160 mL) and cooled to 0°C, triethylamine (TEA, 19 mL; 0.14 mol) was added, resulting a clear solution. To this solution methyl chloroformate (19.74 mL; 0.12 mol) was added carefully within 30 minutes via syringe. Stirring was continued for ~2 hours. Water (200 mL) was added to the reaction mixture and stirring was continued for 5-10 minutes. The organic layer was separated and the aqueous layer was washed with another portion of DCM (100 mL). The combined organic layers were dried over sodium sulfate, before being evaporated. To the crude product was added acetone (50 mL) and the mixture was stirred for 3 hours before being filtered off. The product was washed with heptane (50 mL) and dried at 50°C and 21 mbar for 1 h.<a name=”

Yield: 20.52 g (65%)

Purity: 98.7 area-% at 220 nm; (0.3% of Impurity I)

XRPD diffraction peaks: 7.1, 11.6, 13.5, 13.7, 16.3, 16.7, 18.0, 18.4, 21.1, 22.1, 23.1, 23.9, 24.4, 25.5, 27.0, 27.5, 28.0, 28.6, 30.8, 31.2, 31.9, 32.3, 33.7, 34.2, 34.4, 34.9, 35.1, 35.7, 36.0, 36.8, 38.3, 40.1, 40.5, 41.7, 42.4, 43.0, 43.4, 45.0, 45.3, 46.2, 46.4, 47.0, 48.6, 49.4, 49.9, 52.0 + 0.2 degrees two theta.

The Form A according to Procedure C showed a habitus as depicted in Figure 7a

Procedure D:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form A The starting material (10 g; 41.5 mmol) was suspended in toluene (70 mL) at 23°C, triethylamine (TEA; 6.3 mL; 45.6 mmol) was added. Methyl chloroformate (6.58 mL; 41.5 mmol) was slowly added within -30 minutes. After stirring for 2 hours water (40 mL) was added and shortly after acetone (110 mL), stirring was continued for ~2 minutes. The organic layer was separated and washed with brine (15 mL). After drying over sodium sulfate, the solvent was evaporated, yielding a slightly grey solid as crude product (9.42 g). The raw product was suspended in acetone (20 mL) and heptane (20 mL). The mixture was heated to reflux for 15 minutes resulting in a clear solution with just a small amount of solid. The mixture was cooled to RT and stirred overnight (precipitation started at 45°C, cooling: flask left in cooling oil bath ~lh to RT). The resulting product showed polymorphic form A.

Yield: 7.83 g (74%)

Purity: 99.4 area-% at 200 nm

The form A according to Procedure D showed a habitus as depicted in Figure 7b<a name=”

Procedure E:

The starting material (1 g; 4.15 mmol) was suspended in dichloromethane (50 mL) at RT. Methyl chloroformate (0.64 mL; 8.3 mmol) was added and stirring was continued overnight, in process control by HPLC showed no conversion.

Procedure F:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form A

The starting material (7 g; 0.03 mol) and Na2CO3 were suspended in ethylacetate (50 mL). To the suspension was added methyl chloroformate (3.37 mL; 0.04 mol) in one portion. The reaction mixture was heated to 70°C. The temperature was kept for 15.5 h. The reaction mixture was cooled to 20°C and ethyl acetate (70 mL) was added to the white suspension. The solids were filtrated off and the ethyl acetate layer was washed with water (40 mL), dried over Na2S04 and evaporated to yield 6.4 g of the white crystalline crude product.

The crude product was suspended in a mixture of ethylacetate (10 mL) and heptane (10 mL). The suspension was heated to reflux for 30 minutes, then cooled to 23°C and stirred overnight. The product was filtrated off and dried at 8 mbar and 50°C overnight.

Yield: 5.62 g (75%)

Purity: 99.4 area-% at 200 nm

The form A according to Procedure E showed a habitus as depicted in Figure 7c

Procedure G:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester in polymorphic form B; short: (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form B

(A) 9 g of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methylester was heated to 115°C. The melted compound was stirred for -20 minutes and then dropped into a precooled mortar (0°C).<a name=”

Purity of form B: 98.8 area-% at 200nm

XRPD-pattern: (Figure 4)

(B) 3.00 g of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester (form A) was suspended in 150 mL of dibutyl ether. Suspension was heated to 120° C while mixing. Solution was left at 25°C for 2 days. Crystallized material was filtered and dried at 23 °C at 12 mbar.

XRPD-pattern: (Figure 4′)

A measure of the relative volume change of a solid as a response to pressure change is called compressibility. An API should exhibit good compressibility which is dependent on the polymorphic state.

Experimental data:

The compressibility of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester form B and form A was assessed using a die and a flat-faced punch fitted on a TA-XT2 Texture analyser (Stable Micro Systems Ltd., Godalming, UK). 200 mg of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester sample is compressed in a steel mould (with the rate of displacement 0.03 mm/s). Cyclic procedure (similar to tapping) was performed: compressing, then retracting, relaxation for 15 s and then repeated compressive steps (altogether 10 steps). Each step exerts 0.2 MPa pressure on to the sample. Sample density is calculated by dividing the weight by the sample volume for each cycle. Maximum density is reached within 10 steps. Measurements were performed in duplicates for each sample, results are expressed as an average of duplicate measurements.

Results:

<a name=”

Form B of (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester exhibits a higher density at compression, indicating superior compressibility compared to form A.

Procedure H:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester in polymorphic form C; short: (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form C

(E)-But-2-enedioic acid mono-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl] ester (10 g; 41.5 mmol) was suspended in dichloromethane (DCM; 100 mL) and cooled to 0°C, triethylamine (TEA; 6.3 mL; 45.6 mmol) was added, resulting a clear solution. To the reaction mixture was added methyl chloroformate (6.58 mL; 41.5 mmol) within 30 minutes via a syringe pump. After 15 min of stirring at 0°C, DMAP (0.51 g; 4 mmol) was added into the reaction mixture at 0°C. The resulting solution was stirred at 0°C for 2.5 hours, then the cold suspension was poured into water (70 mL), the reactor was washed with further DCM (20 mL), which was added also to the DCM/water mixture. The organic layer was separated and washed with HCl (32% aq) (5 mL) in water (60 mL), then with water (50 mL) and finally with brine (50 mL). To the obtained deep red to brown solution was added silica (40-63 um) and the mixture was stirred for 5 minutes, before being filtered off to yield a colorless solution, which was evaporated to yield a colorless oil (crude product). The obtained oil was dissolved in a mixture of ethyl acetate/heptane (1/4) (20 mL). The mixture was stirred for 2 days before being filtered off. The product was dried under vacuum.

Yield: 2.87 g (26%)

Purity: 90.9 area-% at 200 nm

XRPD diffraction peaks: 11.2, 11.8, 13.0, 13.6, 13.6, 16.8, 18.1, 19.6, 20.6, 21.2, 21.5, 22.3, 23.2, 23.7, 24.3, 24.4, 25.2, 25.6, 26.5, 27.6, 28.4, 29.1, 30.3, 31.1, 32.0, 33.1, 33.8, 36.1, 36.7, 37.5, 38.4, 38.9, 41.6, 42.5, 43.2, 44.8, 46.5, 48.7, 49.6, 49.9 + 0.2 degrees two theta.<a name=”

Procedure I:

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester in polymorphic form D; short: (E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form D

(E)-But-2-enedioic acid 2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl ester methyl ester Form B (1 g) was suspended in acetonitrile (3 mL). The suspension was stirred for 7 days in a closed screw cap vials followed by slow evaporation of the solvent under ambient conditions within 3 days.

Purity of form D: 96.3 area-% at 200 nm

XRPD diffraction peaks: 6.9, 11.7, 13.6, 13.9, 16.4, 16.9, 18.2, 20.9, 21.3, 22.3, 23.3, 24.0, 24.6, 25.7, 27.5, 27.7, 31.0, 31.3, 32.1, 32.4, 33.9, 35.3, 35.7, 38.4, 41.9, 42.7, 43.1, 43.6, 44.4, 46.5, 48.9 + 0.2 degrees two theta.

Procedure J:

The starting material (obtained via isolation of (Z)-But-2-enedioic acid mono-[2-(2, 5-dioxo-pyrrolidin-1-yl)-ethyl] ester) (400 g; 1.7 mol) and Na2CO3 (264 g; 2.5 mol) were suspended in ethylacetate (2.7 L). To the suspension was added methyl chloroformate (193 mL; 2.5 mol) at 20°C. The reaction mixture was heated to 45°C within 90 minutes (linear heated). The mixture was kept on stirring for 5.5 hours. Ethylacetate (4 L) was added to the white suspension (at 45 °C). The suspension was stirred for 15 minutes before being filtrated off (45 °C suspension). The reactor was rinsed with another portion of ethylacetate (1 L). The filtrated solids were discarded. To the ethylacetate solution was added a mixture of HClaq (32%) (50 mL) and water (1 L) and the mixture was vigorously stirred for 10 minutes (at 35°C). Then the ethylacetate layer was separated (at ~35°C). The ethylacetate layer was transferred back to the reactor and stirred over sodium sulfate for 30 minutes, sodium sulfate was filtrated off and the ethylacetate layer was reduced to 900 mL. The suspension was transferred into a 3 L flask, equipped with a KPG stirrer and reflux condenser. The mixture was heated to reflux (stirring speed 160 rpm), the suspension was stirred until a clear solution was obtained (-30 minutes). Then heptane (550 mL) was added dropwise within 30 minutes<a name=”

under reflux conditions. Then the mixture (still solution) was slowly cooled to RT. The mixture was stirred O/N. The product was filtrated off and the filter cake was rinsed with heptane (500 mL) to yield the crystalline product (362.56 g; 86%).

purity: 99.8 area% at 218 nm (no Impurity I).

Alternative Procedure: Synthesis of (E)-But-2-enedioic acid 2-(2,5-dioxo- pyrrolidin-1-yl) -ethyl ester methyl ester

Procedure A

Monomethylfumarate (20 g, 0.15 mmol) was suspended in dry dichloromethane (400 mL) at RT, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (32.42 g, 0.17 mol), N-(2-hydroxyethyl)succinimide (21.57 g, 0.15 mol) and dimethylaminopyridine (0.94 g, 7.7 mmol) were added. The solution was stirred O/N at RT. The formed yellow solution was diluted with dichloromethane (300 mL) and washed twice with water (2×500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the crude product was added methyl tert. butyl ether (850 mL) and the reaction mixture was refluxed for 2.5 hours, cooled to RT, then filtrated and heated to reflux again for ~2 hours. After cooling to RT, the mixture was stored at ~5°C for 4 days. The white precipitate was filtrated off and washed with isopropylacetate (25 mL). The crystalline product was dried at 50°C and 7 mbar.

Yield: 10.8 g (28%)

Procedure B

Monomethylfumarate (1.5 g; 11.5 mmol) was suspended in dry DCM (30 mL) at 0°C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (2.47 g; 12.8 mmol), N- (2-hydroxyethyl)succinimide (1.62 g; 11.3 mmol) and DMAP (0.07 g; 0.6 mmol) were added. The solution was stirred overnight at RT. The formed yellow solution was diluted with DCM (50 mL) and washed with water twice (2×35 mL). The organic layer<a name=”

was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (n-heptane:ethyl acetate 1:1->1:2). The final product showed polymorphic form A. The form A according to alternative Procedure B showed a prismatic habitus as depicted in Figure 7d

Yield: 2.3 g (78%)

Purity: 99.5 area-% at 200 nm

Example 5: Kinetic investigations

Monomethyl maleate was prepared in analogy to WO 2014/197860. Samples of 13.2 grams of monomethyl maleate in 50 mL of toluene and 0.1 equivalents of the isomerization catalyst were reacted at 80°C. Samples were taken after the given times and analyzed by HPLC at 200 nm. The absorbance ratio of monomethyl fumarate (3.8 min.) to monomethyl maleate (2.8 min.) was taken as conversion parameter. The results are shown in Figure 1. As it can be seen from Figure 1 the conversion of monomethyl maleate to monomethyl fumarate in the presence of is TMS (trimethylsilylchloride) is advantageously enhanced compared to the one in the presence of AcCl (acetyl chloride).

Example 6: Yield determination

Six samples of 13.2 g (0.1 mol) monomethyl maleate were diluted with toluene (50 mL) and 0.1 eq of the isomerization catalyst (trimethylsilylchloride or acetyl chloride) were added, three samples with trimethylsilylchloride and three samples with acetyl chloride. The resulting reaction mixtures were heated to the temperatures of 45 °C, 51°C and 80°C. After 22 hours the reaction mixtures were cooled to room temperature, the product was filtrated off and dried at 50°C/8-16 mbar overnight. The results are shown in Figure 2 As it can be seen from Figure 2 the isolated yields of the conversion of monomethyl maleate to monomethyl fumarate in the presence of TMS (trimethylsilylchloride) is at any

PATENT

CN 110698442

PATENT

WO 2021053476

PATENT

IN 201921037120

PATENT

WO 2021074842

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021074842

The drug compound having the adopted name “Diroximel fumarate” has chemical name: 2-(2,5-Dioxopyrrolidin-l-yl)ethyl methyl fumarate as below.

Diroximel fumarate is an investigational, novel oral fumarate with a distinct chemical structure and developed by Alkermes pic, for the treatment of relapsing-remitting multiple sclerosis (RRMS) and is currently under review by U.S. Food and Drug Administration. Biogen, under an exclusive license from Alkermes, intends to market Diroximel fumarate under the brand name VUMERITY™.

US 8669281 B1 first disclosed Diroximel fumarate, its preparation, composition and use thereof for treating multiple sclerosis. US 10080733 B2 further discloses the crystalline solid form of Diroximel fumarate having an X-ray powder diffraction pattern comprising 2Q peaks at 11.6, 21.0, 24.3, 27.4, and 27.9 ±0.2 2Q.

WO 2017/108960 A1 also discloses various alternative synthetic approaches to make Diroximel fumarate and crystalline solid forms thereof, designated as Polymorphic forms A to D.

Hence, there remains a need for alternate solid forms of Diroximel fumarate and preparative processes thereof, exhibiting desired bioavailability and stability. Hence, it is desirable to provide a viable solid form of Diroximel fumarate. The known processes for the preparation of Diroximel fumarate are not viable at industrial scale due to the use of expensive reagents and catalyst such as coupling agents disclosed in US 8669281 Bl, with very low yields. Hence, there remains a need for the improved process to make Diroximel fumarate.

In another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of monomethyl fumarate with (2,5-dioxopyrrolidin-l-yl)ethanol in the presence of an acid halide.

n another aspect, the present application provides a process for the preparation of Diroximel fumarate, comprising the step of esterification of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid with methylation agent selected from the group consisting of 2,2-dimethoxypropane, trimethyl orthoformate and dimethyl carbonate.

Diroximel Fumarate

Example-7: Preparation of l-(2-hydroxyethyl)pyrrolidine-2,5-dione

A mixture of succinimide (100 g), ethylene carbonate (70.6 mL) and triethylamine (14 mL) was heated to 90 °C and stirred at the same temperature for 24 hours. The reaction mixture was cooled to 0 °C; methyl /ert-butyl ether (300 mL) was added and the resulting mixture was stirred for 30 minutes at the same temperature. The solid was filtered and dried under vacuum for 5 minutes. The solid was combined with ethyl acetate (100 mL) at 0 °C and stirred at the same temperature for 30 minutes. The solid was filtered and dried in rotatory vacuum dryer at 40 °C for 30 minutes to obtain 142.5 g of the title compound as off-white solid with HPLC purity of 99.6%.

Example-8: Preparation of Diroximel fumarate

To a mixture of (E)-4-methoxy-4-oxobut-2-enoic acid (4.0 g) and dichloromethane (40 mL) at 5 °C, Oxalyl chloride (5.85 g) was added slowly in 10 minutes, then a drop of DMF was added at the same temperature and allowed the reaction mixture to warm up to 27 °C. After complete evolution of the gas, solvent was evaporated from the reaction mixture. To a mixture of l-(2-hydroxyethyl)pyrrolidine-2,5-dione (5.06 g) and dichloromethane (35 mL), diisopropylethylamine (DIPEA) (9.93 g) was added and cooled the reaction mixture to 5 °C. The former mixture of (E)-4-methoxy-4-oxobut-2-enoic acid chloride in dichloromethane was slowly added to this later mixture at 5 °C for 20 minutes and stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and the organic layer was separated. Organic layer was washed with 10% citric acid solution and then with brine solution. The solvent from the separated organic layer was evaporated completely at 30 °C and the resultant solid was combined with acetone (15 mL) at 27 °C and stirred for 8 hours at the same temperature. The solid was filtered and the cake was washed with chilled acetone (3 mL) and then with cyclohexane (4 mL). The wet solid was dried at 40 °C under vacuum to obtain 3.3 g of the title compound with HPLC purity of 99.95 %

Example-9: Preparation of Diroximel fumarate

To a mixture of (E)-4-methoxy-4-oxobut-2-enoic acid (100.0 g) and dichloromethane (1000 mL) at 5 °C, Oxalyl chloride (117 g) was added slowly in 15 minutes, then catalytic DMF (1 mL) was added slowly at the same temperature and allowed the reaction mixture to warm up to 27 °C. After complete evolution of the gas, solvent was evaporated from the reaction mixture. To a mixture of l-(2-hydroxyethyl)pyrrolidine-2,5-dione (110 g) and dichloromethane (900 mL), diisopropylethylamine (DIPEA) (139 g) was added and cooled the reaction mixture to -5 °C. The former mixture of (E)-4-methoxy-4-oxobut-2-enoic acid chloride in dichloromethane (100 mL) was slowly added to this later mixture at – 5 °C for 60 minutes and stirred at the same temperature for 1 hour. The reaction mixture was quenched with water and the organic layer was separated. Organic layer was washed with 10% citric acid solution, 10% NaHC03 solution and then with brine solution. The solvent from the separated organic layer was evaporated completely at 30 °C and the resultant solid was combined with acetone (400 mL) at 27 °C. The reaction mixture was heated to 45 °C and stirred at the same temperature for 1 hour. The mixture was cooled to 27 °C and stirred for 8 hours at the same temperature. The solid was filtered and the cake was washed with methanol (200 mL). The wet solid was dried at 45 °C under vacuum to obtain 120 g of the title compound with HPLC purity of 99.97 %

Example-10: Preparation of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid

A mixture of succinimide (100 g), ethylene carbonate (70.6 mL) and triethylamine (14 mL) was heated to 90 °C and stirred at the same temperature for 24 hours. The reaction mixture was cooled to 50 °C and triethylamine was removed by evaporation under vacuum. The reaction mixture was heated to 90 °C to distill out the traces of triethylamine under vacuum. The reaction mixture was cooled to 40 °C. Acetone (300 mL), maleic anhydride (106.2 g) and triethylamine (6.31 mL) were added. The resulting mixture was stirred at 40 °C for 6 hours. The mixture was cooled to 20 °C and acetyl chloride (12 mL) was added slowly over a period of 30 minutes. The mixture was slowly heated to 50 °C and stirred for 20 hours at the same temperature followed 2 hours at 0 °C. The solid was filtered and washed with cold acetone (2 x 120 mL).The wet solid was dried at 40 °C for 2 hours to obtain 194.2 g of the title compound as white solid with HPLC purity of 99.55%

Example-11: Preparation of Diroximel fumarate

Diroximel Fumarate

To a mixture of (E)-4-(2-(2,5-dioxopyrrolidin-l-yl)ethoxy)-4-oxobut-2-enoic acid (5 g) and 2,2-dimethoxypropane (50 mL) at 29 °C, concentrated hydrochloric acid (1 mL) and water (5 mL) were added and stirred at the same temperature for 17 hours at the same temperature. The pH of the reaction mixture was adjusted to 7 with a saturated aqueous solution of NaHCCh and the solvent was evaporated completely at 40 °C. To the resultant solid, water (50 mL) was added at 29 °C and stirred for 15 minutes. The solid was filtered and dried under vacuum at 29 °C for 5 hours. The resultant solid was combined with methyl /er/-butyl ether (50 mL) at 29 °C and stirred for 20 hours at the same temperature. The solid obtained was filtered and washed with diethyl ether (20 mL). The wet solid was dried under vacuum for 3 hours at 29 °C to obtain 3.3 g of the title compound as white solid with HPLC purity of 98.11%

Example-12: Preparation of Amorphous solid dispersion of Diroximel fumarate with Copovidone

Diroximel fumarate (100 mg) and Copovidone (500 mg) were dissolved in acetone (30 mL) at 30 °C. The clear solution was filtered to make it particle free and the solvent was evaporated in a rotavapor at 45 °C under reduced pressure to obtain the title amorphous solid dispersion. The solid dispersion (100 mg) obtained was combined with Syloid (500 mg) and ground for 20 minutes to obtain the admixture of title compound. XRPD: Amorphous.

Example-13: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 43 °C and methyl tert. butyl ether (30 mL) was added to the clear solution. A suspension of crystalline Diroximel fumarate seed (0.25 g) in methyl tert. butyl ether (10 m) was added at 40 °C and stirred the mixture at the same temperature for 30 minutes. Methyl tert. butyl ether (280 mL) was added slowly for 2 hours at 41 °C. The mixture was cooled to 25 °C in 3

hours and then to 0 °C in 1 hour. The mixture was stirred at 0 °C for 1 hour and the solid was filtered. The wet solid was washed with methyl tert. butyl ether (40 mL) and dried at 42 °C for 6 hours to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 7.776 pm, Dv (50) 31.292 pm & Dv (90) 133.437 pm

Example-14: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 43 °C and DM water (100 mL) was added to the clear solution. A crystalline Diroximel fumarate seed (0.20 g) was added at 42 °C and stirred the mixture at the same temperature for 10 minutes. DM water (100 mL) was added slowly at 41 °C. The mixture was cooled to 28 °C in 1 hour. The mixture was stirred at 28 °C for 2 hour and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 8.59 pm, Dv (50) 61.08 pm & Dv (90) 187.07 pm

Example-15: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in acetone (80 mL) at 45 °C and DM water (400 mL) was added to the clear solution. The mixture was cooled to 30 °C in 1 hour and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 7.22 pm, Dv (50) 45.5 pm &

Dv (90) 136.7 pm

Example-16: Crystallization of Diroximel fumarate

Diroximel fumarate (20 g) was dissolved in Isopropyl acetate (360 mL) at 55 °C and cooled to 28 °C. A crystalline Diroximel fumarate seed (0.25 g) was added at 28 °C and cool to 5 °C. The mixture was stirred for 1 hour at the same temperature and the solid was filtered to obtain the title compound.

PXRD: Crystalline; Malvern particle size: Dv (10) 7.3 pm, Dv (50) 43.18 pm & Dv (90) 133.56 pm

PATENT

IN 201941042131

References

  1. Jump up to:a b “Vumerity- diroximel fumarate capsule”DailyMed. Retrieved 1 February 2021.
  2. Jump up to:a b c “Vumerity EPAR”European Medicines Agency. 14 September 2021. Retrieved 24 November 2021.
  3. ^ Wang Y, Bhargava P (July 2020). “Diroximel fumarate to treat multiple sclerosis”. Drugs of Today56 (7): 431–437. doi:10.1358/dot.2020.56.7.3151521PMID 32648853S2CID 220471534.
  4. ^ Kourakis S, Timpani CA, de Haan JB, Gueven N, Fischer D, Rybalka E (October 2020). “Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?”Pharmaceuticals (Basel, Switzerland)13 (10): 306. doi:10.3390/ph13100306PMC 7602023PMID 33066228.
  5. Jump up to:a b “Drug Approval Package: Vumerity”U.S. Food and Drug Administration (FDA). 21 April 2020. Retrieved 1 February 2021.
  6. ^ “Diroximel fumarate”.
  7. Jump up to:a b “Vumerity: Pending EC decision”European Medicines Agency. 15 September 2021. Retrieved 17 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

Diroximel fumarate
Diroximel fumarate.png
Clinical data
Trade names Vumerity
Other names ALKS-8700
AHFS/Drugs.com Monograph
MedlinePlus a620002
License data
Routes of
administration
By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C11H13NO6
Molar mass 255.226 g·mol−1
3D model (JSmol)

/////////Diroximel fumarate, EU 2021, EMA 2021, APPROVALS 2021, VUMERITY, ジロキシメルフマル酸エステル , K0N0Z40J3W, RDC-5108, дироксимела фумарат ديروكسيميل فومارات 富马地罗昔美 

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Maribavir


Maribavir.svg
ChemSpider 2D Image | Maribavir | C15H19Cl2N3O4

Maribavir

  • Molecular FormulaC15H19Cl2N3O4
  • Average mass376.235 Da

FDA APROVED 11/23/2021, Livtencity1263 W94, 1263W94
176161-24-3[RN]
1H-Benzimidazol-2-amine, 5,6-dichloro-N-(1-methylethyl)-1-β-L-ribofuranosyl-
UNII-PTB4X93HE1, марибавир , ماريبافير  ,马立巴韦 , BW-1263W94 
Camvia, D04859, G1263, GW257406X 
1263W94; BW-1263W94; GW-1263; GW-257406X; SHP-620; VP-41263 
Company:GlaxoSmithKline (Originator) , Shire 
MOA:UL97 kinase inhibitorIndication:CMV prophylaxis

To treat post-transplant cytomegalovirus (CMV) infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for CMV
Press Release

SYNRoute 1

Reference:1. WO9601833A1.

Syn

US 6204249

File:Maribavir synthesis.svg

https://patents.google.com/patent/WO2001077083A1/enExample 7: 5,6-Dichloro-2-(isoproylamino)-1-(β-L-ribofuranosyl)-1 H-benzimidazolesoprylamino (10 mL) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-0-acetyl-β-L- ribofuranosyl)-1 H-benzimidazole (1.0 g, 1.9 mmol) were combined with absolute ethanol (20 mL) and stirred at 75°C for 48 h. The reaction mixture was concentrated and purified on a silica gel column (2.5 vm x 16 cm, 230-400 mesh) with 1 :20 methanol: dichloromethane to give product contaminated with a small amount of higher Rf material. This was repurified on a chromatotron, fitted with a 2 mm silica gel rotor, with 1 :25 methanol.dichloromethane to give a white solid (0.43 g, 1.15 mmol, 60o/o); [a]20D=(-)22.4 (c=0.5 DMF); UVλ™* (E): pH 7.0:304 nm (95,00), 275 (1 ,800) 260 (8,300); 0.1 NaOH: 304 nm (9,900), 275 (19,00), 260 (8,100); MS (Cl): m/z (re/, intensity) 376 (100, M+1); ‘H NMR (DMSO-de) d 7.59 (s, 1 H, Ar-H), 7.35 (s, 1 H, Ar- H), 6.90 (d, 1 H, NH, J=7.8 Hz), 5.73 (d, 1 H, H-1′, J=6.5 Hz), 5.62 (t, 1 H, OH, J=4.2 Hz), 5.27-5.23 (m, 2H, OH), 4.27 (apparent dd, 1 H, J=13.4 Hz, J=7.6 Hz), 4.11 -3.99 (m, 2H), 3.97 (br. s, 1 H), 3.72-3.61 (m, 2H, H-5’), 1.18 (d, 6H, CH(CH3)2, J=6.6 Hz).Anal. Calcd. for

Figure imgf000030_0001

H2O: C, 45.70; H, 5.37; N, 10.66. Found: C, 45.75; H, 4.98; N, 10.50.

Maribavir was in phase II clinical trials for the treatment of cytomegalovirus (CMV) infection. It was granted orphan drug designation by the FDA for the indication.

The drug was originally developed by the University of Michigan and was licensed to GlaxoSmithKline. ViroPharma (now subsidiary of Shire) acquired worldwide rights to the drug from GlaxoSmithKline in 2003.

Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV).[1][2]

The most common side effects include taste disturbance, nausea, diarrhea, vomiting and fatigue.[2]

Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.[2]

Maribavir was approved for medical use in the United States in November 2021.[2][3]

Medical uses

Maribavir is indicated to treat people twelve years of age and older and weighing at least 35 kilograms (77 lb) with post-transplant cytomegalovirus infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for cytomegalovirus.[2]

Contraindications

Maribavir may reduce the antiviral activity of ganciclovir and valganciclovir, so coadministration with these medications is not recommended.[2]

History

Maribavir is licensed by ViroPharma from GlaxoSmithKline in 2003, for the prevention and treatment of human cytomegalovirus (HCMV) disease in hematopoietic stem cell/bone marrow transplant patients. The mechanism by which maribavir inhibits HCMV replication is by inhibition of an HCMV encoded protein kinase enzyme called UL97 or pUL97.[4] Maribavir showed promise in Phase II clinical trials and was granted fast track status, but failed to meet study goals in a Phase III trial.[5] However, the dosage used in the Phase III trial may have been too low to be efficacious.[6]

A Phase II study with maribavir demonstrated that prophylaxis with maribavir displayed strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants.[7] In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced with maribavir compared to placebo.

ViroPharma conducted a Phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients. In February 2009, ViroPharma announced that the Phase III study failed to achieve its goal, showing no significant difference between maribavir and a placebo at reducing the rate at which CMV DNA levels were detected in patients.[8]

The safety and efficacy of maribavir were evaluated in a Phase III, multicenter, open-label, active-controlled trial that compared maribavir with a treatment assigned by a researcher running the study, which could include one or two of the following antivirals used to treat cytomegalovirus: ganciclovirvalganciclovirfoscarnet, or cidofovir.[2] In the study, 352 transplant recipients with cytomegalovirus infections who did not respond (with or without resistance) to treatment randomly received maribavir or treatment assigned by a researcher for up to eight weeks.[2] The study compared the two groups’ plasma cytomegalovirus DNA concentration levels at the end of the study’s eighth week, with efficacy defined as having a level below what is measurable.[2] Of the 235 participants who received maribavir, 56% had levels of cytomegalovirus DNA below what was measurable versus 24% of the 117 participants who received an investigator-assigned treatment.[2]

The U.S. Food and Drug Administration (FDA) granted the application for maribavir orphan drugbreakthrough therapy and priority review designations.[2][3][9][10] The FDA granted the approval of Livtencity to Takeda Pharmaceuticals Company Limited.[2][3]

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FDA Approves First Treatment for Common Type of Post-Transplant Infection that is Resistant to Other Drugs

Approval is for Cytomegalovirus, a Type of Herpes Virus

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-common-type-post-transplant-infection-resistant-other-drugsFor Immediate Release:November 23, 2021

Today, the U.S. Food and Drug Administration approved Livtencity (maribavir) as the first drug for treating adults and pediatric patients (12 years of age and older and weighing at least 35 kilograms) with post-transplant cytomegalovirus (CMV) infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for CMV. Livtencity works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.

“Transplant recipients are at a much greater risk for complications and death when faced with a cytomegalovirus infection,” said John Farley, M.D., M.P.H., director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research. “Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern. Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.” 

CMV is a type of herpes virus that commonly causes infection in patients after a stem cell or organ transplant. CMV infection can lead to CMV disease and have a major negative impact on transplant recipients, including loss of the transplanted organ and death.

Livtencity’s safety and efficacy were evaluated in a Phase 3, multicenter, open-label, active-controlled trial that compared Livtencity with a treatment assigned by a researcher running the study, which could include one or two of the following antivirals used to treat CMV: ganciclovir, valganciclovir, foscarnet or cidofovir. In the study, 352 transplant recipients with CMV infections who did not respond (with or without resistance) to treatment randomly received Livtencity or treatment assigned by a researcher for up to eight weeks.

The study compared the two groups’ plasma CMV DNA concentration levels at the end of the study’s eighth week, with efficacy defined as having a level below what is measurable. Of the 235 patients who received Livtencity, 56% had levels of CMV DNA below what was measurable versus 24% of the 117 patients who received an investigator-assigned treatment.

The most common side effects of Livtencity include taste disturbance, nausea, diarrhea, vomiting and fatigue. Livtencity may reduce the antiviral activity of ganciclovir and valganciclovir, so coadministration with these drugs is not recommended. Virologic failure due to resistance can occur during and after treatment with Livtencity, therefore CMV DNA levels should be monitored and Livtencity resistance should be checked if the patient is not responding to treatment or relapses.

Livtencity received Breakthrough Therapy and Priority Review designations for this indication. Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). Priority Review designation directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications.

The FDA granted the approval of Livtencity to Takeda Pharmaceuticals Company Limited.
Related Information

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215596lbl.pdf
  2. Jump up to:a b c d e f g h i j k l m “FDA Approves First Treatment for Common Type of Post-Transplant Infection that is Resistant to Other Drugs”U.S. Food and Drug Administration (FDA) (Press release). 23 November 2021. Retrieved 23 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c “Takeda’s Livtencity (maribavir) Approved by U.S. FDA as the First and Only Treatment for People Ages 12 and Older with Post-Transplant Cytomegalovirus (CMV), Refractory (With or Without Genotypic Resistance) to Conventional Antiviral Therapies”Takeda (Press release). 23 November 2021. Retrieved 26 November 2021.
  4. ^ Biron KK, Harvey RJ, Chamberlain SC, Good SS, Smith AA, Davis MG, et al. (August 2002). “Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action”Antimicrobial Agents and Chemotherapy46 (8): 2365–72. doi:10.1128/aac.46.8.2365-2372.2002PMC 127361PMID 12121906.
  5. ^ Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, et al. (April 2011). “Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial”. The Lancet. Infectious Diseases11 (4): 284–92. doi:10.1016/S1473-3099(11)70024-XPMID 21414843.
  6. ^ Snydman DR (April 2011). “Why did maribavir fail in stem-cell transplants?”. The Lancet. Infectious Diseases11 (4): 255–7. doi:10.1016/S1473-3099(11)70033-0PMID 21414844.
  7. ^ Phase 2 Data Shows Maribavir Markedly Reduced Rate Of Cytomegalovirus Infection And Disease In Bone Marrow Transplant PatientsMedical News Today, Jun 2, 2008
  8. ^ ViroPharma:Maribavir Phase III Study Missed Goal;Shares Plunge, CNN Money, February 09, 2009
  9. ^ “Maribavir Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 1 February 2007. Retrieved 26 November 2021.
  10. ^ “Maribavir Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 7 June 2011. Retrieved 26 November 2021.
  • “Maribavir”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02931539 for “Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir” at ClinicalTrials.gov
Clinical data
Trade namesLivtencity
Other names1263W94
License dataUSDailyMedMaribavir
Routes of
administration
By mouth
ATC codeJ05AX10 (WHO)
Legal status
Legal statusUS:℞-only[1][2]
Identifiers
showIUPAC name
CAS Number176161-24-3 
PubChemCID471161
DrugBankDB06234 
ChemSpider413807 
UNIIPTB4X93HE1
ChEMBLChEMBL515408
NIAID ChemDB070966
CompTox Dashboard (EPA)DTXSID60170091 
Chemical and physical data
FormulaC15H19Cl2N3O4
Molar mass376.23 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

/////////Maribavir, APPROVALS 2021, FDA 2021, Livtencity,  Takeda,  Breakthrough Therapy,  Priority Review , ORPHAN, UNII-PTB4X93HE1, марибавир , ماريبافير  ,马立巴韦 , BW-1263W94, Camvia, D04859, G1263, GW257406X, 1263W94, BW-1263W94, GW-1263, GW-257406X, SHP-620, VP-41263,

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Pafolacianine


Pafolacianine skeletal.svg
ChemSpider 2D Image | OTL-38 | C61H67N9O17S4
2D chemical structure of 1628858-03-6
img

Pafolacianine

OTL-38

  • Molecular FormulaC61H67N9O17S4
  • Average mass1326.495 Da

FDA APPROVED NOV 2021

2-{(E)-2-[(3E)-2-(4-{2-[(4-{[(2-Amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-2-carboxyethyl}phenoxy)-3-{(2E)-2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2H-indol-2-ylidene ]ethylidene}-1-cyclohexen-1-yl]vinyl}-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium-5-sulfonate OTL-38Tyrosine, N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-O-[(6E)-6-[(2E)-2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[(E)-2-[3,3-dimethy l-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt

 2-(2-(2-(4-((2S)-2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-2-carboxyethyl)phenoxy)-3-(2-(3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2H-indol-2-ylidene)ethylidene)cyclohex-1-en-1-yl)ethenyl)-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium inner salt,sodium salt (1:4)

  • 3H-Indolium, 2-(2-(2-(4-((2S)-2-((4-(((2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)amino)-2-carboxyethyl)phenoxy)-3-(2-(1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene)ethylidene)-1-cyclohexen-1-yl)ethenyl)-3,3-dimethyl-5-sulfo-1 (4-sulfobutyl)-, inner salt,sodium salt (1:4)

1628423-76-6 [RN]

Pafolacianine sodium.png

Pafolacianine sodium [USAN]
RN: 1628858-03-6
UNII: 4HUF3V875C

C61H68N9Na4O17S4+5

  • Intraoperative Imaging and Detection of Folate Receptor Positive Malignant Lesions

Pafolacianine, sold under the brand name Cytalux, is an optical imaging agent.[1][2]

The most common side effects of pafolacianine include infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity.[2]

It was approved for medical use in the United States in November 2021.[2][3]

Pafolacianine is a fluorescent drug that targets folate receptor (FR).[1]

Medical uses

Pafolacianine is indicated as an adjunct for intraoperative identification of malignant lesions in people with ovarian cancer.[1][2]

History

The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgery.[2] Of the 134 women (ages 33 to 81 years) who received a dose of pafolacianine and were evaluated under both normal and fluorescent light during surgery, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.[2]

The U.S. Food and Drug Administration (FDA) granted the application for pafolacianine orphan drugpriority review, and fast track designations.[2][4] The FDA granted the approval of Cytalux to On Target Laboratories, LLC.[2]

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SYN

WO 2014149073

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014149073

In another aspect of the invention, this disclosure provides a method of synthesizing a compound having the formula

[0029] In a fourth embodiment of the invention, this disclosure provides a method of synthesizing a compound having the formula

[0030] 

 [0032] wherein C is any carbon isotope. In this embodiment, the amino acid linker is selected from a group consisting of methyl 2-di-tert-butyl dicarbonate-amino-3-(4-phenyl)propanoate, 3-(4-hydroxyphenyl)-2-(di-tert-butyl-dicarbonate methylamino)propanoic acid, 2-amino-4-(4-hydroxyphenyl)butanoic acid, and Tert-butyl (2-di-tert-butyl dicarbonate- amino)-3-(4-hydroxyphenyl)propanoate . In a particular embodiment, the aqueous base is potassium hydroxide (KOH). The method of this embodiment may also further include purifying the compound by preparatory HPLC.

EXAMPLE 1 : General synthesis of Pte – L Tyrosine – S0456 (OTL-0038)

[0088] Scheme:

C33H37CIF3N

Reactants for Step I:

[0089] A 500 mL round bottom flask was charged with a stirring bar, pteroic acid

(12.0 g, 29.40 mmol, 1 equiv), (L)-Tyr(-OfBu)-OfBu- HCI (1 1 .63 g, 35.28 mmol, 1 .2

equiv) and HATU (13.45 g, 35.28 mmol, 1 .2 equiv) then DMF (147 mL) was added to give a brown suspension [suspension A]. DIPEA (20.48 mL, 1 17.62 mmol, 4.0 equiv) was added slowly to suspension A at 23 °C, over 5 minutes. The suspension turned in to a clear brown solution within 10 minutes of addition of DIPEA. The reaction was stirred at 23 °C for 2.5 h. Reaction was essentially complete in 30 minutes as judged by LC/MS but was stirred further for 2.5 h. The formation of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI (Figure 12) was confirmed by LC/MS showing m/z 409→m/z 684. LC/MS method: 0-50% acetonitrile in 20 mM aqueous NH4OAc for 5 min using Aquity UPLC-BEH C18, 1 .7μιη 2.1 * 50 mm column . The reaction mixture was cannulated as a steady stream to a stirred solution of aq. HCI (2.0 L, 0.28 M) over the period of 30 minutes to give light yellow precipitate of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI. The precipitated Pte_N 10(TFA)_L_Tyr(- OfBu)-OfBu HCI was filtered using sintered funnel under aspirator vacuum, washed with water (8 * 300 mL) until the pH of the filtrate is between 3 and 4. The wet solid was allowed to dry under high vacuum for 12 hours on the sintered funnel. In a separate batch, where this wet solid (3) was dried under vacuum for 48 hours and then this solid was stored at -20 0 C for 48 h. However, this brief storage led to partial decomposition of 3. The wet cake (58 g) was transferred to a 500 mL round bottom flask and was submitted to the next step without further drying or purification.

Reactants for Step II:

The wet solid (58 g) was assumed to contain 29.40 mmol of the desired compound (3) (i. e. quantitative yield for the step I ).

[0090] A 500 mL round bottom flask was charged with a stirring bar, Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI as a wet cake (58 g, 29.40 mmol, 1 equiv). A solution of TFA:TIPS:H20 (95:2.5:2.5, 200 mL) was added at once to give a light brown suspension. The reaction content was stirred at 23°C for 1 .5 hours and was monitored by LC/MS. The suspension became clear dull brown solution after stirring for 5 minutes. LC/MS method: 0-50% acetonitrile in 20 mM aqueous NH4OAc for 5 min using Aquity UPLC-BEH C18, 1 .7μιη 2.1 * 50 mm column. The formation of Pte_TFA_L_Tyr (Figure 12) was confirmed by showing m/z 684→m/z 572. Reaction time varies from 30 min to 1 .5 hours depending on the water content of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI. The reaction mixture was cannulated as a steady stream to a stirred MTBE (1 .8 L) at 23 °C or 100 °C to give light yellow precipitate of Pte_TFA_L_Tyr. The precipitated Pte_TFA_L_Tyr was filtered using sintered funnel under aspirator vacuum, washed with MTBE (6 * 300 mL) and dried under high vacuum for 8 hours to obtain Pte_TFA_L_Tyr (14.98 g, 83.98% over two steps) as a pale yellow solid. The MTBE washing was tested for absence of residual TFA utilizing wet pH paper (pH between 3-4). The yield of the reaction was between 80-85% in different batches. The deacylated side product was detected in 3.6% as judged by LC/MS. For the different batches this impurity was never more than 5%.

Reactants for Step III:

[0091] A 200 mL round bottom flask was charged with a stirring bar and Pte_TFA_L_Tyr (13.85 g, 22.78 mmol, 1 equiv), then water (95 mL) was added to give a yellow suspension [suspension B]. A freshly prepared solution of aqueous 3.75 M NaOH (26.12 mL, 97.96 mmol, 4.30 equiv), or an equivalent base at a corresponding temperature using dimethylsulfoxide (DMSO) as a solvent (as shown in Table 1 ), was added dropwise to suspension B at 23 °C, giving a clear dull yellow solution over 15 minutes [solution B]. The equivalence of NaOH varied from 3.3 to 5.0 depending on the source of 4 (solid or liquid phase synthesis) and the residual TFA. Trianion 5 (Figure 12) formation was confirmed by LC/MS showing m/z 572→m/z 476 while the solution pH was 9-10 utilizing wet pH paper. The pH of the reaction mixture was in the range of 9-10. This pH is crucial for the overall reaction completion. Notably, pH more than 10 leads to hydrolysis of S0456. Excess base will efficiently drive reaction forward with potential hydrolysis of S0456. The presence of hydrolysis by product can be visibly detected by the persistent opaque purple/blue to red/brown color.

TABLE 1 : Separate TFA deprotection via trianion formation; S0456

[0092] The precipitated OTL-0038 product could also be crashed out by adding the reaction solution steady dropwise to acetone, acetonitrile, isopropanol or ethyl acetate/acetone mixture. Acetone yields optimal results. However, viscous reactions could be slower due to partial insolubility and/or crashing out of S0456. In this reaction, the equivalence of the aqueous base is significant. Excess base will efficiently drive reaction forward with potential hydrolysis of S0456. This solution phase synthesis provides Pte_N10(TFA)_Tyr-OH »HCI salt and desires approximately 4.1 to approximately 4.8 equiv base as a source to hydrolyze the product. Particularly, precipitation of Pte_Tyr_S0456 was best achieved when 1 mL of reaction mixture is added dropwise to the stirred acetone (20 mL). Filtration of the precipitate and washing with acetone (3 x10 mL) gave the highest purity as judged from LC/MS chromatogram.

[0093] During experimentation of this solution-phase synthesis of Pte – L Tyrosine -S0456 (OTL-0038) at different stages, some optimized conditions were observed:

Mode of addition: Separate TFA deprotection via trianion formation; S0456 @ 23 °C; reflux.

Stability data of Pte – L Tyrosine – S0456 (OTL-0038):

Liquid analysis: At 40 °C the liquid lost 8.6% at 270 nm and 1 % at 774 nm. At room temperature the liquid lost about 1 .4% at 270 nm and .5% at 774 nm. At 5 °C the

270 nm seems stable and the 774 nm reasonably stable with a small degradation purity.

Source Purity Linker S0456 Base Solvent Duration % Conversion

4.3-4.6

Solution 0.95

95% 1 equiv equiv H20 15 min 100% phase equiv

K2C03

PATENT

 US 20140271482

FDA approves pafolacianine for identifying malignant ovarian cancer lesions

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pafolacianine-identifying-malignant-ovarian-cancer-lesions

On November 29, 2021, the Food and Drug Administration approved pafolacianine (Cytalux, On Target Laboratories, LLC), an optical imaging agent, for adult patients with ovarian cancer as an adjunct for interoperative identification of malignant lesions. Pafolacianine is a fluorescent drug that targets folate receptor which may be overexpressed in ovarian cancer. It is used with a Near-Infrared (NIR) fluorescence imaging system cleared by the FDA for specific use with pafolacianine.

Efficacy was evaluated in a single arm, multicenter, open-label study (NCT03180307) of 178 women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery. All patients received pafolacianine. One hundred and thirty-four patients received fluorescence imaging evaluation in addition to standard of care evaluation which includes pre-surgical imaging, intraoperative palpation and normal light evaluation of lesions. Among these patients, 36 (26.9%) had at least one evaluable ovarian cancer lesion detected with pafolacianine that was not observed by standard visual or tactile inspection. The patient-level false positive rate of pafolacianine with NIR fluorescent light with respect to the detection of ovarian cancer lesions confirmed by central pathology was 20.2% (95% CI 13.7%, 28.0%).

The most common adverse reactions (≥1%) occurring in patients were nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, pruritus, and hypersensitivity.

The recommended pafolacianine dose is 0.025 mg/kg administered intravenously over 60 minutes, 1 to 9 hours before surgery. The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of pafolacianine.

View full prescribing information for Cytalux.

This application was granted priority review, fast track designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

USFDA approves new drug to help identify cancer lesions

This drug is indicated for use in adult patients with ovarian cancer to help identify cancerous lesions during surgery.By The Health Master -December 2, 2021

The U.S. Food and Drug Administration (USFDA) has approved Cytalux (pafolacianine), an imaging drug intended to assist surgeons in identifying ovarian cancer lesions. The drug is designed to improve the ability to locate additional ovarian cancerous tissue that is normally difficult to detect during surgery.

Cytalux is indicated for use in adult patients with ovarian cancer to help identify cancerous lesions during surgery. The drug is a diagnostic agent that is administered in the form of an intravenous injection prior to surgery.

Alex Gorovets, M.D., deputy director of the Office of Specialty Medicine in the FDA’s Center for Drug Evaluation and Research said, “The FDA’s approval of Cytalux can help enhance the ability of surgeons to identify deadly ovarian tumors that may otherwise go undetected.

By supplementing current methods of detecting ovarian cancer during surgery, Cytalux offers health care professionals an additional imaging approach for patients with ovarian cancer.”

The American Cancer Society estimates there will be more than 21,000 new cases of ovarian cancer and more than 13,000 deaths from this disease in 2021, making it the deadliest of all female reproductive system cancers.

Conventional treatment for ovarian cancer includes surgery to remove as many of the tumors as possible, chemotherapy to stop the growth of malignant cells or other targeted therapy to identify and attack specific cancer cells.

Ovarian cancer often causes the body to overproduce a specific protein in cell membranes called a folate receptor. Following administration via injection, Cytalux binds to these proteins and illuminates under fluorescent light, boosting surgeons’ ability to identify the cancerous tissue.

Currently, surgeons rely on preoperative imaging, visual inspection of tumors under normal light or examination by touch to identify cancer lesions. Cytalux is used with a Near-Infrared fluorescence imaging system cleared by the FDA for specific use with pafolacianine.

The safety and effectiveness of Cytalux was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgery.

Of the 134 women (ages 33 to 81 years) who received a dose of Cytalux and were evaluated under both normal and fluorescent light during surgery, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.

The most common side effects of Cytalux were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity. Cytalux may cause fetal harm when administered to a pregnant woman.

The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of Cytalux. There is a risk of image interpretation errors with the use of Cytalux to detect ovarian cancer during surgery, including false negatives and false positives.

References

  1. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214907s000lbl.pdf
  2. Jump up to:a b c d e f g h i “FDA Approves New Imaging Drug to Help Identify Ovarian Cancer Lesions”U.S. Food and Drug Administration (FDA) (Press release). 29 November 2021. Retrieved 30 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “On Target Laboratories Announces FDA Approval of Cytalux (pafolacianine) injection for Identification of Ovarian Cancer During Surgery”. On Target Laboratories. 29 November 2021. Retrieved 30 November 2021 – via PR Newswire.
  4. ^ “Pafolacianine Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 23 December 2014. Retrieved 30 November 2021.
Clinical data
Trade namesCytalux
Other namesOTL-0038
License dataUS DailyMedPafolacianine
Pregnancy
category
Not recommended
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number1628423-76-6
PubChem CID135565623
DrugBankDB15413
ChemSpider64880249
UNIIF7BD3Z4X8L
ChEMBLChEMBL4297412
Chemical and physical data
FormulaC61H67N9O17S4
Molar mass1326.49 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Pafolacianine, FDA 2021, APPROVALS 2021,  Cytalux, OVARIAN CANCER, OTL 38, 

[Na+].[Na+].[Na+].[Na+].CC1(C)\C(=C/C=C/2\CCCC(=C2Oc3ccc(C[C@H](NC(=O)c4ccc(NCc5cnc6N=C(N)NC(=O)c6n5)cc4)C(=O)O)cc3)\C=C\C7=[N](CCCCS(=O)(=O)O)c8ccc(cc8C7(C)C)S(=O)(=O)O)\N(CCCCS(=O)(=O)O)c9ccc(cc19)S(=O)(=O)O

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Ropeginterferon alfa-2b


PCDLPQTHSL GSRRTLMLLA QMRRISLFSC LKDRHDFGFP QEEFGNQFQK AETIPVLHEM
IQQIFNLFST KDSSAAWDET LLDKFYTELY QQLNDLEACV IQGVGVTETP LMKEDSILAV
RKYFQRITLY LKEKKYSPCA WEVVRAEIMR SFSLSTNLQE SLRSKE
(Disulfide bridge: 2-99, 30-139)

Ropeginterferon alfa-2b

  • AOP2014

CAS 1335098-50-4

UNII981TME683S

FDA APPROVED, 2021/11/12, BESREMI

PEPTIDE, Antineoplastic, Antiviral

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia.1,2 Interferon alfa-2b has been used for decades to treat PV but requires frequent dosing and is not tolerated by all patients.2 Ropeginterferon alfa-2b is a next-generation mono-pegylated type I interferon produced from proline-IFN-α-2b in Escherichia coli that has high tolerability and a long half-life.4,6 Ropeginterferon alfa-2b has shown efficacy in PV in in vitro and in vivo models and clinical trials.3,4

Ropeginterferon alfa-2b was approved by the FDA on November 12, 2021, and is currently marketed under the trademark BESREMi by PharmaEssentia Corporation.6

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera.[1][2][3][4] It is an interferon.[1][3] It is given by injection.[1][3]

The most common side effects include low levels of white blood cells and platelets (blood components that help the blood to clot), muscle and joint pain, tiredness, flu-like symptoms and increased blood levels of gamma-glutamyl transferase (a sign of liver problems).[3] Ropeginterferon alfa-2b can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness.[2] Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).[2]

It was approved for medical use in the European Union in February 2019,[3] and in the United States in November 2021.[2][5] Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.[2]

https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease#:~:text=FDA%20NEWS%20RELEASE-,FDA%20Approves%20Treatment%20for%20Rare%20Blood%20Disease,FDA%2DApproved%20Option%20Patients%20Can%20Take%20Regardless%20of%20Previous%20Therapies,-ShareFor Immediate Release:November 12, 2021

Today, the U.S. Food and Drug Administration approved Besremi (ropeginterferon alfa-2b-njft) injection to treat adults with polycythemia vera, a blood disease that causes the overproduction of red blood cells. The excess cells thicken the blood, slowing blood flow and increasing the chance of blood clots.

“Over 7,000 rare diseases affect more than 30 million people in the United States. Polycythemia vera affects approximately 6,200 Americans each year,” said Ann Farrell, M.D., director of the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research. “This action highlights the FDA’s commitment to helping make new treatments available to patients with rare diseases.”

Besremi is the first FDA-approved medication for polycythemia vera that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.

Treatment for polycythemia vera includes phlebotomies (a procedure that removes excess blood cells though a needle in a vein) as well as medicines to reduce the number of blood cells; Besremi is one of these medicines. Besremi is believed to work by attaching to certain receptors in the body, setting off a chain reaction that makes the bone marrow reduce blood cell production. Besremi is a long-acting drug that patients take by injection under the skin once every two weeks. If Besremi can reduce excess blood cells and maintain normal levels for at least one year, then dosing frequency may be reduced to once every four weeks.

The effectiveness and safety of Besremi were evaluated in a multicenter, single-arm trial that lasted 7.5 years. In this trial, 51 adults with polycythemia vera received Besremi for an average of about five years. Besremi’s effectiveness was assessed by looking at how many patients achieved complete hematological response, which meant that patients had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots. Overall, 61% of patients had a complete hematological response.

Besremi can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness. Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).

Interferon alfa products like Besremi may cause or worsen neuropsychiatric, autoimmune, ischemic (not enough blood flow to a part of the body) and infectious diseases, which could lead to life-threatening or fatal complications. Patients who must not take Besremi include those who are allergic to the drug, those with a severe psychiatric disorder or a history of a severe psychiatric disorder, immunosuppressed transplant recipients, certain patients with autoimmune disease or a history of autoimmune disease, and patients with liver disease.

People who could be pregnant should be tested for pregnancy before using Besremi due to the risk of fetal harm.

Besremi received orphan drug designation for this indication. Orphan drug designation provides incentives to assist and encourage drug development for rare diseases.

The FDA granted the approval of Besremi to PharmaEssentia Corporation.

Medical uses

In the European Union, ropeginterferon alfa-2b is indicated as monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly.[3] In the United States it is indicated for the treatment of polycythemia vera.[1][2][5]

History

The effectiveness and safety of ropeginterferon alfa-2b were evaluated in a multicenter, single-arm trial that lasted 7.5 years.[2] In this trial, 51 adults with polycythemia vera received ropeginterferon alfa-2b for an average of about five years.[2] The effectiveness of ropeginterferon alfa-2b was assessed by looking at how many participants achieved complete hematological response, which meant that participants had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots.[2] Overall, 61% of participants had a complete hematological response.[2] The U.S. Food and Drug Administration (FDA) granted the application for Ropeginterferon_alfa-2b orphan drug designation and granted the approval of Besremi to PharmaEssentia Corporation[2]

REF

  1. Bartalucci N, Guglielmelli P, Vannucchi AM: Polycythemia vera: the current status of preclinical models and therapeutic targets. Expert Opin Ther Targets. 2020 Jul;24(7):615-628. doi: 10.1080/14728222.2020.1762176. Epub 2020 May 18. [Article]
  2. How J, Hobbs G: Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020 Jul 18;12(7). pii: cancers12071954. doi: 10.3390/cancers12071954. [Article]
  3. Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0. [Article]
  4. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, Kralovics R, Gisslinger B, Strecker K, Egle A, Melchardt T, Burgstaller S, Willenbacher E, Schalling M, Them NC, Kadlecova P, Klade C, Greil R: Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015 Oct 8;126(15):1762-9. doi: 10.1182/blood-2015-04-637280. Epub 2015 Aug 10. [Article]
  5. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
  6. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]
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References

  1. Jump up to:a b c d e https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761166s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l “FDA Approves Treatment for Rare Blood Disease”U.S. Food and Drug Administration (FDA) (Press release). 12 November 2021. Retrieved 12 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e f g “Besremi EPAR”European Medicines Agency (EMA). Retrieved 14 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ Wagner SM, Melchardt T, Greil R (March 2020). “Ropeginterferon alfa-2b for the treatment of patients with polycythemia vera”. Drugs of Today. Barcelona, Spain. 56 (3): 195–202. doi:10.1358/dot.2020.56.3.3107706PMID 32282866S2CID 215758794.
  5. Jump up to:a b “U.S. FDA Approves Besremi (ropeginterferon alfa-2b-njft) as the Only Interferon for Adults With Polycythemia Vera” (Press release). PharmaEssentia. 12 November 2021. Retrieved 14 November 2021 – via Business Wire.
Clinical data
Trade namesBesremi
Other namesAOP2014, ropeginterferon alfa-2b-njft
License dataEU EMAby INNUS DailyMedRopeginterferon_alfa
Pregnancy
category
Contraindicated
Routes of
administration
Subcutaneous
Drug classInterferon
ATC codeL03AB15 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]EU: Rx-only [3]
Identifiers
CAS Number1335098-50-4
DrugBankDB15119
UNII981TME683S
KEGGD11027

/////////Ropeginterferon alfa-2b, FDA 2021, APPROVALS 2021,  BESREMI, PEPTIDE, Antineoplastic, Antiviral, AOP 2014, PharmaEssentia

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RTS,S/AS01, RTS,S Mosquirix


 The World Health Organization (WHO) has announced that the Government of Malawi has immunized the first children with RTS,S/AS01 (RTS,S), the world’s first malaria vaccine, according to the World Record Academy.

Sequence:

1MMAPDPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP51NANPNANPNA NPNANPNANP NANPNANPNA NPNKNNQGNG QGHNMPNDPN101RNVDENANAN NAVKNNNNEE PSDKHIEQYL KKIKNSISTE WSPCSVTCGN151GIQVRIKPGS ANKPKDELDY ENDIEKKICK MEKCSSVFNV VNSRPVTNME201NITSGFLGPL LVLQAGFFLL TRILTIPQSL DSWWTSLNFL GGSPVCLGQN251SQSPTSNHSP TSCPPICPGY RWMCLRRFII FLFILLLCLI FLLVLLDYQG301MLPVCPLIPG STTTNTGPCK TCTTPAQGNS MFPSCCCTKP TDGNCTCIPI351PSSWAFAKYL WEWASVRFSW LSLLVPFVQW FVGLSPTVWL SAIWMMWYWG401PSLYSIVSPF IPLLPIFFCL WVYI

RTS,S/AS01 (RTS,S)

RTS,S/AS01, Mosquirix

Cas 149121-47-1

203-400-Antigen CS (Plasmodium falciparum strain NF54 reduced), 203-L-methionine-204-L-methionine-205-L-alanine-206-L-proline-207-L-aspartic acid-210-L-alanine-211-L-asparagine-313-L-asparagine-329-L-glutamic acid-330-L-glutamine-333-L-lysine-336-L-lysine-339-L-isoleucine-373-L-glutamic acid-396-L-arginine-397-L-proline-398-L-valine-399-L-threonine-400-L-asparagine-, (400→1′)-protein with antigen (hepatitis B virus subtype adw small surface reduced) (9CI) 

Other Names

  • Malaria vaccine RTS,S
  • Mosquirix
  • RTS,S

Protein Sequence

Sequence Length: 424

An external file that holds a picture, illustration, etc. Object name is khvi-16-03-1669415-g002.jpg

Figure 2.

Graphical depiction of circumsporozoite (CSP) and RTS,S structures. CSP comprises an N-terminal region containing a signal peptide sequence and Region I that binds heparin sulfate proteoglycans and has embedded within it a conserved five amino acid (KLKQP) proteolytic cleavage site sequence; a central region containing four-amino acid (NANP/NVDP) repeats; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchor addition sequence. The region of the CSP included in the RTS,S vaccine includes the last 18 NANP repeats and C-terminus exclusive of the GPI anchor addition sequence. Hepatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like particles and approximately 25% of the HBsAg monomers in RTS,S are genetically fused to the truncated CSP and serve as protein carriers. The CSP fragment in RTS,S contains three known T-cell epitopes: a highly variable CD4 + T-cell epitope before the TSP-like domain (TH2R), a highly variable CD8 + T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 + T cell epitope (CS.T3) at the C-terminus. (Figure courtesy of a recent publication16 and open access,
PATENTWO 2009080715

https://patents.google.com/patent/WO2009080715A2/tr

XAMPLES

Example 1Recipe for component for a single pediatric dose of RTS, S malaria vaccine (2 vial formulation)Component AmountRTS,S 25μgNaCl 2.25mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μgWater for Injection Make volume to 250 μLThe above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Finally pH is adjusted to 7.0 ± 0.1.This may be provided as a vial together with a separate vial of adjuvant, for example a liposomal formulation of MPL and QS21Component Amount l,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgNaCl 2.25mg Phosphate buffer (NaZK2) 1 OmMWater for Injection Make volume to250 μLFor administration the adjuvant formulation is added to the component formulation, for example using a syringe, and then shaken. Then the dose is administered in the usual way. The pH of the final liquid formulation is about 6.6 +/- 0.1.Example IAA final pediatric liquid formulation (1 vial) according to the invention may be prepared according to the following recipe.Component AmountRTS,S 25μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgWater for Injection Make volume to500 μLThe pH of the above liquid formulation is either adjusted to 7.0 +/- 0.1 (which is favorable for antigen stability, but not favorable at all for the MPL stability), or to 6.1 +/- 0.1 (which is favorable for MPL stability, but not favorable at all for RT S, S stability). Therefore this formulation is intended for rapid use after preparation.The above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Then a premix of liposomes containing MPL with QS21 is added, and finally pH is adjusted. Example IBA final adult dose (1 vial formulation) for the RTS, S according to the invention may be prepared as follows:Component AmountRTS,S 50μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 250μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 1000 μgCholesterol 250 μgMPL 50 μgQS21 50 μgWater for Injection Make volume to500 μLExample 1CExample 1C may prepared by putting Example 1, IA or IB in an amber vial, for example flushed with nitrogen before filing.

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WHO recommends groundbreaking malaria vaccine for children at risk

Historic RTS,S/AS01 recommendation can reinvigorate the fight against malaria6 October 2021https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk

The World Health Organization (WHO) is recommending widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission. The recommendation is based on results from an ongoing pilot programme in Ghana, Kenya and Malawi that has reached more than 800 000 children since 2019.

“This is a historic moment. The long-awaited malaria vaccine for children is a breakthrough for science, child health and malaria control,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus. “Using this vaccine on top of existing  tools to prevent malaria could save tens of thousands of young lives each year.”

Malaria remains a primary cause of childhood illness and death in sub-Saharan Africa. More than 260 000 African children under the age of five die from malaria annually.

In recent years, WHO and its partners have been reporting a stagnation in progress against the deadly disease.

“For centuries, malaria has stalked sub-Saharan Africa, causing immense personal suffering,” said Dr Matshidiso Moeti, WHO Regional Director for Africa. “We have long hoped for an effective malaria vaccine and now for the first time ever, we have such a vaccine recommended for widespread use. Today’s recommendation offers a glimmer of hope for the continent which shoulders the heaviest burden of the disease and we expect many more African children to be protected from malaria and grow into healthy adults.”

WHO recommendation for the RTS,S malaria vaccine

Based on the advice of two WHO global advisory bodies, one for immunization and the other for malaria, the Organization recommends that:

WHO recommends that in the context of comprehensive malaria control the RTS,S/AS01 malaria vaccine be used for the prevention of P. falciparum malaria in children living in regions with moderate to high transmission as defined by WHO.  RTS,S/AS01 malaria vaccine should be provided in a schedule of 4 doses in children from 5 months of age for the reduction of malaria disease and burden.

Summary of key findings of the malaria vaccine pilots

Key findings of the pilots informed the recommendation based on data and insights generated from two years of vaccination in child health clinics in the three pilot countries, implemented under the leadership of the Ministries of Health of Ghana, Kenya and Malawi. Findings include:

  • Feasible to deliver: Vaccine introduction is feasible, improves health and saves lives, with good and equitable coverage of RTS,S seen through routine immunization systems. This occurred even in the context of the COVID-19 pandemic.
  • Reaching the unreached: RTS,S increases equity in access to malaria prevention.
    • Data from the pilot programme showed that more than two-thirds of children in the 3 countries who are not sleeping under a bednet are benefitting from the RTS,S vaccine.
    • Layering the tools results in over 90% of children benefitting from at least one preventive intervention (insecticide treated bednets or the malaria vaccine).
  • Strong safety profile: To date, more than 2.3 million doses of the vaccine have been administered in 3 African countries – the vaccine has a favorable safety profile.
  • No negative impact on uptake of bednets, other childhood vaccinations, or health seeking behavior for febrile illness. In areas where the vaccine has been introduced, there has been no decrease in the use of insecticide-treated nets, uptake of other childhood vaccinations or health seeking behavior for febrile illness.
  • High impact in real-life childhood vaccination settings: Significant reduction (30%) in deadly severe malaria, even when introduced in areas where insecticide-treated nets are widely used and there is good access to diagnosis and treatment.
  • Highly cost-effective: Modelling estimates that the vaccine is cost effective in areas of moderate to high malaria transmission.

Next steps for the WHO-recommended malaria vaccine will include funding decisions from the global health community for broader rollout, and country decision-making on whether to adopt the vaccine as part of national malaria control strategies.

Financial support

Financing for the pilot programme has been mobilized through an unprecedented collaboration among three key global health funding bodies: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Note to editors:

  • The malaria vaccine, RTS,S, acts against P. falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa.
  • The Malaria Vaccine Implementation Programme is generating evidence and experience on the feasibility, impact and safety of the RTS,S malaria vaccine in real-life, routine settings in selected areas of Ghana, Kenya and Malawi.
  • Pilot malaria vaccine introductions are led by the Ministries of Health of Ghana, Kenya and Malawi.
  • The pilot programme will continue in the 3 pilot countries to understand the added value of the 4th vaccine dose, and to measure longer-term impact on child deaths.
  • The Malaria Vaccine Implementation Programme is coordinated by WHO and supported by in-country and international partners, including PATH, UNICEF and GSK, which is donating up to 10 million doses of the vaccine for the pilot.
  • The RTS,S malaria vaccine is the result of 30 years of research and development by GSK and through a partnership with PATH, with support from a network of African research centres.
  • The Bill & Melinda Gates Foundation provided catalytic funding for late-stage development of RTS,S between 2001 and 2015.

RTS,S/AS01 (trade name Mosquirix) is a recombinant protein-based malaria vaccine. In October 2021, the vaccine was endorsed by the World Health Organization (WHO) for “broad use” in children, making it the first malaria vaccine candidate, and first vaccine to address parasitic infection, to receive this recommendation.[3][4][5]

The RTS,S vaccine was conceived of and created in the late 1980s by scientists working at SmithKline Beecham Biologicals (now GlaxoSmithKline (GSK) Vaccines) laboratories in Belgium.[6] The vaccine was further developed through a collaboration between GSK and the Walter Reed Army Institute of Research in the U.S. state of Maryland[7] and has been funded in part by the PATH Malaria Vaccine Initiative and the Bill and Melinda Gates Foundation. Its efficacy ranges from 26 to 50% in infants and young children.

Approved for use by the European Medicines Agency (EMA) in July 2015,[1] it is the world’s first licensed malaria vaccine and also the first vaccine licensed for use against a human parasitic disease of any kind.[8] On 23 October 2015, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) jointly recommended a pilot implementation of the vaccine in Africa.[9] This pilot project for vaccination was launched on 23 April 2019 in Malawi, on 30 April 2019 in Ghana, and on 13 September 2019 in Kenya.[10][11]

Background

Main article: Malaria vaccine

Potential malaria vaccines have been an intense area of research since the 1960s.[12] SPf66 was tested extensively in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective.[13] Other vaccine candidates, targeting the blood-stage of the malaria parasite’s life cycle, have also been insufficient on their own.[14] Among several potential vaccines under development that target the pre-erythrocytic stage of the disease, RTS,S has shown the most promising results so far.[15]

Approval history

The EMA approved the RTS,S vaccine in July 2015, with a recommendation that it be used in Africa for babies at risk of getting malaria. RTS,S was the world’s first malaria vaccine to get approval for this use.[16][8] Preliminary research suggests that delayed fractional dosing could increase the vaccine’s efficacy up to 86%.[17][18]

On 17 November 2016, WHO announced that the RTS,S vaccine would be rolled out in pilot projects in three countries in sub-Saharan Africa. The pilot program, coordinated by WHO, will assess the extent to which the vaccine’s protective effect shown in advanced clinical trials can be replicated in real-life settings. Specifically, the programme will evaluate the feasibility of delivering the required four doses of the vaccine; the impact of the vaccine on lives saved; and the safety of the vaccine in the context of routine use.[19]

Vaccinations by the ministries of health of Malawi, Ghana, and Kenya began in April and September 2019 and target 360,000 children per year in areas where vaccination would have the highest impact. The results are planned to be used by the World Health Organization to advise about a possible future deployment of the vaccine.[10][11][20] In 2021 it was reported that the vaccine together with other anti-malaria medication when given at the most vulnerable season could reduce deaths and illness from the disease by 70%.[21][22]

Funding

RTS,S has been funded, most recently, by the non-profit PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline with funding from the Bill and Melinda Gates Foundation.[23] The RTS,S-based vaccine formulation had previously been demonstrated to be safe, well tolerated, immunogenic, and to potentially confer partial efficacy in both malaria-naive and malaria-experienced adults as well as children.[24]

Components and mechanism

 

The RTS,S vaccine is based on a protein construct first developed by GlaxoSmithKline in 1986. It was named RTS because it was engineered using genes from the repeat (‘R’) and T-cell epitope (‘T’) of the pre-erythrocytic circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite together with a viral surface antigen (‘S’) of the hepatitis B virus (HBsAg).[7] This protein was then mixed with additional HBsAg to improve purification, hence the extra “S”.[7] Together, these two protein components assemble into soluble virus-like particles similar to the outer shell of a hepatitis B virus.[25]

A chemical adjuvant (AS01, specifically AS01E) was added to increase the immune system response.[26] Infection is prevented by inducing humoral and cellular immunity, with high antibody titers, that block the parasite from infecting the liver.[27]

The T-cell epitope of CSP is O-fucosylated in Plasmodium falciparum[28][29] and Plasmodium vivax,[30] while the RTS,S vaccine produced in yeast is not.

References

  1. Jump up to:a b “Mosquirix H-W-2300”European Medicines Agency (EMA). Retrieved 4 March 2021.
  2. ^ “RTS,S Malaria Vaccine: 2019 Partnership Award Honoree”YouTube. Global Health Technologies Coalition. Retrieved 6 October 2021.
  3. ^ Davies L (6 October 2021). “WHO endorses use of world’s first malaria vaccine in Africa”The Guardian. Retrieved 6 October2021.
  4. ^ Drysdale C, Kelleher K. “WHO recommends groundbreaking malaria vaccine for children at risk” (Press release). Geneva: World Health Organization. Retrieved 6 October 2021.
  5. ^ Mandavilli A (6 October 2021). “A ‘Historical Event’: First Malaria Vaccine Approved by W.H.O.” New York Times. Retrieved 6 October 2021.
  6. ^ “HYBRID PROTEIN BETWEEN CS FROM PLASMODIUM AND HBsAG”.
  7. Jump up to:a b c Heppner DG, Kester KE, Ockenhouse CF, Tornieporth N, Ofori O, Lyon JA, et al. (March 2005). “Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research”Vaccine23 (17–18): 2243–50. doi:10.1016/j.vaccine.2005.01.142PMID 15755604Archived from the original on 23 July 2018.
  8. Jump up to:a b Walsh F (24 July 2015). “Malaria vaccine gets ‘green light'”BBC NewsArchived from the original on 21 July 2020. Retrieved 25 July 2015.
  9. ^ Stewart S (23 October 2015). “Pilot implementation of first malaria vaccine recommended by WHO advisory groups” (Press release). Geneva: World Health OrganizationArchived from the original on 19 September 2021.
  10. Jump up to:a b Alonso P (19 June 2019). “Letter to partners – June 2019”(Press release). Wuxi: World Health Organization. Retrieved 22 October 2019.
  11. Jump up to:a b “Malaria vaccine launched in Kenya: Kenya joins Ghana and Malawi to roll out landmark vaccine in pilot introduction” (Press release). Homa Bay: World Health Organization. 13 September 2019. Retrieved 22 October 2019.
  12. ^ Hill AV (October 2011). “Vaccines against malaria”Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences366 (1579): 2806–14. doi:10.1098/rstb.2011.0091PMC 3146776PMID 21893544.
  13. ^ Graves P, Gelband H (April 2006). Graves PM (ed.). “Vaccines for preventing malaria (SPf66)”The Cochrane Database of Systematic Reviews (2): CD005966. doi:10.1002/14651858.CD005966PMC 6532709PMID 16625647.
  14. ^ Graves P, Gelband H (October 2006). Graves PM (ed.). “Vaccines for preventing malaria (blood-stage)”The Cochrane Database of Systematic Reviews (4): CD006199. doi:10.1002/14651858.CD006199PMC 6532641PMID 17054281.
  15. ^ Graves P, Gelband H (October 2006). Graves PM (ed.). “Vaccines for preventing malaria (pre-erythrocytic)”The Cochrane Database of Systematic Reviews (4): CD006198. doi:10.1002/14651858.CD006198PMC 6532586PMID 17054280.
  16. ^ “First malaria vaccine receives positive scientific opinion from EMA”European Medicines Agency. 24 July 2015. Retrieved 24 July 2015.
  17. ^ Birkett A (16 September 2016). “A vaccine for malaria elimination?”PATH.
  18. ^ Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, et al. (September 2016). “Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study”The Journal of Infectious Diseases214 (5): 762–71. doi:10.1093/infdis/jiw237PMID 27296848.
  19. ^ “Malaria: The malaria vaccine implementation programme (MVIP)”.
  20. ^ “WHO | MVIP countries: Ghana, Kenya and Malawi”.
  21. ^ Chandramohan D, Zongo I, Sagara I, Cairns M, Yerbanga RS, Diarra M, et al. (September 2021). “Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention”The New England Journal of Medicine385 (11): 1005–1017. doi:10.1056/NEJMoa2026330PMID 34432975.
  22. ^ Roxby P (26 August 2021). “Trial suggests malaria sickness could be cut by 70%”BBC NewsArchived from the original on 3 October 2021. Retrieved 26 August 2021.
  23. ^ Stein R (18 October 2011). “Experimental malaria vaccine protects many children, study shows”Washington Post.
  24. ^ Regules JA, Cummings JF, Ockenhouse CF (May 2011). “The RTS,S vaccine candidate for malaria”Expert Review of Vaccines10 (5): 589–99. doi:10.1586/erv.11.57PMID 21604980S2CID 20443829.
  25. ^ Rutgers T, Gordon D, Gathoye AM, Hollingdale M, Hockmeyer W, Rosenberg M, De Wilde M (September 1988). “Hepatitis B Surface Antigen as Carrier Matrix for the Repetitive Epitope of the Circumsporozoite Protein of Plasmodium Falciparum”Nature Biotechnology6 (9): 1065–1070. doi:10.1038/nbt0988-1065S2CID 39880644.
  26. ^ RTS,S Clinical Trials Partnership (July 2015). “Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial”Lancet386 (9988): 31–45. doi:10.1016/S0140-6736(15)60721-8PMC 5626001PMID 25913272.
  27. ^ Foquet L, Hermsen CC, van Gemert GJ, Van Braeckel E, Weening KE, Sauerwein R, et al. (January 2014). “Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection”The Journal of Clinical Investigation124 (1): 140–4. doi:10.1172/JCI70349PMC 3871238PMID 24292709.
  28. ^ Swearingen KE, Lindner SE, Shi L, Shears MJ, Harupa A, Hopp CS, et al. (April 2016). “Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics”PLOS Pathogens12 (4): e1005606. doi:10.1371/journal.ppat.1005606PMC 4851412PMID 27128092.
  29. ^ Lopaticki S, Yang AS, John A, Scott NE, Lingford JP, O’Neill MT, et al. (September 2017). “Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts”Nature Communications8 (1): 561. Bibcode:2017NatCo…8..561Ldoi:10.1038/s41467-017-00571-yPMC 5601480PMID 28916755.
  30. ^ Swearingen KE, Lindner SE, Flannery EL, Vaughan AM, Morrison RD, Patrapuvich R, et al. (July 2017). “Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites”PLOS Neglected Tropical Diseases11 (7): e0005791. doi:10.1371/journal.pntd.0005791PMC 5552340PMID 28759593.

Further reading

  • Wilby KJ, Lau TT, Gilchrist SE, Ensom MH (March 2012). “Mosquirix (RTS,S): a novel vaccine for the prevention of Plasmodium falciparum malaria”. The Annals of Pharmacotherapy46 (3): 384–93. doi:10.1345/aph.1Q634PMID 22408046.
  • Asante KP, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, et al. (October 2011). “Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial”. The Lancet. Infectious Diseases11 (10): 741–9. doi:10.1016/S1473-3099(11)70100-1PMID 21782519.

External links

Vaccine description
TargetP. falciparum; to a lesser extent Hepatitis B
Vaccine typeProtein subunit
Clinical data
Trade namesMosquirix
Routes of
administration
intramuscular injection (0.5 mL)[1]
Legal status
Legal statusIn general: ℞ (Prescription only)

A poster advertising trials of the RTS,S vaccine[2]

malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2021, is RTS,S, known by the brand name Mosquirix.[1] It requires four injections.[1]

Research continues with other malaria vaccines. The most effective malaria vaccine is R21/Matrix-M, with a 77% efficacy rate shown in initial trials, and significantly higher antibody levels than with the RTS,S vaccine.[2] It is the first vaccine that meets the World Health Organization‘s (WHO) goal of a malaria vaccine with at least 75% efficacy.[3][2]

Approved vaccines

RTS,S

Main article: RTS,S

RTS,S (developed by PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK) with support from the Bill and Melinda Gates Foundation) is the most recently developed recombinant vaccine. It consists of the P. falciparum circumsporozoite protein (CSP) from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and additionally elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in the trial stage, due to its poor immunogenicity. RTS,S attempted to avoid these by fusing the protein with a surface antigen from hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of 8 volunteers when challenged with P. falciparum.[4]

RTS,S/AS01 (commercial name Mosquirix),[5] was engineered using genes from the outer protein of P. falciparum malaria parasite and a portion of a hepatitis B virus plus a chemical adjuvant to boost the immune response. Infection is prevented by inducing high antibody titers that block the parasite from infecting the liver.[6] In November 2012, a Phase III trial of RTS,S found that it provided modest protection against both clinical and severe malaria in young infants.[7]

As of October 2013, preliminary results of a Phase III clinical trial indicated that RTS,S/AS01 reduced the number of cases among young children by almost 50 percent and among infants by around 25 percent. The study ended in 2014. The effects of a booster dose were positive, even though overall efficacy seems to wane with time. After four years reductions were 36 percent for children who received three shots and a booster dose. Missing the booster dose reduced the efficacy against severe malaria to a negligible effect. The vaccine was shown to be less effective for infants. Three doses of vaccine plus a booster reduced the risk of clinical episodes by 26 percent over three years, but offered no significant protection against severe malaria.[8]

In a bid to accommodate a larger group and guarantee a sustained availability for the general public, GSK applied for a marketing license with the European Medicines Agency (EMA) in July 2014.[9] GSK treated the project as a non-profit initiative, with most funding coming from the Gates Foundation, a major contributor to malaria eradication.[10]

On 24 July 2015, Mosquirix received a positive opinion from the European Medicines Agency (EMA) on the proposal for the vaccine to be used to vaccinate children aged 6 weeks to 17 months outside the European Union.[11][12][1] A pilot project for vaccination was launched on 23 April 2019, in Malawi, on 30 April 2019, in Ghana, and on 13 September 2019, in Kenya.[13][14]

In October 2021, the vaccine was endorsed by the World Health Organization for “broad use” in children, making it the first malaria vaccine to receive this recommendation.[15][16][17]

Agents under development

A completely effective vaccine is not available for malaria, although several vaccines are under development. Multiple vaccine candidates targeting the blood-stage of the parasite’s life cycle have been insufficient on their own.[18] Several potential vaccines targeting the pre-erythrocytic stage are being developed, with RTS,S the only approved option so far.[19][7]

R21/Matrix-M

The most effective malaria vaccine is R21/Matrix-M, with 77% efficacy shown in initial trials. It is the first vaccine that meets the World Health Organization’s goal of a malaria vaccine with at least 75% efficacy.[3] It was developed through a collaboration involving the University of Oxford, the Kenya Medical Research Institute, the London School of Hygiene & Tropical MedicineNovavax, the Serum Institute of India, and the Institut de Recherche en Sciences de la Santé in NanoroBurkina Faso. The R21 vaccine uses a circumsporozoite protein (CSP) antigen, at a higher proportion than the RTS,S vaccine. It includes the Matrix-M adjuvant that is also utilized in the Novavax COVID-19 vaccine.[20]

A Phase II trial was reported in April 2021, with a vaccine efficacy of 77% and antibody levels significantly higher than with the RTS,S vaccine. A Phase III trial is planned with 4,800 children across four African countries. If the vaccine is approved, over 200 million doses can be manufactured annually by the Serum Institute of India.[2]

Nanoparticle enhancement of RTS,S

In 2015, researchers used a repetitive antigen display technology to engineer a nanoparticle that displayed malaria specific B cell and T cell epitopes. The particle exhibited icosahedral symmetry and carried on its surface up to 60 copies of the RTS,S protein. The researchers claimed that the density of the protein was much higher than the 14% of the GSK vaccine.[21][22]

PfSPZ vaccine

Main article: PfSPZ Vaccine

The PfSPZ vaccine is a candidate malaria vaccine developed by Sanaria using radiation-attenuated sporozoites to elicit an immune response. Clinical trials have been promising, with trials taking place in Africa, Europe, and the US protecting over 80% of volunteers.[23] It has been subject to some criticism regarding the ultimate feasibility of large-scale production and delivery in Africa, since it must be stored in liquid nitrogen.

The PfSPZ vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.[24]

In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020.[25]

saRNA vaccine against PMIF

A patent was published in February 2021 for a Self-amplifying RNA (saRNA) vaccine that targets the protein PMIF, which is produced by the plasmodium parasite to inhibit the body’s T-cell response. The vaccine has been tested in mice and is described as, “probably the highest level of protection that has been seen in a mouse model” according to Richard Bucala, co-inventor of the vaccine. There are plans for phase one tests in humans later in 2021.[26]

Other developments

  • SPf66 is a synthetic peptide based vaccine developed by Manuel Elkin Patarroyo team in Colombia, and was tested extensively in endemic areas in the 1990s. Clinical trials showed it to be insufficiently effective, with 28% efficacy in South America and minimal or no efficacy in Africa.[27]
  • The CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.[citation needed]
  • The NYVAC-Pf7 multi-stage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes. These came from a variety of stages during the life cycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using Rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects, had very poor antibody responses. Despite this following administration of the vaccine some candidates had complete protection when challenged with P.falciparum. This result has warranted ongoing trials.[citation needed]
  • In 1995 a field trial involving [NANP]19-5.1 proved to be very successful. Out of 194 children vaccinated none developed symptomatic malaria in the 12-week follow up period and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein (5.1) and 19 repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.[28]
  • A chemical compound undergoing trials for treatment of tuberculosis and cancer—the JmJc inhibitor ML324 and the antitubercular clinical candidate SQ109—is potentially a new line of drugs to treat malaria and kill the parasite in its infectious stage. More tests still need to be carried out before the compounds would be approved as a viable treatment.[29]

Considerations

The task of developing a preventive vaccine for malaria is a complex process. There are a number of considerations to be made concerning what strategy a potential vaccine should adopt.

Parasite diversity

P. falciparum has demonstrated the capability, through the development of multiple drug-resistant parasites, for evolutionary change. The Plasmodium species has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite’s life cycle. This enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. The process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. The development of resistance could cause a significant reduction in efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment.[30]

Choosing to address the symptom or the source

The parasite induces two main response types from the human immune system. These are anti-parasitic immunity and anti-toxic immunity.

  • “Anti-parasitic immunity” addresses the source; it consists of an antibody response (humoral immunity) and a cell-mediated immune response. Ideally a vaccine would enable the development of anti-plasmodial antibodies in addition to generating an elevated cell-mediated response. Potential antigens against which a vaccine could be targeted will be discussed in greater depth later. Antibodies are part of the specific immune response. They exert their effect by activating the complement cascade, stimulating phagocytic cells into endocytosis through adhesion to an external surface of the antigenic substances, thus ‘marking’ it as offensive. Humoral or cell-mediated immunity consists of many interlinking mechanisms that essentially aim to prevent infection entering the body (through external barriers or hostile internal environments) and then kill any micro-organisms or foreign particles that succeed in penetration. The cell-mediated component consists of many white blood cells (such as monocytesneutrophilsmacrophageslymphocytesbasophilsmast cellsnatural killer cells, and eosinophils) that target foreign bodies by a variety of different mechanisms. In the case of malaria both systems would be targeted to attempt to increase the potential response generated, thus ensuring the maximum chance of preventing disease.[citation needed]
  • “Anti-toxic immunity” addresses the symptoms; it refers to the suppression of the immune response associated with the production of factors that either induce symptoms or reduce the effect that any toxic by-products (of micro-organism presence) have on the development of disease. For example, it has been shown that Tumor necrosis factor-alpha has a central role in generating the symptoms experienced in severe P. falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a, preventing respiratory distress and cerebral symptoms. This approach has serious limitations as it would not reduce the parasitic load; rather it only reduces the associated pathology. As a result, there are substantial difficulties in evaluating efficacy in human trials.

Taking this information into consideration an ideal vaccine candidate would attempt to generate a more substantial cell-mediated and antibody response on parasite presentation. This would have the benefit of increasing the rate of parasite clearance, thus reducing the experienced symptoms and providing a level of consistent future immunity against the parasite.

Potential targets

See also: PfSPZ Vaccine

Parasite stageTarget
SporozoiteHepatocyte invasion; direct anti-sporozite
HepatozoiteDirect anti-hepatozoite.
Asexual erythrocyticAnti-host erythrocyte, antibodies blocking invasion; anti receptor ligand, anti-soluble toxin
GametocytesAnti-gametocyte. Anti-host erythrocyte, antibodies blocking fertilisation, antibodies blocking egress from the mosquito midgut.

By their very nature, protozoa are more complex organisms than bacteria and viruses, with more complicated structures and life cycles. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. These have been summarised into the life cycle stage and the antibodies that could potentially elicit an immune response.

The epidemiology of malaria varies enormously across the globe, and has led to the belief that it may be necessary to adopt very different vaccine development strategies to target the different populations. A Type 1 vaccine is suggested for those exposed mostly to P. falciparum malaria in sub-Saharan Africa, with the primary objective to reduce the number of severe malaria cases and deaths in infants and children exposed to high transmission rates. The Type 2 vaccine could be thought of as a ‘travellers’ vaccine’, aiming to prevent all cases of clinical symptoms in individuals with no previous exposure. This is another major public health problem, with malaria presenting as one of the most substantial threats to travellers’ health. Problems with the available pharmaceutical therapies include costs, availability, adverse effects and contraindications, inconvenience and compliance, many of which would be reduced or eliminated entirely if an effective (greater than 85–90%) vaccine was developed.[citation needed]

The life cycle of the malaria parasite is particularly complex, presenting initial developmental problems. Despite the huge number of vaccines available, there are none that target parasitic infections. The distinct developmental stages involved in the life cycle present numerous opportunities for targeting antigens, thus potentially eliciting an immune response. Theoretically, each developmental stage could have a vaccine developed specifically to target the parasite. Moreover, any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite’s development. More than 30 of these antigens are being researched[when?] by teams all over the world in the hope of identifying a combination that can elicit immunity in the inoculated individual. Some of the approaches involve surface expression of the antigen, inhibitory effects of specific antibodies on the life cycle and the protective effects through immunization or passive transfer of antibodies between an immune and a non-immune host. The majority of research into malarial vaccines has focused on the Plasmodium falciparum strain due to the high mortality caused by the parasite and the ease of a carrying out in vitro/in vivo studies. The earliest vaccines attempted to use the parasitic circumsporozoite protein (CSP). This is the most dominant surface antigen of the initial pre-erythrocytic phase. However, problems were encountered due to low efficacy, reactogenicity and low immunogenicity.[citation needed]

  • The initial stage in the life cycle, following inoculation, is a relatively short “pre-erythrocytic” or “hepatic” phase. A vaccine at this stage must have the ability to protect against sporozoites invading and possibly inhibiting the development of parasites in the hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected liver cells). However, if any sporozoites evaded the immune system they would then have the potential to be symptomatic and cause the clinical disease.
  • The second phase of the life cycle is the “erythrocytic” or blood phase. A vaccine here could prevent merozoite multiplication or the invasion of red blood cells. This approach is complicated by the lack of MHC molecule expression on the surface of erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the antibodies could potentially be directed. Another approach would be to attempt to block the process of erythrocyte adherence to blood vessel walls. It is thought that this process is accountable for much of the clinical syndrome associated with malarial infection; therefore a vaccine given during this stage would be therapeutic and hence administered during clinical episodes to prevent further deterioration.
  • The last phase of the life cycle that has the potential to be targeted by a vaccine is the “sexual stage”. This would not give any protective benefits to the individual inoculated but would prevent further transmission of the parasite by preventing the gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It therefore would be used as part of a policy directed at eliminating the parasite from areas of low prevalence or to prevent the development and spread of vaccine-resistant parasites. This type of transmission-blocking vaccine is potentially very important. The evolution of resistance in the malaria parasite occurs very quickly, potentially making any vaccine redundant within a few generations. This approach to the prevention of spread is therefore essential.
  • Another approach is to target the protein kinases, which are present during the entire lifecycle of the malaria parasite. Research is underway on this, yet production of an actual vaccine targeting these protein kinases may still take a long time.[31]
  • Report of a vaccine candidate capable to neutralize all tested strains of Plasmodium falciparum, the most deadly form of the parasite causing malaria, was published in Nature Communications by a team of scientists from the University of Oxford in 2011.[32] The viral vector vaccine, targeting a full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) was found to induce an antibody response in an animal model. The results of this new vaccine confirmed the utility of a key discovery reported from scientists at the Wellcome Trust Sanger Institute, published in Nature.[33] The earlier publication reported P. falciparum relies on a red blood cell surface receptor, known as ‘basigin’, to invade the cells by binding a protein PfRH5 to the receptor.[33] Unlike other antigens of the malaria parasite which are often genetically diverse, the PfRH5 antigen appears to have little genetic diversity. It was found to induce very low antibody response in people naturally exposed to the parasite.[32] The high susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody demonstrated a significant promise for preventing malaria in the long and often difficult road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust Senior Investigator at the University of Oxford, the next step would be the safety tests of this vaccine. At the time (2011) it was projected that if these proved successful, the clinical trials in patients could begin within two to three years.[34]
  • PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by Plasmodium falciparum, was found to be a key target of the immune system’s response against the parasite. Studies of blood samples from 296 mostly Kenyan children by researchers of Burnet Institute and their cooperators showed that antibodies against PfEMP1 provide protective immunity, while antibodies developed against other surface antigens do not. Their results demonstrated that PfEMP1 could be a target to develop an effective vaccine which will reduce risk of developing malaria.[35][36]
  • Plasmodium vivax is the common malaria species found in India, Southeast Asia and South America. It is able to stay dormant in the liver and reemerge years later to elicit new infections. Two key proteins involved in the invasion of the red blood cells (RBC) by P. vivax are potential targets for drug or vaccine development. When the Duffy binding protein (DBP) of P. vivax binds the Duffy antigen (DARC) on the surface of RBC, process for the parasite to enter the RBC is initiated. Structures of the core region of DARC and the receptor binding pocket of DBP have been mapped by scientists at the Washington University in St. Louis. The researchers found that the binding is a two-step process which involves two copies of the parasite protein acting together like a pair of tongs which “clamp” two copies of DARC. Antibodies that interfere with the binding, by either targeting the key region of the DARC or the DBP will prevent the infection.[37][38]
  • Antibodies against the Schizont Egress Antigen-1 (PfSEA-1) were found to disable the parasite ability to rupture from the infected red blood cells (RBCs) thus prevent it from continuing with its life cycle. Researchers from Rhode Island Hospital identified Plasmodium falciparum PfSEA-1, a 244 kd malaria antigen expressed in the schizont-infected RBCs. Mice vaccinated with the recombinant PfSEA-1 produced antibodies which interrupted the schizont rupture from the RBCs and decreased the parasite replication. The vaccine protected the mice from lethal challenge of the parasite. Tanzanian and Kenyan children who have antibodies to PfSEA-1 were found to have fewer parasites in their blood stream and milder case of malaria. By blocking the schizont outlet, the PfSEA-1 vaccine may work synergistically with vaccines targeting the other stages of the malaria life cycle such as hepatocyte and RBC invasion.[39][40]

Mix of antigenic components

Increasing the potential immunity generated against Plasmodia can be achieved by attempting to target multiple phases in the life cycle. This is additionally beneficial in reducing the possibility of resistant parasites developing. The use of multiple-parasite antigens can therefore have a synergistic or additive effect.

One of the most successful vaccine candidates in clinical trials[which?][when?] consists of recombinant antigenic proteins to the circumsporozoite protein.[41] (This is discussed in more detail below.)[where?]

Delivery system

 

The selection of an appropriate system is fundamental in all vaccine development, but especially so in the case of malaria. A vaccine targeting several antigens may require delivery to different areas and by different means in order to elicit an effective response. Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes—but in other cases, particularly when using combined antigenic vaccines, this approach is very complex. Some methods that have been attempted include the use of two vaccines, one directed at generating a blood response and the other a liver-stage response. These two vaccines could then be injected into two different sites, thus enabling the use of a more specific and potentially efficacious delivery system.

To increase, accelerate or modify the development of an immune response to a vaccine candidate it is often necessary to combine the antigenic substance to be delivered with an adjuvant or specialised delivery system. These terms are often used interchangeably in relation to vaccine development; however in most cases a distinction can be made. An adjuvant is typically thought of as a substance used in combination with the antigen to produce a more substantial and robust immune response than that elicited by the antigen alone. This is achieved through three mechanisms: by affecting the antigen delivery and presentation, by inducing the production of immunomodulatory cytokines, and by affecting the antigen presenting cells (APC). Adjuvants can consist of many different materials, from cell microparticles to other particulated delivery systems (e.g. liposomes).

Adjuvants are crucial in affecting the specificity and isotype of the necessary antibodies. They are thought to be able to potentiate the link between the innate and adaptive immune responses. Due to the diverse nature of substances that can potentially have this effect on the immune system, it is difficult to classify adjuvants into specific groups. In most circumstances they consist of easily identifiable components of micro-organisms that are recognised by the innate immune system cells. The role of delivery systems is primarily to direct the chosen adjuvant and antigen into target cells to attempt to increase the efficacy of the vaccine further, therefore acting synergistically with the adjuvant.

There is increasing concern that the use of very potent adjuvants could precipitate autoimmune responses, making it imperative that the vaccine is focused on the target cells only. Specific delivery systems can reduce this risk by limiting the potential toxicity and systemic distribution of newly developed adjuvants.

Studies into the efficacy of malaria vaccines developed to date[when?] have illustrated that the presence of an adjuvant is key in determining any protection gained against malaria. A large number of natural and synthetic adjuvants have been identified throughout the history of vaccine development. Options identified thus far for use combined with a malaria vaccine include mycobacterial cell walls, liposomes, monophosphoryl lipid A and squalene.

History

Individuals who are exposed to the parasite in endemic countries develop acquired immunity against disease and death. Such immunity does not however prevent malarial infection; immune individuals often harbour asymptomatic parasites in their blood. This does, however, imply that it is possible to create an immune response that protects against the harmful effects of the parasite.

Research shows that if immunoglobulin is taken from immune adults, purified and then given to individuals who have no protective immunity, some protection can be gained.[42]

Irradiated mosquitoes

In 1967, it was reported that a level of immunity to the Plasmodium berghei parasite could be given to mice by exposing them to sporozoites that had been irradiated by x-rays.[43] Subsequent human studies in the 1970s showed that humans could be immunized against Plasmodium vivax and Plasmodium falciparum by exposing them to the bites of significant numbers of irradiated mosquitos.[44]

From 1989 to 1999, eleven volunteers recruited from the United States Public Health ServiceUnited States Army, and United States Navy were immunized against Plasmodium falciparum by the bites of 1001–2927 mosquitoes that had been irradiated with 15,000 rads of gamma rays from a Co-60 or Cs-137 source.[45] This level of radiation is sufficient to attenuate the malaria parasites so that, while they can still enter hepatic cells, they cannot develop into schizonts nor infect red blood cells.[45] Over a span of 42 weeks, 24 of 26 tests on the volunteers showed that they were protected from malaria.[46]

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Further reading

External links

Screened cup of malaria-infected mosquitoes which will infect a volunteer in a clinical trial
Vaccine description
TargetMalaria
Vaccine typeProtein subunit
Clinical data
Trade namesMosquirix
Routes of
administration
Intramuscular[1]
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number149121-47-1
ChemSpidernone

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