Home » Articles posted by DR ANTHONY MELVIN CRASTO Ph.D (Page 54)

Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

TROPIFEXOR

June 7, 2021 10:57 am / Leave a comment

TROPIFEXOR

トロピフェクサー;

PHASE 2, NASH, PBC, liver fibrosis, bile acid diarrhea, non-alcoholic fatty liver disease

Formula	C29H25F4N3O5S
CAS	1383816-29-2
Mol weight	603.5845

TROPIFEXORLJN 452;LJN-452;LJN452;CS-2712;CPD1549;Tropifexor;Tropifexor (LJN452);LJN452;LJN452,Tropifexor;2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acidтропифексор [Russian] [INN]
تروبيفيكسور [Arabic] [INN]
曲匹法索 [Chinese] [INN]2-[(3-endo)-3-({5-Cyclopropyl-3-[2-(trifluormethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]oct-8-yl]-4-fluor-1,3-benzothiazol-6-carbonsäure [German] [ACD/IUPAC Name]
2-[(3-endo)-3-({5-Cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]oct-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid [ACD/IUPAC Name]
6-Benzothiazolecarboxylic acid, 2-[(3-endo)-3-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-4-isoxazolyl]methoxy]-8-azabicyclo[3.2.1]oct-8-yl]-4-fluoro- [ACD/Index Name]
Acide 2-[(3-endo)-3-({5-cyclopropyl-3-[2-(trifluorométhoxy)phényl]-1,2-oxazol-4-yl}méthoxy)-8-azabicyclo[3.2.1]oct-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylique [French] [ACD/IUPAC Name]
NMZ08KM76Z

Tropifexor fast facts

CAS Reg. No.	1383816-29-2
Molar mass	603.58 g/mol
Empirical formula	C₂₉H₂₅F₄N₃O₅S
Appearance	White crystals
Melting point	221 ºC
Water solubility	6 mg/L

Efficacy	Anti-inflammatory, Farnesoid X receptor (FXR) agonist
Comment	Treatment of non-alcoholic steatohepatitis

Novartis is developing tropifexor, a non-bile acid farnesoid X receptor agonist, and its analog LJP-305, for treating NASH, PBC, liver fibrosis, bile acid diarrhea and non-alcoholic fatty liver disease. In June 2021, this drug was reported to be in phase 2 clinical development.

Nonalcoholic steatohepatitis (NASH) is a liver disease that is becoming more prevalent as worldwide obesity and type 2 diabetes increase. It is characterized by accumulation of fat in the liver, inflammation, hepatocyte ballooning, and fibrosis.

Another liver disease, primary biliary cholangitis (PBC), is a cholestatic condition in which bile flow from the liver to the intestine is reduced or interrupted. It is thought to be autoimmune.

PBC is associated with decreased expression of the farnesoid X receptor (FXR), a ligand-activated nuclear receptor that is highly expressed in the liver and other organs. FXR is a key regulator of bile acid production, conjugation, and transport. FXR activation also suppresses lipogenesis; thus, it has been proposed as a treatment for NASH.

Recently, David C. Tully and colleagues at the Genomics Institute of the Novartis Research Foundation (San Diego) and the Novartis Institutes for Biomedical Research (Emeryville, CA) discovered tropifexor, a highly potent FXR agonist. They began by replacing an indole group in an existing partial FXR agonist with a 2-substituted benzothiazole-6-carboxylic acid, a change that resulted in a dramatic increase in potency. Further changes, including optimization of the benzothiazole substituent, resulted in more potent, orally bioavailable tropifexor.

Tropifexor is an investigational drug which acts as an agonist of the farnesoid X receptor (FXR). It was discovered by researchers from Novartis and Genomics Institute of the Novartis Research Foundation. Its synthesis and pharmacological properties were published in 2017.^[1] It was developed for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). In combination with cenicriviroc, a CCR2 and CCR5 receptor inhibitor, it is undergoing a phase II clinical trial for NASH and liver fibrosis.^[2]

Rats treated orally with tropifexor (0.03 to 1 mg/kg) showed an upregulation of the FXR target genes, BSEP and SHP, and a down-regulation of CYP8B1. Its EC50 for FXR is between 0.2 and 0.26 nM depending on the biochemical assay.

The patent which covers tropifexor and related compounds was published in 2010.^[3]

PATENT

WO-2021104022

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021104022&tab=FULLTEXT&_cid=P11-KPMHAY-19573-1

Novel, stable crystalline polymorphic form II of tropifexor , useful for treating non-alcoholic steatohepatitis (NASH), fatty liver and primary biliary cholangitis (PBC).Tropifexor was originally developed by Novartis and then licensed to Pfizer for cooperative development. It is a non-steroidal FXR (farnesoid receptor) agonist, currently in clinical phase II of indications for NASH (non-alcoholic steatohepatitis), fatty liver and primary biliary cholangitis.
The structure of Tropifexor is shown in the following formula (1):

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug In order to obtain an effective crystal form that is conducive to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
At present, there is no literature that discloses the crystal form of Tropifexor, and there is no related literature report.
The present invention obtains a new crystal form of the compound through a large number of experimental studies on the Tropifexor compound. The new crystal form has the advantages of high solubility, good stability, low moisture absorption, simple preparation process and easy operation, etc., and has excellent properties in industrial production. Superiority.Example 1 Preparation method of Tropifexor crystal form II[0049]After mixing 60.3 mg of Tropifexor and p-aminobenzoic acid (13.7 mg), they were added to ethanol (3.0 ml), stirred at 27° C. to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 51.3 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically consistent with Fig. 1, its DSC pattern was basically the same as Fig. 2, and its TGA pattern was basically the same as Fig. 3.[0050]Example 2 Preparation method of Tropifexor crystal form II[0051]After mixing 60.3 mg of Tropifexor and p-hydroxybenzoic acid (13.8 mg), they were added to ethanol (3.0 ml), stirred at 27° C. to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 48.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically consistent with Fig. 1, its DSC pattern was basically the same as Fig. 2, and its TGA pattern was basically the same as Fig. 3.[0052]Example 3 Preparation method of Tropifexor crystal form II[0053]After mixing 60.3 mg of Tropifexor and salicylic acid (13.8 mg), they were added to ethanol (3.0 ml), stirred at 27°C to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. Filter with suction and place in a drying box at 50°C and vacuum dry to constant weight to obtain 50.0 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically consistent with Fig. 1, its DSC pattern was basically the same as Fig. 2, and its TGA pattern was basically the same as Fig. 3.[0054]Example 4 Preparation method of Tropifexor crystal form II[0055]After mixing 60.3 mg of Tropifexor and 2,4-dihydroxybenzoic acid (15.4 mg), they were added to ethanol (3.0 ml), stirred at 27°C to obtain a clear solution, and then allowed to stand at room temperature for about 2 days to precipitate a solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 49.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form II; its X-ray powder diffraction pattern was basically consistent with Fig. 1, its DSC pattern was basically the same as Fig. 2, and its TGA pattern was basically the same as Fig. 3.

PATENT

WO2021104021 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021104021&_cid=P11-KPMHDR-20595-1

claiming crystalline polymorphic form I of tropifexor,Example 1 Preparation method of Tropifexor crystal form I
50.0 mg of Tropifexor was added to ethanol (1.0 ml), heated to 60° C. and stirred to obtain a clear solution, and then water (3 ml) was added dropwise to the Tropifexor solution. Stir and precipitate solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 38.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form I; its X-ray powder diffraction pattern was basically consistent with Figure 1, its DSC pattern was basically consistent with Figure 2, and its TGA pattern was basically consistent with Figure 3

PATENT

product pat, WO2012087519 , https://patents.google.com/patent/WO2012087519A1/en

has protection in the EU until November 2031, and expire in US in February 2032 with US154 extension.

PATENT

WO 2016097933

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016097933&tab=PCTDESCRIPTION

Example 1

2-r(1 R,3r,5S)-3-(f5-cvclopropyl-3-r2-(trifluoromethoxy)phenyll-1 ,2-oxazol-4-yl)methoxy)-8- azabicvcloi3.2.1 loctan-8-yll-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid (1 -1 B) and

-r(1 R,3r,5S)-3-(f5-cvclopropyl-3-r2-(trifluoromethyl)phenyll-1 ,2-oxazol-4-yl)methoxy)-8-

R^1a = OCF₃ (1 -1A, 1 -1 B)

R ^a = CF₃ (1-2A, 1-2B)

Methyl 2-[(1 R,3r,5S)-3-(i5-cvclopropyl-3-r2-(trifluoromethoxy)phenyll-1 ,2-oxazol-4- yl}methoxy)-8-azabicvcloi3.2.1 loctan-8-yll-4-fluoro-1 ,3-benzothiazole-6-carboxylate (1 -1 A). Into a 25-mL round-bottom flask equipped with a stir bar was added sequentially 4-(((1 R,3r,5S)- 8-azabicyclo[3.2.1 ]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (1 .29 mmol), N,N-dimethylacetamide (3.6 mL), cesium carbonate (3.31 mmol), and methyl 2- bromo-4-fluorobenzo[d]thiazole-6-carboxylate (3.87 mmol). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60 °C and stirred for 1 h. The reaction slurry was allowed to cool to room temperature, and was diluted with 200 mL of ethyl acetate and washed with water (3 ^χ 30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gel chromatography (40 g silica column) with a 15 min gradient of 10 % to 60 % ethyl acetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give methyl 2- [(1 R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8- azabicyclo[3.2.1 ]octan-8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylate (1-1 A) as a white crystalline solid. MS (m/z) : 618.2 (M+1 ).

2-r(1 R,3r,5S)-3-(i5-cvclopropyl-3-r2-(trifluoromethoxy)phenyll-1 ,2-oxazol-4-yl}methoxy)- 8-azabicvcloi3.2.1 loctan-8-yll-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid (1 -1 B). To a 25-mL round-bottom flask equipped with a stir bar was added the ester (0.89 mmol), THF (4 mL),

MeOH (2 mL), and 3 N aqueous KOH solution (1 mL, 3 mmol). The resulting homogenous solution was stirred for 1 hour at 70 °C, cooled to room temperature, and then quenched with AcOH (roughly 0.2 mL of glacial acetic, 3 mmol) until pH=6 was achieved (Whatman class pH strip paper). At this time the reaction was diluted with ethyl acetate (40 mL) and washed with water (3 5 mL). The ethyl acetate fraction was concentrated under vacuum to give to an oily residue. To the resulting oil was then added MeOH (6 mL). The oil quickly dissolved, then immediately began to crystallize. Upon standing for 2.5 hrs, the mother liquor was withdrawn and crystals washed (3 x 2 mL of ice cold MeOH). The crystals were dried via vacuum (10 mm Hg pressure at 45 °C overnight) and then recrystallized from acetonitrile, filtered, and dried under vacuum to give 2-[(1 R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1 ]octan-8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid (1 -1 B). 2-[(1 R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1 ,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1 ]octan-8-yl]-4-fluoro-1 ,3-benzothiazole-6-carboxylic acid (1 -2B).

Examples 1 -2A and the corresponding acid 1 -2B can be prepared following the same procedures, from the reaction of intermediate 4-((8-azabicyclo[3.2.1 ]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole.

PAPER

European journal of medicinal chemistry (2021), 209, 112910

https://www.sciencedirect.com/science/article/abs/pii/S0223523420308825

Abstract

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.

References

^ Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, et al. (December 2017). “Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)”. Journal of Medicinal Chemistry. 60 (24): 9960–9973. doi:10.1021/acs.jmedchem.7b00907. PMID 29148806.
^ Clinical trial number NCT03517540 for “Safety, Tolerability, and Efficacy of a Combination Treatment of Tropifexor (LJN452) and Cenicriviroc (CVC) in Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis. (TANDEM)” at ClinicalTrials.gov
^ WO Application Filing 2012087519, Alper PB, Chianelli D, Mutnick D, Vincent P, Tully DC, “Compositions and methods for modulating fxr”, published 2012-06-28, assigned to Genomics Institute of the Novartis Research Foundation. Retrieved 17 May 2019.

Clinical data


ATC code	None
Identifiers
show IUPAC name
CAS Number	1383816-29-2
PubChem CID	121418176
UNII	NMZ08KM76Z
KEGG	D11548
Chemical and physical data
Formula	C₂₉H₂₅F₄N₃O₅S
Molar mass	603.59 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show

///////////TROPIFEXOR, トロピフェクサー, NOVARTIS, PHASE 2, тропифексор , تروبيفيكسور , 曲匹法索 , LJN 452, LJN-452, LJN452, CS-2712, CPD1549, Tropifexor, Tropifexor (LJN452), LJN452, LJN452, PHASE 2, NASH, PBC, liver fibrosis, bile acid diarrhea, non-alcoholic fatty liver disease

1ccc(c(c1)c2c(c(on2)C3CC3)CO[C@H]4C[C@H]5CC[C@@H](C4)N5c6nc7c(cc(cc7s6)C(=O)O)F)OC(F)(F)F

NEW DRUG APPROVALS

ONE TIME

$10.00

Infigratinib phosphate

June 7, 2021 3:15 am / 1 Comment on Infigratinib phosphate

Infigratinib phosphate

FDA APPR Truseltiq 2021/5/28

インフィグラチニブリン酸塩;

3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea;phosphoric acid

BGJ 398
BGJ-398
BGJ398
NVP-BGJ398
WHO 10032

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Infigratinib acetate	03D0789NYP	1310746-17-8	XHCQHOGMMJKLRU-UHFFFAOYSA-N
Infigratinib hydrochloride	WY8VD4RV77	1310746-15-6	VBAIJSJSFCXDJB-UHFFFAOYSA-N
Infigratinib mesylate	E223Z0KWCC	1310746-12-3	BXJJFNXYWJLBOS-UHFFFAOYSA-N
Infigratinib phosphate	58BH47BV6S	1310746-10-1	GUQNHCGYHLSITB-UHFFFAOYSA-N

International/Other BrandsTruseltiq (BridgeBio Pharma, Inc.)

Formula	C26H31Cl2N7O3. H3PO4
CAS	1310746-10-1FREE form 872511-34-7
Mol weight	658.4706

Originator Novartis
Developer Array BioPharma; Novartis; Novartis Oncology; QED Therapeutics
Class Aniline compounds; Antineoplastics; Chlorobenzenes; Methylurea compounds; Phenyl ethers; Piperazines; Pyrimidines; Small molecules
Mechanism of Action Type 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type 4 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
Orphan Drug Status Yes – Cholangiocarcinoma

RegisteredCholangiocarcinoma
Phase IIIBladder cancer; Urogenital cancer
Phase IIAchondroplasia; Head and neck cancer
Phase IBreast cancer
Phase 0Glioblastoma
DiscontinuedHaematological malignancies; Malignant melanoma; Solid tumours

31 May 2021Clinical development is ongoing in Bladder cancer (QED Therapeutics pipeline, May 2020)
28 May 2021Registered for Cholangiocarcinoma (Second-line therapy or greater, Metastatic disease, Inoperable/Unresectable, Late-stage disease) in USA (PO) – First global approval (under Project Orbis using RTOR program)
28 May 2021Efficacy and safety data from a phase II trial in Cholangiocarcinoma released by QED Therapeutics

Infigratinib, sold under the brand name Truseltiq, is an anti-cancer medication used to treat cholangiocarcinoma (bile duct cancer).^[1]^[2]

Infigratinib is a receptor tyrosine kinase inhibitor (and more specifically an inhibitor of the fibroblast growth factor receptors FGFR1, FGFR2, FGFR3).^[3]^[1]^[2] It was designated an orphan drug by the U.S. Food and Drug Administration (FDA) in 2019,^[4] and it was approved for medical use in the United States in May 2021.^[2]

Infigratinib is a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor. By inhibiting the FGFR pathway, which is often aberrated in cancers such as cholangiocarcinoma, infigratinib suppresses tumour growth.¹ Cholangiocarcinoma is the most common primary malignancy affecting the biliary tract and the second most common primary hepatic malignancy.² Infitratinib is a pan-FGFR inhibitor, as it is an ATP-competitive inhibitor of all four FGFR receptor subtypes.¹

On May 28, 2021, the FDA granted accelerated approval to infigratinib – under the market name Truseltiq – for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.⁵ This approval follows pemigatinib, another FGFR inhibitor approved by the FDA for the same therapeutic indication.

Infigratinib is indicated for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma in adults with a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement as detected by an FDA-approved test.⁴

Medical uses

Infigratinib is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma (bile duct cancer) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.^[1]

PAPER

Journal of Medicinal Chemistry (2011), 54(20), 7066-7083.

https://pubs.acs.org/doi/10.1021/jm2006222

A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.

PATENT

US 9067896

PATENT

WO 2020243442

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020243442

In 2018, it was estimated that 150,350 new patients would be diagnosed with urinary system cancer: 81,190 urinary bladder; 65,340 kidney and renal pelvis; and, 3,820 ureter and other urinary organs. Excluding non-urothelial kidney cancers, approximately 5 to 10% of all urothelial carcinomas are upper tract urothelial carcinomas (UTUC). The incidence of UTUC is 2 to 3 times greater in men than women (Siegel et al, 2018; Roupret et al, 2015).

[0003] In contrast to invasive urinary bladder cancer (UCB), UTUC has a more aggressive clinical course. At the time of diagnosis, 60% of patients with UTUC have invasive cancer compared to 15% to 25% of patients with UCB (Roupret et al, 2015; Margulis et al., 2009). Thirty-six percent have regional disease and 9% distant disease (Raman et al., 2010). A large retrospective review of 1363 patients with UTUC who underwent radical nephroureterectomy (RNU) at 12 centers demonstrated that 28% of the total population had recurrence after RNU (Margulis et al, 2009).

[0004] To reduce the morbidity and mortality in patients with UTUC, neoadjuvant or adjuvant treatment is needed. The POUT study, a large randomized trial in UTUC supports the use of standard-of-care adjuvant cisplatin-based chemotherapy (Birtle et al., 2020). Because many patients with UTUC will have one remaining kidney following RNU and frequently have other significant co-morbid conditions, cisplatin-based therapy is not well tolerated (NCCN Guidelines Version 3, 2018). Renal function before and after RNU greatly limits the number of patients with UTUC who are eligible for platinum-based neoadjuvant or adjuvant therapy. Therefore, targeted therapies are needed for treating UTUC (Lane et al., 2010).

[0005] Despite demonstrated survival benefit for neoadjuvant treatment of invasive UCB, many patients with invasive UCB are unlikely to receive (neo)adjuvant cisplatin-based chemotherapy, due in part to cisplatin ineligibility (Porter et al., 2011). In addition, residual disease following neoadjuvant therapy is associated with a poor prognosis (Grossman et al, 2003). Therefore,

there remains an unmet need for a substantial proportion of patients with invasive UCB who are ineligible or refuse to receive cisplatin-based adjuvant chemotherapy or who have residual disease following neoadjuvant therapy.

Infigratinib, as depicted in formula (I), is a selective and ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, also known as 3-(2,6-dichloro-3,5-dimethoxyphenyl)- 1 – { 6- [4-(4-ethyl- 1 -piperazin- 1 -yljphenylamino] -pyrimidinyl-4-yl } – 1 -methylurea. Infigratinib selectively inhibits the kinase activity of FGFR1, FGFR2, FGFR3, and

FGFR4.

PATENT

WO 2011071821

https://patents.google.com/patent/WO2011071821A1/en3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l-yl)- phenylamino]-pyrimidin-4-yl}-l -methyl-urea (described in USSN 11/570983, filed June 23, 2005, and incorporated by reference in its entirety herein) has the structure of Formula I:

The compound of Formula I is a protein kinase inhibitor and is useful in the treatment of proliferative diseases mediated by protein kinases. In particular, the compound of Formula I inhibits FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases. It is therefore useful in the treatment of cancers including AML, melanocyte neoplasia, breast cancer, colon cancer, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi’s sarcoma.[0003] It is well known that the crystalline form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug’s ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability. Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form.Crystalline forms may also include different hydrates or solvates of the same compound. In deciding which form is preferable, the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables. It is entirely possible that one form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different form may be preferred for greater dissolution rate and/or superior bioavailability. It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will display such desirable properties.Example 2: Manufacture of the Free Base of the Compound of Formula I

IA. N- [4-(4-ethyl-piperazin- 1 -yl)-phenyl] -N’ -methyl-pyrimidine-4,6-diamine[0077] A mixture of 4-(4-ethylpiperazin-l-yl)-aniline (1 g, 4.88 mmol), (6-chloro- pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.), and 4N HC1 in dioxane (15 ml) is heated in a sealed tube to 150°C for 5h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]⁺; t_R= 1.10 min (gradient J); TLC: R_f = 0.21 (DCM/MeOH, 93:7).B. 4-(4-Ethylpiperazin- 1 -yl)-aniline[0078] A suspension of l-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MH]⁺; TLC: R_f = 0.15 (DCM/MeOH + 1 % NH₃^aq, 9:l).C. 1 -Ethyl-4-(4-nitro-phenyl)-piperazine[0079] A mixture of l-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80°C for 15h. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9:1. The aqueous layer is separated and extracted with DCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography(DCM MeOH + 1 % NH₃^aq, 9:1) affords 6.2 g of the title compound as a yellow solid: ESI- MS: 236.0 [MH]⁺; t_R= 2.35 min (purity: 100%, gradient J); TLC: R_f = 0.50 (DCM/MeOH + 1 % NH₃^aq, 9:1).D. (6-chloro-pyrimidin-4-yl)-methyl-amine[0080] This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6- dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50°C. After completion of the addition the reaction mixture was stirred for lh at room temperature. Then, water (50 ml) is added and the suspension formed is chilled in an ice bath to 5°C. The precipitated product is filtered off, washed with cold isopropanol/water 2:1 (45 ml) and water. The collected material is vacuum dried over night at 45°C to afford the title compound as colorless powder: tR = 3.57 min (purity: >99%, gradient A), ESI-MS: 144.3 / 146.2 [MH]⁺.E. (3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-l-{6-[4-(4-ethyl-piperazin-l-yl)-phenylamino]- pyrimidin-4-yl} – 1 -methyl-urea)[0081] The title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl- isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-l-yl)-phenyl]-N’-methyl- pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5h at reflux. Purification of the crude product by silica gel column chromatography (DCM MeOH + 1 % NH₃^aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0 / 561.9 [MHf; t_R= 3.54 min (purity: 100%, gradient J); TLC: R_f = 0.28 (DCM/MeOH + 1 % NH₃^aq, 95:5). Analysis: C₂₆H₃iN₇0₃Cl₂, calc. C 55.72% H 5.57% N 17.49% O 8.56% CI 12.65%; found C 55.96% H 5.84% N 17.17% O 8.46% CI 12.57%. The title compound was characterized by XRPD, thermal and other methods as described below. Example 3: Manufacture of the Monophosphoric Acid Salt Form A of the Compound of Formula I.[0082] To a round bottom flask was added 3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-{6-[4- (4-ethylpiperazin-l-yl)phenylamino]-pyrimidine-4-yl}-l -methyl-urea (134 g, 240 mmol) and IPA (2000 ml). The suspension was stirred and heated to 50°C and a solution of phosphoric acid (73.5 g, 750 mmol) in water (2000 ml) added to it portions. The mixture was stirred at 60°C for 30 min. and filtered through a polypropylene pad. The pad was washed with warm IP A/water (1:1, 200 ml) and the filtrates were combined. To this clear solution, IPA (6000 ml) was added and the mixture was stirred under reflux for 20 min, cooled slowly to room temperature (25° C), and stirred for 24 hours. The white salt product was collected by filtration, washed with IPA (2 ^χ 500 ml) and dried in the oven at 60° C under reduced pressure for two days to provide the phosphate salt (form A) 110 g. Yield 70%. Purity >98% by HPLC. Analysis: C₂6H34 ₇0₇C1₂P, calc. C 47.42% H 5.20% N 14.89% O 17.01% CI 10.77% P 4.70%; found C 47.40% H 5.11% N 14.71% O 17.18% CI 10.73% P 4.87%. The title compound was characterized by XRPD, thermal and other methods as described below.

References

^ Jump up to:^a ^b ^c ^d “Infigratinib prescribing information” (PDF). U.S. Food and Drug Administration. May 2021.
^ Jump up to:^a ^b ^c “BridgeBio Pharma’s Affiliate QED Therapeutics and Partner Helsinn Group Announce FDA Approval of Truseltiq (infigratinib) for Patients with Cholangiocarcinoma” (Press release). BridgeBio Pharma. 28 May 2021. Retrieved 28 May 2021 – via GlobeNewswire.
^ Botrus G, Raman P, Oliver T, Bekaii-Saab T (April 2021). “Infigratinib (BGJ398): an investigational agent for the treatment of FGFR-altered intrahepatic cholangiocarcinoma”. Expert Opinion on Investigational Drugs. 30 (4): 309–316. doi:10.1080/13543784.2021.1864320. PMID 33307867.
^ “Infigratinib Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 11 September 2019. Retrieved 30 May 2021.

External links

“Infigratinib”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02150967 for “A Phase II, Single Arm Study of BGJ398 in Patients With Advanced Cholangiocarcinoma” at ClinicalTrials.gov

Efficacy	Antineoplastic, Angiogenesis inhibitor
Disease	Cholangiocarcinoma (FGFR2 fusion or other rearrangement)

Clinical data

Trade names	Truseltiq
Other names	BGJ-398
License data	US DailyMed: Infigratinib
Routes of administration	By mouth
Drug class	Tyrosine kinase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	872511-34-7
PubChem CID	53235510
DrugBank	DB11886
ChemSpider	26333103
UNII	A4055ME1VK
KEGG	D11589
CompTox Dashboard (EPA)	DTXSID70236238
Chemical and physical data
Formula	C₂₆H₃₁Cl₂N₇O₃
Molar mass	560.48 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESCCN1CCN(CC1)C2=CC=C(C=C2)NC3=CC(=NC=N3)N(C)C(=O)NC4=C(C(=CC(=C4Cl)OC)OC)Cl
hide InChIInChI=1S/C26H31Cl2N7O3/c1-5-34-10-12-35(13-11-34)18-8-6-17(7-9-18)31-21-15-22(30-16-29-21)33(2)26(36)32-25-23(27)19(37-3)14-20(38-4)24(25)28/h6-9,14-16H,5,10-13H2,1-4H3,(H,32,36)(H,29,30,31)Key:QADPYRIHXKWUSV-UHFFFAOYSA-N

////////Infigratinib phosphate, FDA 2021 APPROVALS 2021, Truseltiq, インフィグラチニブリン酸塩 , Orphan Drug, Cholangiocarcinoma, BGJ 398, BGJ-398, BGJ398, NVP-BGJ398, WHO 10032

NEW DRUG APPROVALS

one time

$10.00

Corbevax, BioE COVID-19, BECOV2D

June 6, 2021 9:54 am / Leave a comment

Corbevax

BioE COVID-19, BECOV2D

the Baylor College of Medicine in Houston, United States,

Dynavax Technologies

Adjuvanted protein subunit vaccine

Corbevax is a “recombinant protein sub-unit” vaccine, which means it is made up of a specific part of SARS-CoV-2 — the spike protein on the virus’s surface.

The spike protein allows the virus to enter the cells in the body so that it can replicate and cause disease. However, when this protein alone is given to the body, it is not expected to be harmful as the rest of the virus is absent. The body is expected to develop an immune response against the injected spike protein. Therefore, when the real virus attempts to infect the body, it will already have an immune response ready that will make it unlikely for the person to fall severely ill.

Although this technology has been used for decades to make hepatitis B vaccines, Corbevax will be among the first Covid-19 vaccines to use this platform. Novavax has also developed a protein-based vaccine, which is still waiting for emergency use authorisation from various regulators.

How Corbevax was made

While it is indigenously produced, Corbevax’s beginnings can be traced to the Baylor College of Medicine’s National School of Tropical Medicine. The School had been working on recombinant protein vaccines for coronaviruses SARS and MERS for a decade.

“We knew all the techniques required to produce a recombinant protein (vaccine) for coronaviruses at high levels of efficiency and integrity,” said Dr Peter Hotez, Professor and Dean at the School.

When the genetic sequence for SARS-CoV-2 was made available in February 2020, researchers at the School pulled out the sequence for the gene for the spike protein, and worked on cloning and engineering it. The gene was then put into yeast, so that it could manufacture and release copies of the protein. “It’s actually similar to the production of beer. Instead of releasing alcohol, in this case, the yeast is releasing the recombinant protein,” Dr Hotez said.

After this, the protein was purified to remove any remnants of the yeast “to make it pristine”. Then, the vaccine was formulated using an adjuvant to better stimulate the immune response.

Most of these ingredients are cheap and easy to find.

In August, BCM transferred its production cell bank for this vaccine to Biological E, so that the Hyderabad-based company could take the candidate through trials. The vaccine has received approval for phase 3 trials, which the government expects will be over by July.

Biological E is also expected to scale up production for the world.

How Corbevax is different

Other Covid-19 vaccines approved so far are either mRNA vaccines (Pfizer and Moderna), viral vector vaccines (AstraZeneca-Oxford/Covishield, Johnson & Johnson and Sputnik V) or inactivated vaccines (Covaxin, Sinovac-CoronaVac and Sinopharm’s SARS-CoV-2 Vaccine–Vero Cell).

Inactivated vaccines, which include killed particles of the whole SARS-CoV-2 virus, attempt to target the entire structure of the virus. On the other hand, Corbevax, like the mRNA and viral vector Covid-19 vaccines, targets only the spike protein, but in a different way.

Viral vector and mRNA and vaccines use a code to induce our cells to make the spike proteins against which the body have to build immunity. “In this case (Corbevax), we’re actually giving the protein,” said Dr Hotez.

Like most other Covid-19 vaccines, Corbevax is administered in two doses. However, as it is made using a low-cost platform, it is also expected to be among the cheapest available in the country.

Why Corbevax matters

This is the first time the Indian government has placed an order for a vaccine that has not received emergency use authorisation, paying Rs 1,500 crore in advance to block an order that could vaccinate 15 crore Indian citizens. The Centre has provided major pre-clinical and clinical trial support towards the vaccine’s development, including a grant-in-aid of Rs 100 crore from the Department of Biotechnology.

A major reason for India placing such a big order is the difficulties it is facing in enhancing vaccine supplies. While the US, UK and the EU had made advance payments and at-risk investments into vaccines like Pfizer, AstraZeneca and Moderna, India waited until after its first two vaccines were approved before placing limited orders. Even after the government eased regulatory requirements for foreign vaccines, it did not receive a speedy response from companies like Pfizer and Moderna, their supplies already blocked through orders from other countries. India is currently in negotiations for a limited supply of Pfizer’s vaccine, and expecting to secure up to two billion doses of Covid vaccines by December this year. Given the ease with which it can be mass produced, Corbevax could make up a sizeable portion of this expected supply.

Biological E, the manufacturer of Corbevax

Biological E, headquartered in Hyderabad, was founded by Dr D V K Raju in 1953 as a biological products company that pioneered the production of heparin in India. By 1962, it forayed into the vaccines space, producing DPT vaccines on a large-scale. Today, it is among the major vaccine makers in India and, by its own claim, the “largest” tetanus vaccine producer in the world.

It has seven WHO-prequalified shots, including a five-in-one vaccine against diphtheria, tetanus, pertussis, hepatitis B and haemophilus influenza type-b infections. Its vaccines are supplied to over 100 countries and it has supplied more than two billion doses in the last 10 years alone.

Since 2013, the company has been under the management of Mahima Datla — the third generation of the founding family. During her time as managing director, the company has received WHO prequalification of its Japanese encephalitis, DTwP and Td as well as measles and rubella vaccines and also commenced commercial operations in the US.

REF

https://indianexpress.com/article/explained/corbevax-vaccine-biological-e-india-7344928/

Corbevax^[1] or BioE COVID-19, is a COVID-19 vaccine candidate developed by Indian biopharmacutical firm Biological E. Limited (BioE), the Baylor College of Medicine in Houston, United States, and Dynavax Technologies. It is a protein subunit vaccine.^[2]^[3]^[4]^[5]

Clinical research

Phase I and II trials

In phase I clinical trial was carried to evaluate the safety and immunogenicity of the vaccine candidate in about 360 participants.^[5]The phase II concluded in April 2021.^[6]^[7]

Phase III trials

In April 2021, the Drugs Controller General of India permitted the vaccine candidate to start phase III clinical trials. A total of 1,268 healthy participants between the age of 18 and 80 years to be selected from 15 sites across India for the trial and intended to be part of a larger global Phase III study.^[8]^[7]

Manufacturing and Orders

In April 2021, the U.S. International Development Finance Corporation (DFC) announced that it would fund the expansion of BioE’s manufacturing capabilities, so that it could produce at least 1 billion doses by end of 2022.^[9]

On 3 June, India’s Ministry of Health and Family Welfare pre-ordered 300 million doses of Corbevax.^[10]

References

^ Bharadwaj, Swati (3 June 2021). “Telangana: Biological E starts at risk manufacturing of Corbevax”. The Times of India. Retrieved 3 June 2021.
^ “A prospective open label randomised phase-I seamlessly followed by phase-II study to assess the safety, reactogenicity and immunogenicity of Biological E’s novel Covid-19 vaccine containing Receptor Binding Domain of SARS-CoV-2 for protection against Covid-19 disease when administered intramuscularly in a two dose schedule (0, 28D) to healthy volunteers”. ctri.nic.in. Clinical Trials Registry India. 13 January 2021. CTRI/2020/11/029032. Archived from the original on 12 November 2020.
^ “CEPI partners with Biological E Limited to advance development and manufacture of COVID-19 vaccine candidate”. cepi.net. CEPI. Retrieved 5 March 2021.
^ Chui M (16 November 2020). “Biological E. Limited and Baylor COVID-19 vaccine begins clinical trial in India”. Baylor College of Medicine.
^ Jump up to:^a ^b Leo L (16 November 2020). “Biological E initiates human trials of vaccine”. Mint.
^ “Coronavirus | Biological E gets nod to start Phase III trials of COVID-19 vaccine”. The Hindu. 24 April 2021.
^ Jump up to:^a ^b Leo, Leroy (24 April 2021). “Biological E completes phase-2 covid vaccine trial, gets SEC nod for phase-3”. mint.
^ “A Prospective, multicentre, Phase II Seamlessly Followed by Phase III Clinical Study to Evaluate the Immunogenicity and Safety of Biological E’s CORBEVAX Vaccine for Protection Against COVID-19 Disease When Administered to COVID-19-Negative Adult Subjects”. ctri.nic.in. Clinical Trials Registry India. 5 June 2021. CTRI/2021/06/034014.
^ Basu, Nayanima (25 April 2021). “US assures export of raw materials to India for Covid vaccines as Doval speaks to Sullivan”. ThePrint.
^ “Health ministry buys 300 mn doses of Biological-E’s Covid vaccine in advance”. Hindustan Times. 3 June 2021. Retrieved 4 June 2021.

External links

CorbevaxVaccine descriptionTargetSARS-CoV-2Vaccine typeProtein subunitClinical dataTrade namesCorbevaxOther namesBECOV2DRoutes of
administrationIntramuscularATC code
- None
“What Is Biological E Vaccine? Can It Be The Most ‘Affordable’ Jab? Know Here”. Outlook India.
“Explained: How Corbevax is different”. The Indian Express.

COVID-19 pandemic
Part of a series on the

COVID-19 (disease)SARS-CoV-2 (virus)
show Timeline
show Locations
showInternational response
showMedical response
show Impact
COVID-19 portal

///////////Biological E, SARS-CoV-2, Baylor College, CORONA VIRUS, COVID 19, Corbevax, BioE COVID-19, BECOV2D, INDIA, Dynavax Technologies

NEW DRUG APPROVALS

ONE TIME

$10.00

Ibrexafungerp citrate, Brexafemme

June 5, 2021 3:28 am / Leave a comment

Ibrexafungerp citrate

アイブレキサフンジェルプクエン酸塩;

Formula	C44H67N5O4. C6H8O7
cas	Citrate1965291-08-0 free 1207753-03-4
Mol weight	922.1574

Brexafemme, fda approved 2021, 2021/6/1

Antifungal, Cell wall biosynthesis inhibitor, Treatment of invasive fungal infections due to Candida spp. or Aspergillus spp., vulvovaginal candidiasis

SCY-078 citrate, MK-3118; SCY-078,

WHO 10597

UNII-M4NU2SDX3E

M4NU2SDX3E

(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.0^1,14.0^2,11.0^5,10]henicos-2-ene-6-carboxylic acid;2-hydroxypropane-1,2,3-tricarboxylic acid

Originator Merck & Co; SCYNEXIS
Class Antifungals; Glycosides; Triterpenes
Mechanism of ActionBeta-1,3-D glucan synthetase inhibitors
Orphan Drug StatusYes – Invasive bronchopulmonary aspergillosis; Candidiasis

RegisteredVulvovaginal candidiasis
Phase IIICandidiasis
Phase IIInvasive bronchopulmonary aspergillosis
Phase IUnspecified
PreclinicalPneumocystis pneumonia

01 Jun 2021Registered for Vulvovaginal candidiasis (In adolescents, In children, In the elderly, In adults) in USA (PO)
01 May 2021Ibrexafungerp – SCYNEXIS receives Qualified Infectious Disease Product status for Vulvovaginal candidiasis (Recurrent, Prevention) in USA
30 Apr 2021Efficacy data from phase III VANISH-303 and VANISH-306 trials in Vulvovaginal Candidiasis presented at the 2021 American College of Obstetricians and Gynecologists Annual Meeting (ACOG-2021)

Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC) (vaginal yeast infection).^[1] It is taken by mouth.^[1]

Ibrexafungerp is a triterpenoid antifungal.^[1]

Ibrexafungerp was approved for medical use in the United States in June 2021.^[1]^[2] It is the first approved drug in a novel antifungal class.^[2]

Medical uses

Ibrexafungerp is indicated for the treatment of adult and postmenarchal pediatric females with vulvovaginal candidiasis (VVC).^[1]^[2]

Syn

https://www.sciencedirect.com/science/article/abs/pii/S0960894X20307721

Abstract

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@gmail.com

……

SYN

Bioorg. Med. Chem. Lett. 2021, 32, 127661.

PATENT

WO 2010019204

https://patents.google.com/patent/WO2010019204A1/en

SYN

https://doi.org/10.1021/acs.jmedchem.3c00501

Ibrexafungerp (Brexafemme). Ibrexafungerp (1), formerly SCY-078 or MK-3118 and developed by Scynexis Inc., is a first-in-class triterpenoid antifungal that inhibits the biosynthesis of β-(1,3)
D-glucan in the fungal cell wall. This mechanism of action provides an opportunity for the treatment
of fungal infections that are azole- or echinocandrin-resistant strains. In June 2021, ibrexafungerp received its first approval by the United States Food and Drug Administration (USFDA) for
the treatment of vulvovaginal candidiasis in adult and postmenarchal pediatric females.
24,25 Ibrexafungerp is a semisynthetic derivative of the natural product enfumafungin that
incorporates a pyridine triazole moiety on the core phenanthropyran ring system as well as a pendant 2-amino-2,3,3trimethyl-butyl ether. The drug demonstrates potent, broad spectrum activity against Candida sp. and is orally bioavailable.
As shown in Scheme 1, the synthesis of ibrexafungerp started with the natural product enfumafungin (1.1). The lactol of enfumafungin was reduced using triethylsilane and trifluoroacetic acid to give pyran 1.2. Treatmentwith H2SO4 in methanol resulted in cleavage of the glucose moiety to generate 1.3 in 87%
yield over 2 steps. Carboxylic acid 1.3 was converted to the corresponding benzyl ester upon treatment with benzyl bromide to give compound 1.4in an89%yield. Reaction of 1.4 with (R)
N-sulfonyl aziridine 1.5 (prepared as shown in Scheme 2) in the presence of potassium t-pentylate and the cation complexing agent 18-crown-6 provided ether 1.6 in 78% yield. Metal reduction with sodiumin liquid ammoniaconcurrently removed the N-sulfonyl benzyl groups to generate compound 1.7, which
was converted to hydrazine intermediate 1.8 with anhydrous hydrazine and BF32·OEt 28-30 in 1,2-dichloroethane (DCE). Cyclocondensation of 1.8 with acyl amidine derivative 1.9 upon heating in acetic acid then provided ibrexafungerp (1) in 66% yield.
Thepreparationof(R)-N-sulfonylaziridine1.5 isdescribedin Scheme 2. Condensation of 3,3-dimethylbutan-2-one (1.10)with (R)-p-toluenesulfinamide (1.11) gave an 84% yield of compound 1.12, which cyclized upon treatment with trimethylsulfoxonium chloride and n-butyllithium to give chiral toluenesulfinyl aziridine 1.13 in 64% yield. Oxidation of 1.13 with meta-chloroperoxybenzoic acid afforded the tosyl-pro
tected (R)-alpha-disubstituted aziridine 1.5..
(24) Lee, A. Ibrexafungerp: First approval. Drugs 2021, 81, 1445−
1450.
(25) Jallow, S.; Govender, N. P. Ibrexafungerp: A first-in-class oral
triterpenoid glucan synthase inhibitor. J. Fungi 2021, 7, 163.
(26) Lamoth, F.; Alexander, B. D. Antifungal activities of SCY-078
(MK-3118) and standard antifungal agents against clinical non
aspergillus mold isolates. Antimicrob. Agents Chemother. 2015, 59,
4308−4311

(27) Scorneaux, B.; Angulo, D.; Borroto-Esoda, K.; Ghannoum, M.;
Peel, M.; Wring, S. SCY-078 is fungicidal against Candida species in
time-kill studies. Antimicrob. Agents Chemother. 2017, 61, e01961-16.
(28) Apgar, J. M.; Wilkening, R. R.; Parker, D. L.; Meng, D.;
Wildonger, K. J.; Sperbeck, D.; Greenlee, M. L.; Balkovec, J. M.;
Flattery, A. M.; Abruzzo, G. K.; Galgoci, A. M.; Giacobbe, R. A.; Gill, C.
J.; Hsu, M.-J.; Liberator, P.; Misura, A. S.; Motyl, M.; Nielsen Kahn, J.;
Powles, M.; Racine, F.; Dragovic, J.; Fan, W.; Kirwan, R.; Lee, S.; Liu,
H.; Mamai, A.; Nelson, K.; Peel, M. Ibrexafungerp: an orally active β
1,3-glucan synthesis inhibitor. Bioorg. Med. Chem. Lett. 2021, 32,
127661.
(29) Greenlee, M. L.; Wilkening, R.; Apgar, J.; Sperbeck, D.;
Wildonger, K. J.; Meng, D.; Parker, D. L.; Pacofsky, G. J.; Heasley, B.
H.; Mamai, A.; Nelson, K. Antifungal Agents. WO 2010019204, 2010.
(30) Greenlee, M. L.; Wilkening, R.; Apgar, J.; Wildonger, K. J.; Meng,
D.; Parker, D. L. Antifungal Agents. WO 2010019203A1, 2010.
(31) Imran, M.; Khan, S. A.; Alshammari, M. K.; Alqahtani, A. M.;
Alanazi, T. A.; Kamal, M.; Jawaid, T.; Ghoneim, M. M.; Alshehri, S.;
Shakeel, F. Discovery, development, inventions and patent review of
fexinidazole: The first all-oral therapy for human African trypanoso
miasis. Pharmaceuticals 2022, 15, 128.

SYN

European Journal of Medicinal Chemistry 245 (2023) 114898

The gram-scale synthesis of this drug is demonstrated in Scheme 3 [50]. Starting with triterpene glycoside enfumafungin 14, a reduction of the bridging hemiacetal with triethylsilane provided the intermediate 15, followed by hydrolysis, etherification and benzyl protection, gave compound 16 in 76% yield over 2 steps. Subsequent ring-opening alkylation reaction of 16 with tosyl protected aziridine 17 gave com pound 18, which then underwent Borch reduction to provide the in termediate 19. Treatment of 19 with biaryl 20 in the presence of boron trifluoride diethyl etherate gave rise to the substitution product ibrexafungerp. In this synthetic method, the pyridine-triazolium biaryl and chiral benzene sulfonamide were elegantly introduced into the triterpene enfumafungin through ring-opening and substitution reactions to give the triterpene derivative. These elegant and practical synthetic
methods could be employed as the versatile tools for the synthesis of other drug molecules.

[50] J.M. Apgar, R.R. Wilkening, D.L. Parker, J.D. Meng, K.J. Wildonger, D. Sperbeck,
M.L. Greenlee, J.M. Balkovec, A.M. Flattery, G.K. Abruzzo, A.M. Galgoci, R.
A. Giacobbe, C.J. Gill, M.J. Hsu, P. Liberator, A.S. Misura, M. Motyl, J.N. Kahn,
M. Powles, F. Racine, J. Dragovic, W. Fan, R. Kirwan, S. Lee, H. Liu, A. Mamai,
K. Nelson, M. Peel, Ibrexafungerp: an orally active β-1, 3-glucan synthesis
inhibitor, Bioorg, Med. Chem. Lett. 32 (2021), 127661.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf
^ Jump up to:^a ^b ^c “Scynexis Announces FDA Approval of Brexafemme (ibrexafungerp tablets) as the First and Only Oral Non-Azole Treatment for Vaginal Yeast Infections”. Scynexis, Inc. (Press release). 2 June 2021. Retrieved 2 June 2021.

External links

“Ibrexafungerp”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03734991 for “Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (VANISH 303)” at ClinicalTrials.gov
Clinical trial number NCT03987620 for “Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (Vanish 306)” at ClinicalTrials.gov

Ibrexafungerp, also known as SCY-078 or MK-3118, is a novel enfumafungin derivative oral triterpene antifungal approved for the treatment of vulvovaginal candidiasis (VVC), also known as a vaginal yeast infection.^1,9 It was developed out of a need to treat fungal infections that may have become resistant to echinocandins or azole antifungals.¹ Ibrexafungerp is orally bioavailable compared to the echinocandins caspofungin, micafungin, and anidulafungin; which can only be administered parenterally.^1,2 Similar to echinocandins, ibrexafungerp targets the fungal β-1,3-glucan synthase, which is not present in humans, limiting the chance of renal or hepatic toxicity.^6,9

Ibrexafungerp was granted FDA approval on 1 June 2021.⁹

β-1,3-glucan synthase is composed of a catalytic subunit, FKS1 or FKS2, and a GTP-binding regulatory subunit, Rho1.^5,6 This synthase is involved in the synthesis of β-1,3-glucan, a fungal cell wall component.⁶

Ibrexafungerp acts similarly to the echinocandin antifungals, by inhibiting the synthesis of β-1,3-glucan synthase.^1,9 While echinocandins bind to the FKS1 domain of β-1,3-glucan synthase, enfumafungin and its derivatives bind at an alternate site which allows them to maintain their activity against fungal infections that are resistant to echinocandins.^3,4

Ibrexafungerp has been shown in animal studies to distribute well to vaginal tissue, making it a favourable treatment for vulvovaginal candidiasis.⁴

Wring SA, Randolph R, Park S, Abruzzo G, Chen Q, Flattery A, Garrett G, Peel M, Outcalt R, Powell K, Trucksis M, Angulo D, Borroto-Esoda K: Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis. Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: AAC.02068-16. doi: 10.1128/AAC.02068-16. Print 2017 Apr. [Article]
Hector RF, Bierer DE: New beta-glucan inhibitors as antifungal drugs. Expert Opin Ther Pat. 2011 Oct;21(10):1597-610. doi: 10.1517/13543776.2011.603899. Epub 2011 Jul 25. [Article]
Kuhnert E, Li Y, Lan N, Yue Q, Chen L, Cox RJ, An Z, Yokoyama K, Bills GF: Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases. Environ Microbiol. 2018 Sep;20(9):3325-3342. doi: 10.1111/1462-2920.14333. Epub 2018 Sep 13. [Article]
Larkin EL, Long L, Isham N, Borroto-Esoda K, Barat S, Angulo D, Wring S, Ghannoum M: A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: AAC.02611-18. doi: 10.1128/AAC.02611-18. Print 2019 May. [Article]
Ha YS, Covert SF, Momany M: FsFKS1, the 1,3-beta-glucan synthase from the caspofungin-resistant fungus Fusarium solani. Eukaryot Cell. 2006 Jul;5(7):1036-42. doi: 10.1128/EC.00030-06. [Article]
Perlin DS: Mechanisms of echinocandin antifungal drug resistance. Ann N Y Acad Sci. 2015 Sep;1354:1-11. doi: 10.1111/nyas.12831. Epub 2015 Jul 17. [Article]
Wring S, Murphy G, Atiee G, Corr C, Hyman M, Willett M, Angulo D: Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus. Clin Pharmacol Drug Dev. 2019 Jan;8(1):60-69. doi: 10.1002/cpdd.588. Epub 2018 Jun 27. [Article]
Ghannoum M, Arendrup MC, Chaturvedi VP, Lockhart SR, McCormick TS, Chaturvedi S, Berkow EL, Juneja D, Tarai B, Azie N, Angulo D, Walsh TJ: Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections. Antibiotics (Basel). 2020 Aug 25;9(9). pii: antibiotics9090539. doi: 10.3390/antibiotics9090539. [Article]
FDA Approved Drug Products: Brexafemme (Ibrexafungerp) Oral Tablet [Link]

Clinical data

Pronunciation	/aɪˌbrɛksəˈfʌndʒɜːrp/ eye-BREKS-ə-FUN-jurp
Trade names	Brexafemme
Other names	SCY-078
License data	US DailyMed: Ibrexafungerp
Pregnancy category	Contraindicated^[1]
Routes of administration	oral, intravenous
Drug class	Antifungal
ATC code	J02AX07 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Pharmacokinetic data
Protein binding	>99%^[1]
Metabolism	Hydroxylation (CYP3A4) then conjugation (glucuronidation, sulfation)^[1]
Elimination half-life	20 hours^[1]
Identifiers
IUPAC name
CAS Number	1207753-03-4as citrate: 1965291-08-0
PubChem CID	46871657as citrate: 137552087
DrugBank	DB12471as citrate: DBSALT003185
UNII	A92JFM5XNUas citrate: M4NU2SDX3E
KEGG	D11544as citrate: D11545
ChEMBL	ChEMBL4297513as citrate: ChEMBL4298168
CompTox Dashboard (EPA)	DTXSID901336871
Chemical and physical data
Formula	C₄₄H₆₇N₅O₄
Molar mass	730.051 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

/////////Ibrexafungerp citrate, Brexafemme, アイブレキサフンジェルプクエン酸塩 , SCY-078 citrate, UNII-M4NU2SDX3E, M4NU2SDX3E, MK-3118; SCY-078, Orphan Drug, Merck, SCYNEXIS, WHO 10597, ANTI FUNGAL

CC(C)C(C)C1(CCC2(C3CCC4C5(COCC4(C3=CCC2(C1C(=O)O)C)CC(C5OCC(C)(C(C)(C)C)N)N6C(=NC=N6)C7=CC=NC=C7)C)C)C.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

NEW DRUG APPROVALS

ONE TIME

$10.00

PTX-COVID19-B

June 4, 2021 1:14 pm / Leave a comment

PTX-COVID19-B

mRNA-based vaccine

Providence Therapeutics; Canadian government

bioRxiv (2021), 1-50.

https://www.biorxiv.org/content/10.1101/2021.05.11.443286v1

Safe and effective vaccines are needed to end the COVID-19 pandemic caused by SARS-CoV-2. Here we report the preclinical development of a lipid nanoparticle (LNP) formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351 and P.1 lineages. No adverse effects were induced by PTX-COVID19-B in both mice and hamsters. These preclinical results indicate that PTX-COVID19-B is safe and effective. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 1 clinical trial ongoing (ClinicalTrials.gov number: NCT04765436).

PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine, a vaccine for the prevention of the COVID-19 disease caused by an infection of the SARS-CoV-2 coronavirus, created by Providence Therapeutics—a private Canadian drug company co-founded by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson.^[1] in 2013. A team of eighteen working out of Sunnybrook Research Institute in Toronto, Ontario developed PTX-COVID19-B^[2] in less than four weeks, according to the Calgary Herald.^[3] Human trials with sixty volunteers began on January 26, 2021 in Toronto.^[4]^[5]^[6]

Providence, which has no manufacturing facilities, partnered with Calgary-based Northern mRNA—the “anchor tenant” in their future manufacturing facilities pending financing.^[2]

On 30 April 2021, Sorenson announced that Providence Therapeutics would be leaving Canada and any vaccine that it developed would not be manufactured in Canada.^[2]

Overview

Providence Therapeutics Holdings Inc. was co-founded in Toronto, Ontario^[7]^[8] by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson Ph.D, who was also the Chief Scientific Officer.^[9]^[3]

PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine. In an interview with CTV news, Sorenson said they were “building some of the important building blocks for the messenger RNA … that provides instructions to cells … to build proteins that may treat or prevent disease”.

As of January 2021, Northern RNA’s Calgary lab was proposed as the site where manufacturing of PTX-COVID19-B would take place.^[10] Providence Therapeutics’ partner, Northern RNA, which located at 421 7 Avenue SW in Calgary, has been described as Providence Therapeutics northern division.^[7]^[8]

A February 2021 Manitoba government press release said that the Winnipeg-based Emergent BioSolutions would be manufacturing the vaccine.^[11]

Human trials

Phase 1

Human trials began on January 26, 2021 with 60 volunteers between the ages of 18 to 65 in Toronto.^[12]^[13]^[3] Of these, 15 would receive a placebo and 3 groups of 15 would receive different doses of the vaccine.^[10] The volunteers will be monitored for 13 months. The company said that enough data would be available in May which could result in a Phase 2 clinical testing beginning soon after that, pending regulatory approval. If the results of a subsequent larger human trial are positive, the vaccine could enter a commercialization phase in 2022.^[14] The Phase 1 clinical trial lead was Piyush Patel. At the 29 April meeting with the House of Commons, Sorenson estimated that PTX-COVID19-B could be approved by Health Canada by “January or February 2022”.^[15]^:8

Provincial funding

Shortly after the first human trials on PTX-COVID19-B began in late January, on 11 February 2021, Manitoba Premier Brian Pallister announced a “term sheet” between the province and Providence Therapeutics through which Manitoba would receive 2 million doses of PTX-COVID19-B pending its approval by Health Canada.^[11] The term sheet includes “best-price guarantee” PTX-COVID19-B.^[13] According to a provincial statement released by the Manitoba government, pending approval of the vaccine, the actual manufacturing would take place in Winnipeg by Emergent BioSolutions.^[11] Pallister said that, “Building a secure, made-in-Canada vaccine supply will put Canadians at the head of the line to get a COVID vaccine, where we belong.”^[11] The down payment would be 20% with a subsequent 40% to be paid when the vaccine was approved by Health Canada; the balance would be paid on delivery of the doses.^[13] Specifics about the contract were released in April 2021: the total cost was estimated as CAD $36 million and the agreement included a clause for a non-refundable advance payment of CAD $7.2 million.^[2] Sorenson made this comment to Global News: “Under no circumstances is Manitoba going to be on the hook for $7.2 million unless they get real value out of it”.

Federal funding

Canada’s National Research Council (NRC) provided Providence Therapeutics with CAD $5 million for the launch of January 2021 first phase of PTX-COVID19-B clinical trials.^[2]

As part of the federal government’s “next generation manufacturing supercluster” program, Providence and Northern mRNA had also been “cleared to access up to $5 million” towards the manufacturing start up process, according to a federal government spokesperson.^[2]

The CBC report in late April 2021 also stated that “it could be eligible for a slice of $113 million in additional funding from the National Research Council of Canada Industrial Research Assistance Program”. The federal government had provided funding to some other companies in Canada that were also working to develop a COVID-19 vaccine.^[2]

Sorenson as Providence Therapeutics CEO posted an open letter to Prime Minister Justin Trudeau, in which he requested $CDN 150 million upfront to be used to pay for clinical trial and material costs.^[16]^[9]

On 29 April 2021, Sorenson appeared before the House of Commons standing committee on international trade, to ask the Minister of Procurement, Anita Anand, to consider PTX-COVID19-B as an alternative to Moderna and Pfizer for the “2022 booster vaccines”.^[15] Sorenson said that the NRC had approached Providence Therapeutics in 2020 after the company had announced their Phase I trial PTX-COVID19-B. Sorenson told the Standing Committee that, “We’ve had really good dialogue ever since phase I started. That process has gone on. That started probably [in February], as we geared up to conclude our phase I trial and release data. Although the NRC is capped at $10 million, which is certainly not sufficient to carry out phase II and phase III trials, the NRC has, through the bureaucracy, elevated us back up to the strategic innovation fund. That occurred about three weeks ago. We’re now working with the strategic innovation fund.”^[15]^:7

He later said that no reply had been received from the government.^[17]

In a meeting with the federal COVID-19 vaccine task force and Sorenson, task force members expressed concerns that “Providence might not be able to scale up production fast enough”.^[2]

Clinical trials

PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64… https://clinicaltrials.gov/ct2/show/NCT04765436

Hyderabad Drugmaker To Make Canada Firm’s mRNA Covid Vaccine In India.. https://www.ndtv.com/india-news/hyderabad-drugmaker-biological-e-to-make-canada-firms-mrna-covid-vaccine-in-india-2454000

Biological E., will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement

Hyderabad-based Biological E said on Tuesday it has entered into a licensing agreement with Providence Therapeutics Holdings to manufacture the Canadian company’s mRNA COVID-19 vaccine in India.

Biological E., which also has a separate deal to produce about 600 million doses of Johnson & Johnson’s COVID-19 shot annually, will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement.

Providence will sell up to 30 million doses of its mRNA vaccine, PTX-COVID19-B, to Biological E, and will also provide the necessary technology transfer of the shot, with a minimum production capacity of 600 million doses in 2022 and a target capacity of 1 billion doses.

Financial details of the transaction were not disclosed.

India has been struggling with a devastating second wave of the pandemic and has managed to fully vaccinate only about 3% of its population. On Monday, the Serum Institute of India said it will increase production of AstraZeneca’s shot by nearly 40% in June, a step towards bridging the shortfall in the country.

“The mRNA platform has emerged as the front runner in delivering the first vaccines for emergency use to combat the COVID-19 pandemic,” said Mahima Datla, Biological E.’s managing director.

Messenger ribonucleic acid (mRNA) vaccines prompt the body to make a protein that is part of the virus, triggering an immune response. US companies Pfizer and Moderna use mRNA technology in their COVID-19 shots.

The drug regulator has approved clinical trials of another mRNA vaccine developed by local firm Gennova Biopharmaceuticals, and the government has said it will fund the studies.

Providence Therapeutics Announces Very Favorable Interim Phase 1 Trial Data for PTX-COVID19-B, its mRNA Vaccine Against COVID-19

https://www.providencetherapeutics.com/providence-therapeutics-announces-very-favorable-interim-phase-1-trial-data-for-ptx-covid19-b-its-mrna-vaccine-against-covid-19May 12, 2021

CALGARY, AB, May 12, 2021 / – Providence Therapeutics Holdings Inc. (“Providence”) announced today very favorable interim clinical data of PTX-COVID19-B, its vaccine candidate against SARS-CoV-2 (“COVID-19”), from its Phase 1 study entitled “PRO-CL-001, A Phase 1, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” (the “Phase 1 Study”), which found that PTX-COVID19-B met Providence’s target results for safety, tolerability, and immunogenicity in the participants of the Phase 1 Study.

Highlights from Providence Therapeutics’ “Phase 1 Study”:

PTX-COVID19-B was generally safe and well tolerated
PTX-COVID19-B exhibited strong virus neutralization capability across the 16µg, 40µg and 100µg dose cohorts
PTX-COVID19-B 40µg dose was selected for Phase 2 study
PTX-COVID19-B will be evaluated in additional Phase 1 population cohorts

The Phase 1 Study was designed with dose-escalations and was performed in seronegative adult subjects without evidence of recent exposure to COVID-19. The subjects were randomized to receive either the PTX-COVID19-B vaccine or a placebo in a 3:1 ratio. A total of 60 subjects participated in the Phase 1 Study.

The overall results of the Phase 1 Study are that PTX-COVID19-B was safe and well tolerated at the three dose levels of 16µg, 40µg and 100µg. Adverse events identified in the Phase 1 Study were generally mild to moderate in severity, self-resolving and transient. There were no serious adverse events reported in the Phase 1 Study. The most common adverse event reported in the Phase 1 Study was redness and pain at the injection site. Systemic reactions reported in the Phase 1 Study were generally mild to moderate and well tolerated with headache being the most common reaction reported. The reported adverse events of the Phase 1 Study were in line with the expectations of management of Providence as they compare very favorably to the adverse events data published on other mRNA vaccines for COVID-19 that have been approved for use by various health authorities around the world.

Based on the results of the Phase 1 Study, Providence intends to use a 40µg dose for the Phase 2 study of PTX-COVID19-B that is anticipated to be initiated in June 2021. Additional Phase 1 studies in adolescent and elderly populations are also planned to be undertaken by Providence.

PTX-COVID19-B vaccination induced high anti-S IgG antibodies:

Participants in the Phase 1 Study were vaccinated on day zero and day twenty-eight. Plasma samples were collected on day 1, day 8, day 28 (prior to the participant receiving the second dose), and day 42 to determine levels of IgG anti-S protein using electrochemiluminescence (“ECL”) assays from Meso Scale Discovery (“MSD”). Study participants in all three vaccine dose cohorts of the Phase 1 Study developed a strong IgG antibody response against Spike protein that was detected by day 28 and enhanced by day 42. No antibodies against S protein were detected in participants in the Phase 1 Study injected with placebo. The highest levels of antibodies were found in the 40 and 100 µg doses. By day 42, PTX-COVID19-B vaccinated participants had more than one log higher antibody levels than convalescent subjects-plasma (indicated in the dotted line) which was evaluated in the same assay.

Based on the interim data of the Phase 1 Study, the level of antibodies produced in participants by PTX-COVID19-B compare favorably to the levels of antibodies produced by other mRNA vaccines that have been approved for use against COVID-19 based on the recently published report from Stanford University, where IgG responses in individuals vaccinated with the COVID-19 mRNA vaccine compared to COVID-19 infected patients were evaluated[1].

PTX-COVID19-B vaccination induced high neutralizing antibody levels:

Neutralizing activity from the Phase 1 Study participants’ plasma was evaluated by S-ACE2 MSD assay. The results indicate that the antibodies block the interaction between S protein with the ACE2 receptor and the decrease in ECL signal is used to calculate percentage inhibition of the plasma at the same dilution. All participants in the Phase 1 Study from the 16, 40 and 100 µg dose levels showed blocking activity by day 28 and all of them reached 100% blocking activity by day 42 with samples diluted 1:100 or greater. Moreover, the quantification of the antibody levels in ng/mL with a reference standard showed that all participants in the Phase 1 Study produced neutralizing antibodies by day 28 with the first immunization and increase ten-fold by day 42, two weeks after the administration of the second dose. These results indicate that PTX-COVID19-B induced a strong neutralizing antibody response which compares very favorably to the published results of other mRNA vaccines. Further studies are being conducted by Providence to determine neutralization activity using a pseudo-virus assay.

Providence intends to advance a Phase 2 clinical trial in early June 2021, with multiple trial sites in Canada. The Phase 2 clinical trial is anticipated to be structured as a comparator trial using Pfizer/BioNTech vaccine as the positive control.

About Providence Therapeutics

Providence is a leading Canadian clinical stage biotechnology company pioneering mRNA therapeutics and vaccines with operations in Calgary, Alberta and Toronto, Ontario. In response to a worldwide need for a COVID-19 vaccine, Providence expanded its focus beyond oncology therapies and devoted its energy and resources to develop a world-class mRNA vaccine for COVID-19. Providence is focused on serving the needs of Canada, and other countries that may be underserved by large pharmaceutical programs. For more information, please visit providencetherapeutics.com.

References

^ “Canadian company urges human trials after COVID-19 vaccine results in mice”. Lethbridge News Now. 5 August 2020. Retrieved 19 March 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h Tasker, John Paul (30 April 2021). “COVID-19 vaccine maker Providence says it’s leaving Canada after calls for more federal support go unanswered”. CBC News. Retrieved 1 May 2021.
^ Jump up to:^a ^b ^c Stephenson, Amanda (26 January 2021). “Made-in-Canada COVID vaccine to be manufactured in Calgary”. Calgary Herald. Retrieved 22 March 2021.
^ Clinical trial number NCT04765436 for “PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” at ClinicalTrials.gov
^ “Providence Therapeutics Holdings Inc: PTX-COVID19-B”. Montreal: McGill University. Retrieved 19 March 2021.
^ “Made-in-Canada coronavirus vaccine starts human clinical trials”. Canadian Broadcasting Corporation. 26 January 2021.
^ Jump up to:^a ^b “Company Profile”. PitchBook.
^ Jump up to:^a ^b “Company Profile”. DNB.
^ Jump up to:^a ^b Code, Jillian (5 February 2021). “‘Do something’ Made-In-Canada vaccine CEO pleads for federal government to respond”. CTV News. Calgary, Alberta. Retrieved 22 March 2021.
^ Jump up to:^a ^b Fieldberg, Alesia (26 January 2021). “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”. CTV. Retrieved 2 May 2021.
^ Jump up to:^a ^b ^c ^d “Manitoba Supports Made-In-Canada COVID-19 Vaccine to Protect Manitobans” (Press release). 11 February 2021. Retrieved 3 May 2021.
^ Providence Therapeutics Holdings Inc.: a Phase I, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64 (Report). Clinical Trials via U.S. National Library of Medicine. 19 February 2021. Retrieved 1 May2021.
^ Jump up to:^a ^b ^c Gibson, Shane (11 February 2021). “Manitoba agrees to purchase 2M doses of Providence Therapeutics coronavirus vaccine”. Global News. Retrieved 2 May 2021.
^ “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”. CTV. Retrieved 2 May 2021.
^ Jump up to:^a ^b ^c Evidence (PDF), 43rd Parliament, 2nd Session. Standing Committee on International Trade, 29 April 2021, retrieved 2 May2021
^ Sorenson, Brad (5 February 2021). “An Open Letter to the Government of Canada”. Retrieved 3 May 2021.
^ Dyer, Steven. “‘Canada had an opportunity’, Calgary company explores taking vaccine development out of Canada”. CTV. Retrieved 2 May 2021.

Vaccine description
Target	SARS-CoV-2
Vaccine type	mRNA
Clinical data
Routes of administration	Intramuscular

COVID-19 pandemic
Part of a series on the

COVID-19 (disease)SARS-CoV-2 (virus)
show Timeline
show Locations
showInternational response
showMedical response
show Impact
COVID-19 portal

////////PTX-COVID19-B, canada, hyderabad, providence, Gennova Biopharmaceuticals, biological e, COVID-19, SARS-CoV-2 , corona virus, covid 19, phase 1

NEW DRUG APPROVALS

ONE TIME

$10.00

Imdevimab

June 1, 2021 3:24 am / 1 Comment on Imdevimab

(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS NYAMYWVRQA PGKGLEWVAV ISYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRTED TAVYYCASGS DYGDYLLVYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
QSALTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVSKRPSGV
SNRFSGSKSG NTASLTISGL QSEDEADYYC NSLTSISTWV FGGGTKLTVL GQPKAAPSVT
LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK AGVETTTPSK QSNNKYAASS
YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS
(Disulfide bridge: H22-H96, H147-H203, H223-L215, H229-H’229, H264-H324-H370-H428, H’22-H’96, H’147-H’203, H’223-L’215, H’264-H’324, H’370-H’428, L22-L90, L138-L197, L’22-L’90, L’138-L’197)

Imdevimab

イムデビマブ;

Immunoglobulin G1, anti-(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10987 γ1-chain), disulfide with human monoclonal REGN10987 λ-chain, dimer

Formula	C6396H9882N1694O2018S42
CAS	2415933-40-1
Mol weight	144141.7693

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

ANTIVIRAL

SARS-CoV-2 spike glycoprotein

REGN 10987
RG 6412

Fact Sheet – US Food and Drug Administration

https://www.fda.gov › media › download
PDFBenefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab.

Casirivimab/imdevimab, sold under the brand name REGEN-COV,^[1] is an experimental medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial “antibody cocktail” designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic.^[3]^[4] It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together.^[1]^[5]^[6] The combination of two antibodies is intended to prevent mutational escape.^[7]

Trials

In a clinical trial of people with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in people at high risk for disease progression within 28 days after treatment when compared to placebo.^[2] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.^[2]

The data supporting the emergency use authorization (EUA) for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms.^[2] Of these participants, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.^[2]

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline.^[2] Viral load reduction in participants treated with casirivimab and imdevimab was larger than in participants treated with placebo at day seven.^[2] However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment.^[2] For participants at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated participants on average compared to 9% in placebo-treated participants.^[2] The effects on viral load, reduction in hospitalizations and ER visits were similar in participants receiving either of the two casirivimab and imdevimab doses.^[2]

As of September 2020, REGEN-COV is being evaluated as part of the RECOVERY Trial.^[8]

On 12 April 2021, Roche and Regeneron announced that the Phase III clinical trial REGN-COV 2069 met both primary and secondary endpoints, reducing risk of infection by 81% for the non-infected patients, and reducing time-to-resolution of symptoms for symptomatic patients to one week vs. three weeks in the placebo group.^[9]

Authorization

On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19.^[2]^[10]^[11] This includes those who are 65 years of age or older or who have certain chronic medical conditions.^[2] Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.^[2]

Casirivimab and imdevimab are not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.^[2] A benefit of casirivimab and imdevimab treatment has not been shown in people hospitalized due to COVID-19.^[2] Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized people with COVID-19 requiring high flow oxygen or mechanical ventilation.^[2]

The EUA was issued to Regeneron Pharmaceuticals Inc.^[2]^[10]^[12]

On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.^[13]^[14] In February 2021, the CHMP concluded that the combination, also known as REGN-COV2, can be used for the treatment of confirmed COVID-19 in people who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.^[15]

The Central Drugs Standards Control Organisation (CDSCO) in India, on 5 May 2021, granted an Emergency Use Authorisation to Roche (Genentech)^[16] and Regeneron^[17] for use of the casirivimab/imdevimab cocktail in the country. The announcement came in light of the second wave of the COVID-19 pandemic in India. Roche India maintains partnership with Cipla, thereby permitting the latter to market the drug in the country.^[18]

Deployment

Although Regeneron is headquartered in Tarrytown, New York (near New York City), REGEN-COV is manufactured at the company’s primary U.S. manufacturing facility in Rensselaer, New York (near the state capital at Albany).^[19] In September 2020, to free up manufacturing capacity for REGEN-COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.^[20]

Regeneron has a deal in place with Roche (Genentech)^[21]to manufacture and market REGEN-COV outside the United States.^[10]^[22]

On 2 October 2020, Regeneron Pharmaceuticals announced that US President Donald Trump had received “a single 8 gram dose of REGN-COV2” after testing positive for SARS-CoV-2.^[23]^[24] The drug was provided by the company in response to a “compassionate use” (temporary authorization for use) request from the president’s physicians.^[23]

References

^ Jump up to:^a ^b ^c “REGEN-COV- casirivimab and imdevimab kit”. DailyMed. Retrieved 18 March 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”. U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020. This article incorporates text from this source, which is in the public domain.
^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”. Reuters. Retrieved 14 September 2020.
^ “Regeneron’s COVID-19 Response Efforts”. Regeneron Pharmaceuticals. Retrieved 14 September 2020.
^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”. BBC News Online. Retrieved 14 September2020.
^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”. ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”. Science. 369 (6506): 1014–1018. Bibcode:2020Sci…369.1014B. doi:10.1126/science.abd0831. PMC 7299283. PMID 32540904.
^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”. Recovery Trial. Retrieved 14 September 2020.
^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”. streetinsider.com. Archived from the original on 2021-04-12. Retrieved 2021-04-12.
^ Jump up to:^a ^b ^c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
^ “Casirivimab and Imdevimab”. Regeneron Pharmaceuticals. Retrieved 19 March 2021.
^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”. http://www.cipla.com. Retrieved 2021-05-06.
^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”. The Daily Gazette.
^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”. BioProcess International.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ “Roche and Regeneron link up on a coronavirus antibody cocktail”. CNBC. 19 August 2020. Retrieved 14 September 2020.
^ Jump up to:^a ^b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”. The New York Times. ISSN 0362-4331. Retrieved 2 October 2020.
^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”. http://www.precisionvaccinations.com. Archived from the original on 3 October 2020.

External links

“Casirivimab”. Drug Information Portal. U.S. National Library of Medicine.
“Imdevimab”. Drug Information Portal. U.S. National Library of Medicine.
“Casirivimab and Imdevimab EUA Letter of Authorization” (PDF). U.S. Food and Drug Administration (FDA).
“Frequently Asked Questions on the Emergency Use Authorization of Casirivimab + Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).

Combination of
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG.
Casirivimab	Monoclonal antibody against spike protein of SARS-CoV-2
Imdevimab	Monoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade names	REGEN-COV
Other names	REGN-COV2
AHFS/Drugs.com	Monograph
License data	US DailyMed: Casirivimab
Routes of administration	Intravenous
ATC code	None
Legal status
Legal status	US: Unapproved (Emergency Use Authorization)^[1]^[2]
Identifiers
DrugBank	DB15691
KEGG	D11938 D11939

////////Imdevimab, ANTI VIRAL, PEPTIDE, CORONA VIRUS, COVID19, APPROVALS 2020, FDA 2020, イムデビマブ, REGN 10987, RG 6412,

NEW DRUG APPROVALS

one time

$10.00

Casirivimab

May 31, 2021 3:22 am / Leave a comment

(Heavy chain)
QVQLVESGGG LVKPGGSLRL SCAASGFTFS DYYMSWIRQA PGKGLEWVSY ITYSGSTIYY
ADSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCARDR GTTMVPFDYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
DIQMTQSPSS LSASVGDRVT ITCQASQDIT NYLNWYQQKP GKAPKLLIYA ASNLETGVPS
RFSGSGSGTD FTFTISGLQP EDIATYYCQQ YDNLPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H147-H203, H223-L214, H229-H’229, H232-H’232, H264-H324, H370-H428, H’22-H’96, H’147-H’203, H’223-L’214, H’264-H’324, H’370-H’428, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Casirivimab

カシリビマブ;

Immunoglobulin G1, anti-(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10933 γ1-chain), disulfide with human monoclonal REGN10933 κ-chain, dimer

Formula	C6454H9976N1704O2024S44
CAS	2415933-42-3
Mol weight	145233.3296

Monoclonal antibody
Treatment and prophylaxis of SARS-CoV-2 infection (COVID-19)

SARS-CoV-2 spike glycoprotein

Protein Sequence
Sequence Length: 1328, 450, 450, 214, 214

REGN 10933
RG 6413

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19 November 21, 2020

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms [about 88 pounds]) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19. This includes those who are 65 years of age or older or who have certain chronic medical conditions.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.

Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.

Casirivimab and imdevimab are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. A benefit of casirivimab and imdevimab treatment has not been shown in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

“The FDA remains committed to advancing the nation’s public health during this unprecedented pandemic. Authorizing these monoclonal antibody therapies may help outpatients avoid hospitalization and alleviate the burden on our health care system,” said FDA Commissioner Stephen M. Hahn, M.D. “As part of our Coronavirus Treatment Acceleration Program, the FDA uses every possible pathway to make new treatments available to patients as quickly as possible while continuing to study the safety and effectiveness of these treatments.”

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. Casirivimab and imdevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.

“The emergency authorization of these monoclonal antibodies administered together offers health care providers another tool in combating the pandemic,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “We will continue to facilitate the development, evaluation and availability of COVID-19 therapies.”

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that casirivimab and imdevimab administered together may be effective in treating patients with mild or moderate COVID-19. When used to treat COVID-19 for the authorized population, the known and potential benefits of these antibodies outweigh the known and potential risks. There are no adequate, approved and available alternative treatments to casirivimab and imdevimab administered together for the authorized population.

The data supporting this EUA for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms. Of these patients, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline. Viral load reduction in patients treated with casirivimab and imdevimab was larger than in patients treated with placebo at day seven. However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment. For patients at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated patients on average compared to 9% in placebo-treated patients. The effects on viral load, reduction in hospitalizations and ER visits were similar in patients receiving either of the two casirivimab and imdevimab doses.

Under the EUA, fact sheets that provide important information about using casirivimab and imdevimab administered together in treating COVID-19 as authorized must be made available to health care providers and to patients and caregivers. These fact sheets include dosing instructions, potential side effects and drug interactions. Possible side effects of casirivimab and imdevimab include: anaphylaxis and infusion-related reactions, fever, chills, hives, itching and flushing.

The EUA was issued to Regeneron Pharmaceuticals Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Related Information

Trials

As of September 2020, REGEN-COV is being evaluated as part of the RECOVERY Trial.^[8]

Authorization

The EUA was issued to Regeneron Pharmaceuticals Inc.^[2]^[10]^[12]

Deployment

Regeneron has a deal in place with Roche (Genentech)^[21]to manufacture and market REGEN-COV outside the United States.^[10]^[22]

References

^ Jump up to:^a ^b ^c “REGEN-COV- casirivimab and imdevimab kit”. DailyMed. Retrieved 18 March 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”. U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020. This article incorporates text from this source, which is in the public domain.
^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”. Reuters. Retrieved 14 September 2020.
^ “Regeneron’s COVID-19 Response Efforts”. Regeneron Pharmaceuticals. Retrieved 14 September 2020.
^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”. BBC News Online. Retrieved 14 September2020.
^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”. ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”. Science. 369 (6506): 1014–1018. Bibcode:2020Sci…369.1014B. doi:10.1126/science.abd0831. PMC 7299283. PMID 32540904.
^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”. Recovery Trial. Retrieved 14 September 2020.
^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”. streetinsider.com. Archived from the original on 2021-04-12. Retrieved 2021-04-12.
^ Jump up to:^a ^b ^c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
^ “Casirivimab and Imdevimab”. Regeneron Pharmaceuticals. Retrieved 19 March 2021.
^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”. http://www.cipla.com. Retrieved 2021-05-06.
^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”. The Daily Gazette.
^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”. BioProcess International.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ “Roche and Regeneron link up on a coronavirus antibody cocktail”. CNBC. 19 August 2020. Retrieved 14 September 2020.
^ Jump up to:^a ^b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”. The New York Times. ISSN 0362-4331. Retrieved 2 October 2020.
^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”. http://www.precisionvaccinations.com. Archived from the original on 3 October 2020.

External links

“Casirivimab”. Drug Information Portal. U.S. National Library of Medicine.
“Imdevimab”. Drug Information Portal. U.S. National Library of Medicine.
“Casirivimab and Imdevimab EUA Letter of Authorization” (PDF). U.S. Food and Drug Administration (FDA).
“Frequently Asked Questions on the Emergency Use Authorization of Casirivimab + Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).

Combination of
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG.
Casirivimab	Monoclonal antibody against spike protein of SARS-CoV-2
Imdevimab	Monoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade names	REGEN-COV
Other names	REGN-COV2
AHFS/Drugs.com	Monograph
License data	US DailyMed: Casirivimab
Routes of administration	Intravenous
ATC code	None
Legal status
Legal status	US: Unapproved (Emergency Use Authorization)^[1]^[2]
Identifiers
DrugBank	DB15691
KEGG	D11938

//////////// Casirivimab, ANTI VIRAL, PEPTIDE, SARS-CoV-2, MONOCLONAL ANTIBODY, FDA 2020, 2020APPROVALS, CORONA VIRUS, COVID 19, カシリビマブ, REGN-COV2, REGN10933+REGN10987 combination therapy, REGN 10933, RG 6413

NEW DRUG APPROVALS

ONE TIME

$10.00

OCID 5090, Enmetazobactam

May 23, 2021 2:04 pm / Leave a comment

OCID 5090

Enmetazobactam

Beta-lactamase inhibitor.

AAI-101
RN: 1001404-83-6
UNII: 80VUN7L00C

2/22/2024 FDA APPROVED, To treat complicated urinary tract infections, Exblifep

Molecular Formula, C11-H14-N4-O5-S, Molecular Weight, 314.3206

(2S,3S,5R)-3-Methyl-3-((3-methyltriazol-3-ium-1-yl)methyl)-4,4,7-trioxo-4^6-thia-1-azabicyclo(3.2.0)heptane-2-carboxylate

1H-1,2,3-Triazolium, 3-(((2S,3S,5R)-2-carboxy-3-methyl-4,4-dioxido-7-oxo-4-thia-1-azabicyclo(3.2.0)hept-3-yl)methyl)-1-methyl-, inner salt
Enmetazobactam

The Board of directors of Orchid Pharma Ltd has announced that the company had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the company is happy to announce that the molecule has cleared the Phase 3 clinical trials.

Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.

As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.

Orchid had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the molecule has cleared the Phase 3 clinical trials.

INVENTOR

Senthilkumar U P

ORCHID

Summary of Profile of Dr. U. P. Senthilkumar, R&D Centre, Orchid Pharma Ltd.
Dr. U. P. Senthilkumar Ph.D., the principal inventor of novel beta-lactamase inhibitor, OCID5090, is currently serving as the senior vice-president at Orchid’s Research and Development Centre, Chennai.
With illustrious credentials — top ranks in B.Sc. and M.Sc. degrees, first rank in the Graduate Aptitude Test in Engineering (GATE), UGC-CSIR Junior Research Fellowship (JRF) and the prestigious Dr. K.S. Krishnan Fellowship from the Department of Atomic Energy (DAE) and publication of M.Sc. project work in the Indian Journal of Chemistry in 1987 — Mr. Senthilkumar chose to pursue his doctoral research in synthetic organic chemistry with his mentor Prof.
Ramasubbu Jeyaraman at Bharathidasan University, Tiruchirapalli. His research focus on the conformational preferences of sterically challenged novel N-Nitroso heterocycles and their conformation dependent anti-cancer properties, led to the publication of 9 articles in reputed peer-reviewed international journals – a commendable accomplishment in the 90s.
After a brief post-doctoral stint on fluorescent dicyclopentapyridines, Dr. U. P. Senthilkumar joined Torrent Research Centre at Ahmedabad and started his new endeavor of drug discovery on ACE inhibitors. At the process research and development laboratory, he was actively involved in asymmetric and stereo-selective synthesis of Active Pharmaceutical Ingredients (APIs), and exploited the full potential of chiral prep-HPLC to realize the target molecules.
After joining Orchid Pharma Ltd., Chennai, Dr. Senthilkumar led the efforts in the development of differentiated and patentable manufacturing processes for APIs related to both non-antibiotics and beta-lactam antibiotics. He played a significant role in successfully implementing the manufacturing processes overcoming several challenging problems. In addition, his scientific insights and breath of understanding on the patent landscape were invaluable and impactful in
creating significant value to the organization and growth of the company in realizing the mission to become a leader in the pharmaceutical generic business.
One finds more than 100 articles/patents/publications to his credit, which include inventions on new drugs, drug-intermediates, products, processes, new synthetic routes, rearrangements and novel polymorphs. As a Leadership Persona of the IP management team, he had exhibited a thoroughness of the science/invention and meticulously executed the task of prosecution of few hundred patents in many countries from both New Drug Discovery and Process Chemistry space.
All the successful effort earned Orchid Pharma Ltd the National Intellectual Property Award from the Department of Industrial Policy and Promotion, Ministry of Commerce and Industry,Government of India.
Through his executive and decision-making skills combined with scientific rationale and clarity, Dr. Senthilkumar played significant role in the selection of products and creation of generic product portfolio for Orchid, with unique IP strategies, analysis of patents, patent mapping, designing & developing invalidation/non-infringing positions, and early launch opportunity, including first-to-file (FTF) positioning. His appearance in the US courts, for deposition in couple of patent litigations, and successful accomplishment of the same are testimony to his depth, thoroughness of science and the ability to defend the invention with grit and professionalism.
Additionally, his effectual role in the first-to-launch of one of the large volume sterile penicillins with regulatory exclusivity, achieved successfully by overcoming the citizen petition process in the regulatory pathway, is another shining example of his leadership and scientific strength.
To support in-house projects as well as multinational pharma majors, Dr. Senthilkumar has taken up CRAMS (Contract Research and Manufacturing Services) and CMC (Chemistry, Manufacturing and Control) for new chemical entities. Besides, he passionately focused on novel beta-lactamase inhibitors and their antibiotic combinations that were envisaged by him to exhibit potent activity against multi-drug resistant bacteria. His dedicated effort brought a novel extended spectrum beta-lactamase inhibitor, OCID5090, which was out-licensed to Allecra Inc. OCID5090/cefepime combination has completed successfully the Phase III clinical trials for treating complicated urinary-track-infections (cUTI), including acute pyelonephritis (AP), and rightfully, OCID5090 has gotten the US FDA fast track designation as a Qualified Infectious Disease product (QIDP) that provides a five-year additional market exclusivity and priority review.
His never-ending passion for research is infectious and roped him with academic institutions to explore novel technologies including electron-beam irradiated heterogeneous catalysis. His commendable knowledge on intellectual property is being utilized by the IP Cells of various institutions as well as the Tamil Nadu State Technology Development and Promotion Centre.
A sincere student he is, Dr. Senthilkumar is also a founder-member of Prof. Ramasubbu Jeyaraman Science Foundation (RJSF). Since 2011, he has been playing a significant role in rganizing several academic events (seminars, work-shops, invited lectures, state-level proficiency tests, and research-orientation programs) for post-graduate chemistry students to create passion for research. His concern and help for poor and rural students show his human face.

SYN

PATENT

US 20080015156

https://patents.google.com/patent/US20080015156A1/en

[0050]
[0051]To a suspension of (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (25 g) in acetone (100 mL) at 25-30° C. was added slowly N,O-bis(silylacetamide) (18.6 g) with stirring. The reaction mixture was stirred at this temperature (25-30° C.) for 15-20 min. To the clear solution obtained, methyl iodide (100 mL) was added over a period of 15 min. and stirred at 25-30 min. for 24 h. The precipitated solid was separated by filtration and washed with acetone (25 mL). Wet weight of the solid obtained was 30 g.
[0052]The above wet solid was stirred with purified water (300 mL) at 10-15° C. for 2.5 h. To the resulted reaction mixture was added sodium thiosulfate (0.1 g) and stirred at 10-15° C. for 10-15 min. To the reaction mixture, dichloromethane (300 mL) was added, stirred and the organic layer separated. The aqueous layer was washed with a solution of Amberlite LA-2 resin (5% solution in dichloromethane twice, followed by dichloromethane twice. To the aqueous solution, activated carbon (1 g) was added, stirred for 15 min, filtered and washed with purified water (25 mL). The solution was filtered and lyophilized to get the title compound in pure form (10 g). ¹H NMR (400 MHz, DMSO) δ ppm: 1.39 (s, 3H), 3.14 (dd, J=16.0, 1.3 Hz, 1H), 3.55 (dd, J=16.0, 4.2 Hz, 1H), 3.97 (s, 1H), 4.34 (s, 3H), 5.05 (dd, J=4.2, 1.3 Hz, 1H), 5.29 (d, J=14.7 Hz, 1H), 5.42 (d, J=14.7 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H). Mass m/z: M+1 peak at 315. Alternatively the solution could be subjected to spray-drying to yield the title compound.

PATENT

WO 2012070071

IN 2010CH03555

US 20140057888

PATENT

WO 2015173378

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7D714EA925DF9198DA8D15083DF88C7D.wapp2nB?docId=WO2015173378&tab=PCTDESCRIPTION

Scheme 1

Examples

Synthesis of (2535.5R)-3-methyl-3-((3-methyl-lH-1.2 -triazol-3-ium-l-yl)methvn-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4),

Compound (4) was prepared according to Scheme 2.

Scheme 2

i) Ν,Ο-bis-trimethylsilylacetamide, CH₂CI₂; ii) CH₃OTf; iii) Na 2-ethylhexanoate

In a round bottom flask under nitrogen flow 100 g of Tazobactam acid (1) and 500 mL of Dichloromethane are loaded. The temperature is adjusted to +30/35°C then 37 g of Ν,Ο-Bis(trimethylsilyl) acetamide are loaded in 15-20 minutes maintaining the temperature to +35/42°C. The mixture is heated to reflux (+40/42°C) for 60 minutes. If the solution is not clear, N,0-Bis(trimethylsilyl) acetamide is loaded in small portions (0,5-1.0 g each) waiting 15 minutes every time till a clear solution containing intermediate (2) is obtained. 0.55 moles of N,0-Bis(trimethylsilyl) acetamide is used, with further 0.1-0.2 equivalents being added if the reaction is not complete.

Then the temperature is cooled down to 0/+5°C and 70 g of Methyl trifluoromethanesulfonate are loaded in 60-90 minutes maintaining the temperature at 0/+5°C. After 30 minutes the reaction is monitored by HPLC to control the disappearance of intermediate (2) and formation of intermediate (3). The reaction is monitored every 30 minutes until completion.

In a round bottom flask, under nitrogen, are loaded 500 mL of Ethanol and 55 g of Sodium 2-Ethylhexanoate and the temperature is adjusted to +20/25°C, then the reaction solution containing intermediate (3) is added in 60-90 minutes maintaining the temperature of +20/25 °C under vigorous stirring. The suspension is stirred for 30 minutes then is filtered and washed with 300 mL of Ethanol followed by 500 mL of Dichloromethane under nitrogen. The crude product (4) is dried under nitrogen flow till constant weight (150 g) is obtained. The crude product compound (4) was isolated as a solid product (HPLC assay = 70%, yield = 80%).

Purification of (2_tS’,3^5^)-3-methyl-3-((3-methyl-lH-l,2,3-triazol-3-ium-l-yl)methyl)-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4)

In a round bottom flask 800 mL of Dimethylformamide are loaded, the temperature is adjusted to +20/25°C then crude Compound 4 (150g) obtained above is loaded using 100 mL of Dimethylformamide to facilitate the transfer. The mixture is stirred for 5 minutes and a solution is obtained, then and after a few minutes crystallization takes place. The suspension is stirred for about 3 hours, then is cooled to 0/+5°C and stirred for another 3 hours.

The solid is filtered and washed with 300 mL of Dimethylformamide pre-cooled to 0/+5°C. Compound 4 is then suspended in 700 mL of Ethyl acetate and the temperature is adjusted to +40/45°C. The suspension is stirred for 30 minutes then the solid is filtered and washed with 150 mL of Ethyl acetate pre-heated to +40/45°C. The suspension with

Ethyl acetate is repeated twice. Finally Compound 4 is dried under vacuum at +40°C till constant weight is achieved (66 g, HPLC assay = 99%, yield = 76%).

Compound 4 Sterile filtration and recrystallization Procedure

In a round bottom flask 350 mL of Methanol are loaded, the temperature is adjusted to +30/35°C then 100 g of Compound 4 are loaded and finally the flask is washed with 60 mL of Methanol. After 5-10 minutes a solution is obtained. The solution is diluted with 330 mL of acetone adjusting the temperature to +20/+25°C. The obtained solution is treated with 2,2 g of charcoal for 20 minutes then filtered using a 0.22microM filter and the filter is washed with a mixture of 13 mL of Methanol and 110 mL of Acetone. The temperature of the solution is adjusted to +30/35°C and under vigorous stirring 830 mL of Acetone are loaded in about 15-20 minutes. After stirring for 60 minutes at temperature of +30/35°C 1170 mL of Acetone are loaded in 45-60 minutes. Then the temperature is adjusted to +20/25 °C in about 30-60 minutes and maintained for 30 minutes. The obtained crystalline solid is filtered and washed with 430 mL of Acetone. Finally the product is dried under vacuum at +40°C till constant weight is achieved (83 g of Compound 4) are obtained with an HPLC assay = 98-99%, yield =t 80%).

Mr. Ram Gopal Agarwal

Chairman and Non-Executive Director

Mr. Ram Gopal Agarwal is Founder Chairman of Dhanuka Group.
He is a decisive and action oriented visionary who took over a sick pesticide Company named Northern Mineral Pvt. Ltd. in 1980 and transformed it today into a Rs 1000 Crore organization called Dhanuka Agritech Ltd.
His deep commitment and inspiring leadership in initial turbulent days is an example worth inculcating and his passion to contribute to Indian Agriculture is commendable.
His ability to prioritize and deal effectively with a number of tasks simultaneously reinforced with the skills to make effective decisions, has metamorphosed the business venture into one of the fastest growing Agrochemical Company in India which has thrice been rated as ‘Best under a Billion Company’ by Forbes Magazine.
In order to achieve his aspiration of “Transforming India through Agriculture” he has dedicated himself to bring changes in Agrochemicals Industry and the farming community. His contribution for adopting newer farming techniques at the grass root level, judicious use of agro chemicals in farming and imparting knowledge through his nationwide network of distributors and Dhanuka Doctors in field has resulted in the overall prosperity of farmers.
Mr. Ram Gopal Agarwal has been the past Chairman of CCFI, (Crop Care Federation of India) the apex Chamber of all Indian Agrochemical majors. He is also Chairman of Advisory Committee of AGRO Chemicals Federation of India.
Mr. Ram Gopal Agarwal, Group Chairman, has been bestowed with many Awards for his tremendous contribution in Agro Industry like “Life Time Achievement Award” by Agri Business Summit and Agri Awards 2019, “Distinguished Contribution to Indian Agrochemicals Industry” during India Chem 2016 International Conference organised by FICCI etc.

Mr. Manish Dhanuka

Managing Director

Mr. Manish Dhanuka is the Director of Orchid Pharma Limited; he has the vision to rejuvenate Orchid Pharma Ltd. and take it on a fruitful path. His wide-ranging experience of handling operations, commercial, marketing and finance in the manufacturing industry provides for his analytical and decision-making skills facilitating the restoration of the company to its glorious past and to achieve even greater heights.
He excels in creating economical Pharmaceutical technologies and accelerated evaluation process for improving healthcare. Experience of 25 years in research, evaluation, and teaching in the pharmaceutical industry equips him with the expertise in innovative pharmaceutical technologies…
He holds a B.Tech in Chemical Engineering from IIT, New Delhi, and M.S in Chemical Engineering from the University of Akron, USA.
Before establishing Dhanuka Laboratories Ltd. in 1993, he began his career at Ranbaxy Labs Ltd. in New Delhi and worked there for 5 years. His vision and strategy to grow the Pharmaceutical industry in the Indian sub-continent, have helped the Dhanuka Group of companies enhance its Bulk Drugs manufacturing arm exponentially. He spearheaded the acquisition of Synmedic Laboratories in the year 2013 which is involved in pharmaceutical formulations. This entrepreneurial vigor enabled him to take over the operations of Orchid Pharma Ltd. in March 2020.
Outside of work, he likes to travel for wildlife adventures.

Mr. Mridul Dhanuka

Whole-Time Director

He is associated with Dhanuka Group Ltd. since 2005. He was responsible in successfully realigning the entire supply chain vertical from procurement to sales. At Orchid, he hopes to replicate the Group’s success and put another feather in Dhanuka cap.

CLIP

Orchid Chemicals & Pharmaceuticals, or Orchid Pharma since its recent name change in 2015, was established in 1992 in Chennai to manufacture antibiotics, and entered drug discovery in 2001 with projects in the areas of anti-infectives and treatments for pain.32, 197 In 2002, the company engaged in a joint venture to develop US-based firm Bexel Biotechnology’s BLX-1002, an oral, non-PPAR AMPK activator for the treatment of diabetes,198 later repositioned for NASH (2012), but no further progress has been reported recently.197 In 2008, Orchid invested in Diakron Pharmaceuticals, a US-based company that had an exclusive license to MSD′s investigational oral anticoagulant drug, a direct thrombin inhibitor later known as DPOC-4088 (or DP-4088),199 which reached Phase 1 clinical studies in Europe in 2012 (Supporting Information Table 6b, entries 5–6).200 The company’s own internal discovery efforts had a broad therapeutic focus, covering infectious diseases, inflammation, pain, oncology, metabolic disorders, and CNS diseases. OCID-2987,197, 201 a PDE4 inhibitor for the treatment of inflammatory disorders such as COPD, completed successfully Phase 1 studies in Europe in 2012, and OCID-4681 29,202, 203 a histone deacetylase (HDAC) inhibitor for cancer had received approval in 2011 for Phase 1 studies for solid tumors in India, but we assume both have been abandoned, as cancer and inflammation are not mentioned in the company’s latest annual reports.197 Two additional compounds were abandoned at the preclinical stage: OCID-5005, a STAT-3/IL-6 inhibitor for oncology, and a unnamed Th1/Th2 cytokine synthesis inhibitor for inflammation (Supporting Information Table 2a, entries 134–138).197 Financial issues led Orchid, as of 2009, to sell parts of its business to Hospira (now part of Pfizer). As a consequence, no progress has been reported on its discovery programs since 2010, and no further NCE patent application has been published since 2012. However, in 2013 Orchid licensed its broad-spectrum β-lactamase inhibitor OCID-5090, a zwitterionic N-methylated tazobactam derivative, to the German Allecra Therapeutics for a 20 % stake in the company, for use in combination with antibiotics to treat multidrug-resistant gram negative bacteria.204–207 Allecra’s lead compound AAI202, a combination of cefepime and AAI101/OCID-5090 30, is currently in Phase 1 studies in France.208, 209

NEW DRUG APPROVALS

ONE TIME

$10.00

Dr. B. Gopalan

Scientific Advisor

Dr. Gopalan is a synthetic organic chemist with extensive experience in the field of drug discovery and development. After completing his PhD from University of Madras, he went to Harvard University where he worked with the Nobel Laureate, Prof. E.J. Corey, as a post-doctoral fellow. Subsequent to this he joined Syntex Research Inc. in California to work on the synthesis of unnatural amino acids. After a year, he moved to Bristol-Meyers Squibb, Princeton, New Jersey, to contribute to their program on novel antibiotics and ACE inhibitors. Dr. Gopalan then moved back to India in 1982 to join the Drug Discovery Research Division of Boots Pharmaceuticals (India) Ltd. in Mumbai. Over his decade long stint there he contributed extensively to their drug discovery program, and one of the product candidates that he developed went up to Phase-2 clinical trials in both USA and UK. He then moved to Sun Pharma Advanced Research Center as Vice-President and, after a year, took up the position as General Manager at Glaxo (India) Ltd. in 1993. Here, he worked in a broad range of areas that included process development, synthesis of impurities of APIs, and generation of small molecule libraries to support drug discovery efforts to Glaxo, France. In 1999 he took over as Senior Vice President of the Drug Discovery Chemistry Division of Glenmark Pharmaceuticals Ltd. where he was involved in the design and development of inhibitors for PDE IV and DPP IV, as well as agonists for CB2. After a 6-year stint at Glenmark, Dr. Gopalan joined Matrix Laboratories Ltd. as CSO and Executive Vice-President, where he successfully helped to develop novel and selective inhibitors for PDE4 and DPP4. Five years later he became CSO and Executive Director of Orchid Pharmaceuticals Ltd in Chennai. He served in this capacity for close to a decade, contributing extensively to drug design and development in the broad segments of oncology, anti-infectives, and anti-inflammatory & metabolic disorders. Since 2017, Dr. Gopalan has been associated with CSIR-Indian Institute of Chemical Technology as a Scientific Advisor.

Dr. Gopalan’s illustrious career is endowed with numerous successes. He has been inventor, or co-inventor, of several drugs or candidate drugs. These include the novel potassium channel blockers BTS-67582 (BTI-2927) for tpe-2 diabetes, the PDE IV inhibitors Oglemilast (COPD) and Revamilast (RA); DPP IV inhibitor Melogliptin; a selective Cannaboid-2 agonist Tedalinib (Neuropathic pain); a Beta lactamase inhibitor Enmetazobactum (OCID-5090); OCID-18034 (an inhibitor of KPC enzyme); and OCID-18174 (an inhibitor of P. arugenosa). Most of these compounds were out-licensed to major international pharmaceutical companies such as Forest Laboratories Inc. USA, Teijin of Japan, Merck KGaA of Germany, Allecra of Switzerland, and Merck & Co. USA. Dr.Gopalan has 34 publications in National and International Journals, has contributed a Chapter,Co-authored with Professor K.K.Balasubramanian (IITM) on Applications of Click Chemistry in Drug Discovery and Development in a Book on Click reaction in Organic Synthesis, published by Wiley-VCH VERLAG GmbH &Co,KGaA, Weinheim,Germany,Chapter 2, p 25-70,2016, edited by Prof. S. Chandrasekharan (IISc,Bangalore) & 51 Patents.

Commensurate with his achievements, Dr. Gopalan has also received many awards. The more prominent of these include Inventor’s award by Glenmark (2004), Ranbaxy Science Foundation Award in Pharmaceutical Sciences (2005), and the Lifetime Achievement Award in the Field of Chemistry from Vels University (2011).

//////////OCID 5090, AAI-101, AAI 101, Enmetazobactam, ORCHID, Allecra Therapeutics, PHASE 3

C[n+]1ccn(C[C@@]2(C)[C@@H](N3[C@@H](CC3=O)S2(=O)=O)C(=O)[O-])n1

Idecabtagene vicleucel

May 19, 2021 12:12 pm / Leave a comment

Idecabtagene vicleucel

CAS 2306267-75-2

STN: BLA 125736

An autologous T lymphocyte-enriched cell transduced ex vivo with an anti-BCMA CAR lentiviral vector encoding a chimeric antigen receptor CAR, comprising a CD8 hinge and TM domain, 4-1BB costimulatory domain and CD3ζ signaling domain, targeting human B cell maturation antigen for cancer immunotherapy (Celgene Corp., NJ)

Bb2121

Name	Idecabtagene vicleucel (USAN); Abecma (TN)
Product	ABECMA (Celgene Corporation)
CAS	2306267-75-2
Efficacy	Antineoplastic, Anti-BCMA CAR-T cell
Disease	Multiple myeloma [DS:H00010]
Comment	Cellular therapy product

USFDA 2021/4/21 APPROVED

Dendritic cells (DCs) are antigen-presenting cells (APCs) that process antigens and display them to other cells of the immune system. Specifically, dendritic cells are capable of capturing and presenting antigens on their surfaces to activate T cells such as cytotoxic T cells (CTLs). Further, activated dendritic cells are capable of recruiting additional immune cells such as macrophages, eosinophils, natural killer cells, and T cells such as natural killer T cells.

Despite major advances in cancer treatment, cancer remains one of the leading causes of death globally. Hurdles in designing effective therapies include cancer immune evasion, in which cancer cells escape destructive immunity, as well as the toxicity of many conventional cancer treatments such as radiation therapy and chemotherapy, which significantly impacts a patient’s ability to tolerate the therapy and/or impacts the efficacy of the treatment.

Given the important role of dendritic cells in immunity, derailed dendritic cell functions have been implicated in diseases such as cancer and autoimmune diseases. For example, cancer cells may evade immune detection and destruction by crippling dendritic cell functionality through prevention of dendritic cell recruitment and activation. In addition, dendritic cells have been found in the brain during central nervous system inflammation and may be involved in the pathogenesis of autoimmune diseases in the brain.

One mechanism by which cancers evade immune detection and destruction is by crippling dendritic cell functionality through prevention of dendritic cell (DC) recruitment and activation. Accordingly, there remains a need for cancer therapies that can effectively derail tumor evasion and enhance anti-tumor immunity as mediated, for example, by dendritic cells.

NEW DRUG APPROVALS

ONE TIME

$10.00

DESCRIPTION

ABECMA is a BCMA-directed genetically modified autologous T cell immunotherapy product consisting of a patientâ€™s own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 chimeric antigen receptor (CAR) lentiviral vector (LVV). Autologous T cells transduced with the anti-BCMA02 CAR LVV express the anti-BCMA CAR on the T cell surface. The CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing B cell maturation antigen (BCMA) followed by a human CD8α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3ζ chain, in tandem. Binding of ABECMA to BCMA-expressing target cells leads to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

ABECMA is prepared from the patientâ€™s peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, which are then transduced with the replication-incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in one or more patient-specific infusion bag(s). The product is thawed prior to infusion back into the patient [see DOSAGE AND ADMINISTRATION and HOW SUPPLIED/Storage And Handling].

The ABECMA formulation contains 50% Plasma-Lyte A and 50% CryoStor® CS10, resulting in a final DMSO concentration of 5%.

FDA approves idecabtagene vicleucel for multiple myeloma

On March 26, 2021, the Food and Drug Administration approved idecabtagene vicleucel (Abecma, Bristol Myers Squibb) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved cell-based gene therapy for multiple myeloma.

Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using a patient’s own T-cells, which are collected and genetically modified, and infused back into the patient.

Safety and efficacy were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies; 88% had received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel in the dose range of 300 to 460 x 106 CAR-positive T cells. Efficacy was established based on overall response rate (ORR), complete response (CR) rate, and duration of response (DOR), as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

The ORR was 72% (95% CI: 62%, 81%) and CR rate was 28% (95% CI 19%, 38%). An estimated 65% of patients who achieved CR remained in CR for at least 12 months.

The idecabtagene vicleucel label carries a boxed warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, and prolonged cytopenias. The most common side effects of idecabtagene vicleucel include CRS, infections, fatigue, musculoskeletal pain, and hypogammaglobulinemia.

Idecabtagene vicleucel is approved with a risk evaluation and mitigation strategy requiring that healthcare facilities that dispense the therapy must be specially certified to recognize and manage CRS and nervous system toxicities. To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with idecabtagene vicleucel.

The recommended dose range for idecabtagene vicleucel is 300 to 460 × 106 CAR-positive T cells. View full prescribing information for Abecma.

This application was granted breakthrough therapy 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.

FDA D.I.S.C.O. Burst Edition: FDA approval of ABECMA (idecabtagene vicleucel) the first FDA approved cell-based gene therapy for the treatment of adult patients with relapsed or refractory multiple myeloma

Welcome back to the D.I.S.C.O., FDA’s Drug Information Soundcast in Clinical Oncology, Burst Edition, brought to you by FDA’s Division of Drug Information in partnership with FDA’s Oncology Center of Excellence. Today we have another quick update on a recent FDA cancer therapeutic approval.

On March 26, 2021, the FDA approved idecabtagene vicleucel (brand name Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved cell-based gene therapy for multiple myeloma.

Idecabtagene vicleucel is a B-cell maturation antigen-directed genetically modified autologous chimeric antigen receptor T-cell therapy. Each dose is customized using a patient’s own T-cells, which are collected and genetically modified, and infused back into the patient.

Safety and efficacy were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies, 88% of whom had received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel and was established based on overall response rate, complete response rate, and duration of response, as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

The overall response rate was 72% and complete response rate was 28%. An estimated 65% of patients who achieved complete response remained in complete response for at least 12 months.

The idecabtagene vicleucel label carries a boxed warning for cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, and prolonged cytopenias. Idecabtagene vicleucel is approved with a risk evaluation and mitigation strategy requiring that healthcare facilities dispensing the therapy must be specially certified to recognize and manage cytokine release syndrome and nervous system toxicities. To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with idecabtagene vicleucel.

Full prescribing information for this approval can be found on the web at www.fda.gov, with key word search “Approved Cellular and Gene Therapy Products”.

Health care professionals should report serious adverse events to FDA’s MedWatch Reporting System at www.fda.gov/medwatch.

Follow the Division of Drug Information on Twitter @FDA_Drug_Info External Link Disclaimer and the Oncology Center of Excellence @FDAOncology External Link Disclaimer. Send your feedback via email to FDAOncology@fda.hhs.gov. Thanks for tuning in today to the DISCO Burst Edition.

PAT

WO 2019148089

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=13E7E8E8ABF8F5C23B7142DD561A4767.wapp2nC?docId=WO2019148089&tab=PCTDESCRIPTION

In various aspects, the present invention relates to XCR1 binding agents having at least one targeting moiety that specifically binds to XCR1. In various embodiments, these XCR1 binding agents bind to, but do not functionally modulate ( e.g . partially or fully neutralize) XCR1. Therefore, in various embodiments, the present XCR1 binding agents have use in, for instance, directly or indirectly recruiting a XCR1-expressing cell to a site of interest while still allowing the XCR1-expressing cell to signal via XCR1 (i.e. the binding of the XCR1 binding agent does not reduce or eliminate XCR1 signaling at the site of interest). In various embodiments, the XCR-1 binding agent functionally modulates XCR1. In an embodiment, the targeting moiety is a single domain antibody (e.g. VHH, HUMABODY, scFv, on antibody). In various embodiments, the XCR1 binding agent further comprises a signaling agent, e.g., without limitation, an interferon, an interleukin, and a tumor necrosis factor, that may be modified to attenuate activity. In various embodiments, the XCR1 binding agent comprises additional targeting moieties that bind to other targets (e.g. antigens, receptor) of interest. In an embodiment, the other targets (e.g. antigens, receptor) of interest are present on tumor cells. In another embodiment, the other targets (e.g. antigens, receptor) of interest are present on immune cells. In some embodiments, the present XCR1 binding agent may directly or indirectly recruit an immune cell (e.g. a dendritic cell) to a site of action (such as, by way of non-limiting example, the tumor microenvironment). In some embodiments, the present XCR1 binding agent facilitates the presentation of antigens (e.g., tumor antigens) by dendritic cells.

In various embodiments, the present XCR binding agent or targeting moiety of the present chimeric proteins comprises the heavy chain of SEQ ID NO: 223 and/or the light chain of SEQ ID NO: 224, or a variant thereof (e.g. an amino acid sequence having at least about 90%, or at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, identity with SEQ ID NO: 223 and/or SEQ ID NO: 224).

In various embodiments, the present XCR binding agent or targeting moiety of the present chimeric proteins comprises a heavy chain CDR 1 of SHNLH (SEQ ID NO: 225), heavy chain CDR 2 of AIYPGNGNTAYNQKFKG (SEQ ID NO: 226), and heavy chain CDR 3 of WGSVVGDWYFDV (SEQ ID NO: 227) and/or a light chain CDR 1 of RSSLGLVHRNGNTYLH (SEQ ID NO: 228), light chain CDR 2 of KVSHRFS (SEQ ID NO: 229), and light chain CDR 3 of SQSTFIVPWT (SEQ ID NO: 230), or a variant thereof (e.g. with four or fewer amino acid substitutions, or with three or fewer amino acid substitutions, or with two or fewer amino acid substitutions, or with one amino acid substitution).

Illustrative Disease Modifying Therapies

EXAMPLES

Example 1. Identification and Characterization of Human XCR1 Ab AFNs

As used in this Example and associated figures,“AFN” is a chimera of the anti-Xcr1 5G7 antibody and human IFNa2 with an R149A mutation.

AFNs were made based on the 5G7 anti-hXcr1 Ab using the intact (full) Ab or a scFv format.

The 5G7 heavy chain is:

QAYLQQSGAELVRPGASVKMSCKASGYTFTSHNLHWVKQTPRQGLQWIGAIYPGNGNTAYNQKFKGKATLTVD

KSSSTAYMQLSSLTSDDSAVYFCARWGSVVGDWYFDVWGTGTTVTVSSASTKGPSVFPLAPCSRSTSESTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVE

RKCCVECPPCPAPPAAAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWYVDGVEVHNAKTKPREE

QFNSTFRVVSVLTWHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK (SEQ ID NO: 223)

The 5G7 light chain is:

DWMTQTPLSLPVTLGNQASIFCRSSLGLVHRNGNTYLHWYLQKPGQSPKLLIYKVSHRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 224)

5G7 Heavy chain CDR 1 is SHNLH (SEQ ID NO: 225), Heavy chain CDR 2 is AIYPGNGNTAYNQKFKG (SEQ ID NO: 226), Heavy chain CDR 3 is WGSVVGDWYFDV (SEQ ID NO: 227). 5G7 Light chain CDR 1 is RSSLGLVHRNGNTYLH (SEQ ID NO: 228), Light chain CDR 2 is KVSHRFS (SEQ ID NO: 229), and Light chain CDR 3 is SQSTHVPWT (SEQ ID NO: 230).

The sequence of hulFNa2(R149A) is:

CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMASF SLSTNLQESLRSKE (SEQ ID NO: 231).

In case of the intact Ab AFN, the 5G7 Ab heavy chain was fused to h I FN a2_R149A (human IFNal with a R149A mutation) via a flexible (GGS)2oG-linker and co-expressed with the 5G7 Ab light chain (sequences shown below). 5G7 scFv-AFN was constructed by linking the Ab VL and VH domains via a (GGGS)4 linker and followed by a (GGS)2o-linker and the sequence encoding hlFNa2_R149A. Recombinant proteins, cloned in the pcDNA3.4 expression-vector, were produced in ExpiCHO cells (Thermo Fisher Scientific) and purified on HisPUR spin plates (Thermo Fisher Scientific) according to the manufacturer’s instructions.

To test binding of the AFNs, parental HL1 16 and HL1 16 cells stably expressing hXcrl (HL116-hXcr1) were incubated with a serial dilution AFN for two hours at 4°C. Binding was detected using THE™ HIS antibody-FITC (GenScript) and measured on a MACSQuant X instrument (Miltenyi Biotec) and analysed using the FlowLogic software (Miltenyi Biotec). Data in Figures 1A and 1 B clearly show that both 5G7 Ab-AFN and 5G7 scFv bind specifically to hXcrl expressing cells.

Biological activity was measured on parental HL1 16 cells (an IFN responsive cell-line stably transfected with a p6-16 luciferase reporter) and the derived HL116-hXcr1 cells. Cells were seeded overnight and stimulated for 6 hours with a serial dilution 5G7 AFNs. Luciferase activity was measured on an EnSight Multimode Plate Reader (Perkin Elmer). Data in Figures 2A and 2B clearly illustrate that 5G7 AFNs, in the intact Ab format or as scFv, are clearly more active on cells expressing hXcrl compared to parental cells, illustrating that it is possible to restore signaling of an IFNa2 mutant by specific targeting to hXcrl .

Example 2. Identification and Characterization of Mouse Xcr1 Ab AFNs

As used in this Example and associated figures,“AFN” is a chimera of the anti-Xcr1 MAARX10 antibody and human IFNa2 with Q124R mutation.

Similar to the anti-human Xcr1 Ab, AFNs based on the MARX10 anti-mouse Xcr1 Ab were made, as intact Ab or as scFv. In case of the intact Ab AFN, the MARX10 Ab heavy chain was fused to hlFNa2_Q124R (human IFNa2 with Q124R mutation) via a flexible (GGS)2oG-linker and co-expressed with the MARX10 Ab light chain. scFv-AFN was constructed by linking the Ab VL and VH domains, in VH-VL (scFv(1 )) or VL-VH (scFv(2)) orientation, via a (GGGS)4 linker and followed by a (GGS)2o-linker and h I FN a2_Q 124R.

Selectivity of AFNs (produced and purified as described above for the human Xcr1 Ab AFNs) was tested by comparing binding at 2.5 pg/ml to MOCK or mouse Xcr1 transfected Hek293T cells. Binding was detected using THE™ HIS antibody-FITC (GenScript) and measured on a MACSQuant X instrument (Miltenyi Biotec) and analysed using the FlowLogic software (Miltenyi Biotec). Data in Figure 3 clearly show that all three specifically bind to mXcrl expressing cells.

REF

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-idecabtagene-vicleucel-multiple-myeloma

New England Journal of Medicine (2021), 384(8), 705-716

https://www.rxlist.com/abecma-drug.htm#indications

///////////Idecabtagene vicleucel, breakthrough therapy designation, orphan drug designation, FDA 2021, APPROVALS 2021, Bb2121, Bb , ABECMA

Manufacturer: Celgene Corporation, a Bristol-Myers Squibb Company
Indications:

Treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Product Information

Package Insert – ABECMA
Demographic Subgroup Information – idecabtagene vicleucel [ABECMA]
Refer to Section 1.1 of the Clinical Review Memo for information about participation in the clinical trials and any analysis of demographic subgroup outcomes that is notable.

Supporting Documents

Loncastuximab tesirine

May 18, 2021 5:48 am / 1 Comment on Loncastuximab tesirine

Loncastuximab tesirine

ZYNLONTA FDA APPROVED 2021/4/23

Formula	C6544H10048N1718O2064S52
Exact mass	147387.9585
CAS	1879918-31-6
Efficacy	Antineoplasitc, Anti-CD19 antibody
Disease	Diffuse large B-cell lymphoma not otherwise specified [DS:H02434]
Comment	Antibody-drug conjugate Treatment of hematological cancers

ロンカスツキシマブテシリン; ADCT-402, ADCX 19

Immunoglobulin G1, anti-(human CD19 antigen) (human-Mus musculus monoclonal RB4v1.2 γ1-chain), disulfide with human-Mus musculus monoclonal RB4v1.2 κ-chain, dimer, bis(thioether) with N-[31-(3-mercapt-2,5-dioxo-1-pyrrolidinyl)-1,29-dioxo-4,7,10,13,16,19,22,25-octaoxa-28-azahentriacont-1-yl]-L-valyl-N-[4-[[[[(11S,11aS)-8-[[5-[[(11aS)-5,11a-dihydro-7-methoxy-2-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy]pentyl]oxy]-11,11a-dihydro-11-hydroxy-7-methoxy-2-methyl-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepin-10(5H)-yl]carbonyl]oxy]methyl]phenyl]-L-alaninamide

NEW DRUG APPROVALS

ONETIME

$10.00

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	CD19
Clinical data
Trade names	Zynlonta
Other names	ADCT-402, loncastuximab tesirine-lpyl
License data	US DailyMed: Loncastuximab_tesirine
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	1879918-31-6
DrugBank	DB16222
ChemSpider	none
UNII	7K5O7P6QIU
KEGG	D11338
Chemical and physical data
Formula	C₆₅₄₄H₁₀₀₄₈N₁₇₁₈O₂₀₆₄S₅₂
Molar mass	147481.45 g·mol⁻¹

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Zynlonta	Injection, powder, lyophilized, for solution	5 mg/1mL	Intravenous	ADC Therapeutics America, Inc.	2021-04-30	Not applicable

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valine–alanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine.

Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0.

Loncastuximab tesirine , sold under the brand name Zynlonta, is used for the treatment of large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19, which is expressed in a wide range of B cell hematological tumors.^[2] The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL).

On April 23, 2021, the Food and Drug Administration granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA), a CD19-directed antibody and alkylating agent conjugate, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Approval was based on LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens. Patients received loncastuximab tesirine-lpyl 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment until progressive disease or unacceptable toxicity.

The main efficacy outcome measure was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria. The ORR was 48.3% (95% CI: 39.9, 56.7) with a complete response rate of 24.1% (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration was 10.3 months (95% CI: 6.9, NE). Of the 70 patients who achieved objective responses, 36% were censored for response duration prior to 3 months.

Most common (≥20%) adverse reactions in patients receiving loncastuximab tesirine-lpyl, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

The prescribing information provides warnings and precautions for adverse reactions including edema and effusions, myelosuppression, infections, and cutaneous reactions.

The recommended loncastuximab tesirine-lpyl dosage is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles, by intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). Patients should be premedicated with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before loncastuximab tesirine-lpyl.

Technology

The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors^[3] including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.^[4]

Clinical trials

Two phase I trials are evaluating the drug in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia.^[5] At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented.^[6] Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).^[7]^[8]

Orphan drug designation

Loncastuximab tesirine was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.^[9]

References

^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf
^ WHO Drug Information: International Nonproprietary Names for Pharmaceutical Substances
^ Wang K, Wei G, Liu D (November 2012). “CD19: a biomarker for B cell development, lymphoma diagnosis and therapy”. Experimental Hematology & Oncology. 1 (1): 36. doi:10.1186/2162-3619-1-36. PMC 3520838. PMID 23210908.
^ “Pyrrolobenzodiazepine”. ADC Review.
^ Clinical trial number NCT02669017 for “ADCT-402 in B-NHL” at ClinicalTrials.gov
^ Kahl B, Hamadani M, Caimi PF, Reid EG, Havenith K, He S, Feingold JM, O’Connor O (June 2017). “First clinical results of ADCT‐402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B‐cell linage NHL” (PDF). Hematol Oncol. 35 (S2): 49–51. doi:10.1002/hon.2437_33.
^ “First clinical results of ADCT-402”. ADC Review.
^ Bainbridge K. “Grandfather fighting deadly cancer reveals scans of tumors after testing new drug”. Mirror.
^ “ADCT-402 Orphan Drug Designation” (PDF). ADC Therapeutics press release.

External links

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

https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

/////////Loncastuximab tesirine, FDA 2021, APPROVALS 2021, ZYNLONTA, ロンカスツキシマブテシリン, ORPHAN DRUG, ADCT-402, priority review, ADCX 19

Click to access 15_ICML_Chiara-Tarantelli-ADCT_402_preclinical.pdf

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Author Archives: DR ANTHONY MELVIN CRASTO Ph.D

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Tropifexor fast facts

Abstract

References

Share this:

Medical uses

References

External links

Share this:

How Corbevax was made

How Corbevax is different

Why Corbevax matters

Biological E, the manufacturer of Corbevax

Clinical research

Phase I and II trials

Phase III trials

Manufacturing and Orders

References

External links

Share this:

Medical uses

Abstract

AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

Anthony Melvin Crasto Dr. | Facebook

References

Further reading

External links

Share this:

Human trials

Phase 1

Provincial funding

Federal funding

Providence Therapeutics Announces Very Favorable Interim Phase 1 Trial Data for PTX-COVID19-B, its mRNA Vaccine Against COVID-19

References

Share this:

Fact Sheet – US Food and Drug Administration

Trials

Authorization

Deployment

References

External links

Share this:

Related Information

Trials

Authorization

Deployment

References

External links

Share this:

Mr. Ram Gopal Agarwal

Chairman and Non-Executive Director

Mr. Manish Dhanuka

Managing Director

Mr. Mridul Dhanuka

Whole-Time Director

Dr. B. Gopalan

Scientific Advisor

Share this:

DESCRIPTION

FDA approves idecabtagene vicleucel for multiple myeloma

Product Information

Supporting Documents

Share this: