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Risdiplam

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7 API Suppliers, 5 USDMF, 3 Listed Suppliers, $ API Reference Price

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5 USDMF
3 Listed Suppliers
$ API Reference Price

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47 Drugs in Development

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19 FDF Dossiers, 1 FDA Orange Book, 1 Canada, 16 Australia, 1 South Africa

19 FDF Dossiers
1 FDA Orange Book
1 Canada
16 Australia
1 South Africa

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1 US Medicaid Prescriptions, 3 Annual Reports

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1 US Medicaid Prescriptions
3 Annual Reports

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5 US Patents, 5 US Exclusivities

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5 US Patents
5 US Exclusivities

Synopsis

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US Medicaid (USD)

120,799,423

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3,517

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Chemistry

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Also known as: 1825352-65-5, Rg7916, Evrysdi, Ro7034067, Risdiplam [inn], Risdiplam [usan]

Molecular Formula

C₂₂H₂₃N₇O

Molecular Weight

401.5 g/mol

InChI Key

ASKZRYGFUPSJPN-UHFFFAOYSA-N

FDA UNII

76RS4S2ET1

Risdiplam is an orally bioavailable mRNA splicing modifier used for the treatment of spinal muscular atrophy (SMA). It increases systemic SMN protein concentrations by improving the efficiency of SMN2 gene transcription. This mechanism of action is similar to its predecessor [nusinersen], the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy [onasemnogene abeparvovec], whereas risdiplam offers the ease of oral bioavailability. Risdiplam was approved by the FDA in August 2020 for use in patients 2 months of age or older in the treatment of spinal muscular atrophy (SMA). Set to be substantially cheaper than other available SMA therapies, risdiplam appears to provide a novel and relatively accessible treatment option for patients with SMA regardless of severity or type.

1 2D Structure

Risdiplam

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one

2.1.2 InChI

InChI=1S/C22H23N7O/c1-14-9-18(26-29-11-15(2)24-21(14)29)17-10-20(30)28-12-16(3-4-19(28)25-17)27-8-7-23-22(13-27)5-6-22/h3-4,9-12,23H,5-8,13H2,1-2H3

2.1.3 InChI Key

ASKZRYGFUPSJPN-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=CC(=NN2C1=NC(=C2)C)C3=CC(=O)N4C=C(C=CC4=N3)N5CCNC6(C5)CC6

2.2 Other Identifiers

2.2.1 UNII

76RS4S2ET1

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-4h-pyrido(1,2-a)pyrimidin-4-one

2.3.2 Depositor-Supplied Synonyms

1. 1825352-65-5

2. Rg7916

3. Evrysdi

4. Ro7034067

5. Risdiplam [inn]

6. Risdiplam [usan]

7. Rg-7916

8. 76rs4s2et1

9. Ro-7034067

10. 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one

11. 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(4,7-diazaspiro[2.5]octan-7-yl)-4h-pyrido[1,2-a]pyrimidin-4-one

12. 4h-pyrido(1,2-a)pyrimidin-4-one, 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-

13. Evrysdi (tn)

14. Risdiplam; Rg7916

15. Risdiplam [jan]

16. Risdiplam [mi]

17. Risdiplam [usan:inn]

18. Risdiplam [who-dd]

19. Unii-76rs4s2et1

20. Risdiplam (jan/usan/inn)

21. Risdiplam [orange Book]

22. Chembl4297528

23. Schembl17260852

24. Gtpl11170

25. Dtxsid701109185

26. Amy23728

27. Ex-a2074

28. Mfcd31657372

29. Who 10614

30. Compound 1 [pmid: 30044619]

31. Db15305

32. Ac-36304

33. Br166842

34. Rg7916;ro7034067

35. Hy-109101

36. Cs-0039501

37. D11406

38. F53623

39. Q48969152

40. (7-(4,7-diazaspiro(2.5)octan-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)pyrido(1,2-a)pyrimidin-4-one

41. 7-(4,7-diazaspiro(2.5)oct-7-yl)-2-(2,8-dimethylimidazo(1,2-b)pyridazin-6-yl)-4h-pyrido(1,2-a)pyrimidin-4-one

2.4 Create Date

2016-02-23

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₂₃N₇O
Molecular Weight	401.5 g/mol
XLogP3	0.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	2
Exact Mass	401.19640838 g/mol
Monoisotopic Mass	401.19640838 g/mol
Topological Polar Surface Area	78.1 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	886
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.

Evrysdi is indicated for the treatment of 5q spinal muscular atrophy (SMA) in patients 2 months of age and older, with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Risdiplam helps to alleviate symptoms of spinal muscular atrophy by stimulating the production of a critical protein in which these patients are deficient. Early trials with risdiplam demonstrated up to a 2-fold increase in SMN protein concentration in SMA patients after 12 weeks of therapy.

5.2 MeSH Pharmacological Classification

Neuromuscular Agents

Drugs used for their actions on skeletal muscle. Included are agents that act directly on skeletal muscle, those that alter neuromuscular transmission (NEUROMUSCULAR BLOCKING AGENTS), and drugs that act centrally as skeletal muscle relaxants (MUSCLE RELAXANTS, CENTRAL). Drugs used in the treatment of movement disorders are ANTI-DYSKINESIA AGENTS. (See all compounds classified as Neuromuscular Agents.)

5.3 ATC Code

M09AX10

M - Musculo-skeletal system

M09 - Other drugs for disorders of the musculo-skeletal system

M09A - Other drugs for disorders of the musculo-skeletal system

M09AX - Other drugs for disorders of the musculo-skeletal system

M09AX10 - Risdiplam

5.4 Absorption, Distribution and Excretion

Absorption

The T_max following oral administration is approximately 1-4 hours. Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days. The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.

Route of Elimination

Following the oral administration of 18mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine. Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine.

Volume of Distribution

Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues. The apparent volume of distribution at steady-state is 6.3 L/kg.

Clearance

For a 14.9kg patient, the apparent clearance of risdiplam is 6.3 L/kg.

5.5 Metabolism/Metabolites

The metabolism of risdiplam is mediated primarily by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7. Parent drug comprises approximately 83% of circulating drug material. A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite - this M1 metabolite has been observed _in vitro_ to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.

5.6 Biological Half-Life

The terminal elimination half-life of risdiplam is approximately 50 hours in healthy adults.

5.7 Mechanism of Action

Spinal muscular atrophy (SMA) is a severe and progressive congenital neuromuscular disease resulting from mutations in the survival of motor neuron 1 (_SMN1_) gene responsible for making SMN proteins. Clinical features of SMA include degeneration of motor neurons in the spinal cord which ultimately leads to muscular atrophy and, in some cases, loss of physical strength. SMN proteins are expressed ubiquitously throughout the body and are thought to hold diverse intracellular roles in DNA repair, cell signaling, endocytosis, and autophagy. A secondary _SMN_ gene (_SMN2_) can also produce SMN proteins, but a small nucleotide substitution in its sequence results in the exclusion of exon 7 during splicing in approximately 85% of the transcripts - this means that only ~15% of the SMN proteins produced by _SMN2_ are functional, which is insufficient to compensate for the deficits caused by _SMN1_ mutations. Emerging evidence suggests that many cells and tissues are selectively vulnerable to reduced SMN concentrations, making this protein a desirable target in the treatment of SMA. Risdiplam is an mRNA splicing modifier for _SMN2_ that increases the inclusion of exon 7 during splicing, which ultimately increases the amount of functional SMN protein produced by _SMN2_. It does so by binding to two sites in _SMN2_ pre-mRNA: the 5' splice site (5'ss) of intron 7 and the exonic splicing enhancer 2 (ESE2) of exon 7.

API SUPPLIERS

01

Biophore India Pharmaceuticals Pvt...

India

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Teva Pharmaceutical Industries

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Natco Pharma

India

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ALP Pharm

China

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Sinopep Pharmaceutical Inc

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Risdiplam

GDUFA

DMF Review : Complete

Rev. Date : 2024-05-07

Pay. Date : 2024-04-25

DMF Number : 39602

Submission : 2024-03-08

Status : Active

Type : II

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Alp Pharm Beijing Co Ltd

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Natco Pharma Ltd

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Sinopep-allsino Biopharmaceutical Co...

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Teva Pharmaceutical Industries Ltd

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Listed Suppliers

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Metrochem API Private Limited

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About the Company :

Established in 2004, Metrochem API is one of the fastest-growing APIs, pellets & intermediates manufacturers. It has 6 dedicated manufacturing facilities for its 3 core product ...

Established in 2004, Metrochem API is one of the fastest-growing APIs, pellets & intermediates manufacturers. It has 6 dedicated manufacturing facilities for its 3 core product groups and has been approved by ISO 9001-2015, USFDA, WHO GMP, Cofepris & Japanese authorities. Metrochem’s in-depth industry knowledge, & hi-tech & advanced infrastructure, helps it provide quality products to its customers. Note: None of the products will be supplied to the countries where this could conflict with existing patents. Further, any products under patent will be offered for R&D purposes only. However, the final responsibility lies with the buyer

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Drugs in Development

01 F. Hoffmann-La Roche

Switzerland

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02 Chugai Pharmaceutical

Japan

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F. Hoffmann-La Roche

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Roche Products (Pty) Ltd

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DMF filings hit all-time high in Q3 2024; China tops list with 58% increase in Type II submissions

Drug Master Files, or DMFs, are confidential documents that play a crucial role in the pharmaceutical industry. These files, submitted to the US Food and Drug Administration (FDA), contain detailed information about ingredients, manufacturing processes, and packaging of medicines. They help the FDA oversee drug quality. Of the four types, Type II DMFs involve active pharmaceutical ingredients (APIs) for both branded and generic drugs. The third quarter (Q3) of 2024 saw Type II DMF submissions set a new record. A total of 309 Type II DMFs were submitted to the FDA during this period, a substantial 24.6 percent increase over Q3 2023 (with 248 submissions). The second quarter of 2024 too saw a remarkable increase, with 237 Type II DMFs being submitted compared to 178 in Q2 2023. View FDA DMF Filings in Q3 2024 (Power BI Dashboard, Free Excel Available) China witnesses steep rise in DMF submissions, beats India with maximum filings In Q3 2024, China filed 153 DMFs submissions, marking a substantial 57.7 percent increase from the 97 submissions filed in Q3 2023. India maintained its strong position but fell to the number two spot with 110 DMFs, representing a modest 3.8 percent increase from 106 in Q3 2023. The US, which came a distant third, saw a slight decline in DMF submissions, with 13 filed in Q3 2024, as compared to 18 in Q3 2023. For several years, India had a lead in Type II DMFs. Since 2020, which marked the start of the pandemic, we have noticed a gradual increase in DMFs filed by China. This year, China has surpassed India considerably in the first three quarters. During the first nine months of 2024, China submitted 372, while India filed 286 DMFs. If this lead is maintained in Q4, DMFs from China will surpass that of India in 2024. Amongst European countries, Spain led with seven DMFs, followed by Italy at four, and Germany and the Netherlands at three each. Among other nations, Japan contributed six while Israel submitted four DMFs. In company-wise tally, China’s Jiangsu East-Mab Biomedical Technology topped the list with an impressive 14 DMFs. On its heels were Indian companies — MSN at 13 DMFs, and Vamsi Labs and Hetero Drugs at nine DMFs each. China’s Porton Pharma and Wuxi AppTec filed five, while Shanghai Keze Yongxin Biotechnology, and Qingdao Glycogene Pharmaceutical contributed four submissions each. India's Maithri Drugs also submitted four. Japanese company Santeja filed five. Overall, Asia accounted for nearly 90 percent, with China contributing a dominant 49.5 percent of all DMF submissions. India was at 35.6 percent, the US at 4.2 percent, while Europe contributed 6.5 percent. View FDA DMF Filings in Q3 2024 (Power BI Dashboard, Free Excel Available) Diabetes, obesity, cancer, women’s health drugs emerge as hot molecules in Q3 2024 In terms of molecules, semaglutide (used for the treatment of type 2 diabetes and weight management) and relugolix (to treat prostate cancer and uterine fibroids) saw six DMF filings each in Q3 2024, indicating significant industry interest in these compounds. Following closely behind were semaglutide’s competitor tirzepatide and overactive bladder therapy vibegron, garnering four DMFs each. Finerenone (a non-steroidal drug for chronic kidney disease associated with type 2 diabetes) and voclosporin (an immunosuppressant for lupus nephritis) saw three DMFs each. The last quarter also witnessed the introduction of 14 molecules with first-time DMFs. Among them were acetoxy empagliflozin, cabozantinib fumarate, tivozanib hydrochloride monohydrate, diosmetin, trilaciclib, clenbuterol hydrochloride, fenoterol hydrobromide, tapinarof and fezolinetant. Fezolinetant, with a DMF from Spain’s Moehs Iberica, is the active ingredient in Astellas’ Veozah, which is the first non-hormonal treatment for menopausal symptoms approved by the FDA. Tapinarof, filed by India’s Maithri Drugs, is used in Vtama, a novel steroid-free psoriasis cream. Other compounds that made their DMF debut include berotralstat, calcium phosphoryl choline chloride, phloroglucinol dihydrate, belumosudil mesylate and trimethylphloroglucinol. During Q2 2024, there were 19 drugs that saw DMF submissions for the first time, including molecules like triptorelin, sorafenib, pralsetinib, trilaciclib dihydrochloride, resmetirom (hepatology) and teneligliptin hydrochloride hydrate (metabolic disorders). View FDA DMF Filings in Q3 2024 (Power BI Dashboard, Free Excel Available) GDUFA fee for FY 2025: The FDA’s Generic Drug User Fee Amendments (GDUFA) is a law designed to speed access to safe and effective generic drugs to the public and reduce costs to the industry. The fiscal year 2025 fee rates were published on July 31, 2024. The FDA has revised fees under GDUFA III for all categories. While there is a slight increase in the DMF fee from US$ 94,682 in 2024 to US$ 95,084 in 2025, the ANDA fee has witnessed a significant jump — from US$ 252,453 in 2024 to US$ 321,920 in 2025. FY 2024 and FY 2025 User Fee Rates Generic drug fee category Fees rates for FY 2024 Fees rates for FY 2025 Applications: Abbreviated New Drug Application (ANDA) US$ 2,52,453 US$ 3,21,920 Drug Master File (DMF) US$ 94,682 US$ 95,084 Facilities: Active Pharmaceutical Ingredient (API)—Domestic US$ 40,464 US$ 41,580 API—Foreign US$ 55,464 US$ 56,580 Finished Dosage Form (FDF)—Domestic US$ 2,20,427 US$ 2,31,952 FDF—Foreign US$ 2,35,427 US$ 2,46,952 Contract Manufacturing Organization (CMO)—Domestic US$ 52,902 US$ 55,668 CMO—Foreign US$ 67,902 US$ 70,668 GDUFA Program: Large size operation generic drug applicant US$ 17,29,629 US$ 18,91,664 Medium size operation generic drug applicant US$ 6,91,852 US$ 7,56,666 Small business generic drug applicant US$ 1,72,963 US$ 1,89,166 Our view The highlight of the last few quarters has been the sharp rise in Type II DMF filings from China. The submission of a DMF is not required by law or any FDA regulation. FDA’s DMF guideline offers guidance on acceptable approaches to meeting regulatory requirements. Moreover, DMFs establish trust in APIs from lesser-known companies. With a growing emphasis on compliance and quality assurance, it appears that Chinese drug companies are eager to demonstrate their commitment to high standards and build trust in the US market. And that’s good news for the pharmaceutical industry.