Risdiplam Explained

Tradename:Evrysdi
Dailymedid:Risdiplam
Pregnancy Au:D
Routes Of Administration:By mouth
Atc Prefix:M09
Atc Suffix:AX10
Legal Au:S4
Legal Au Comment:[1] [2]
Legal Ca:Rx-only
Legal Ca Comment:[3] [4]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[5] [6]
Cas Number:1825352-65-5
Pubchem:118513932
Drugbank:DB15305
Chemspiderid:67886354
Unii:76RS4S2ET1
Kegg:D11406
Chembl:4297528
Synonyms:RG7916; RO7034067
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
C:22
H:23
N:7
O:1
Smiles:CC1=CC(=NN2C1=NC(=C2)C)C3=CC(=O)N4C=C(C=CC4=N3)N5CCNC6(C5)CC6
Stdinchi: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
Stdinchikey:ASKZRYGFUPSJPN-UHFFFAOYSA-N

Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA)[7] [8] and the first oral medication approved to treat this disease.[8]

Risdiplam is a survival of motor neuron 2-directed RNA splicing modifier.

In clinical trials, the most common adverse events included fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. Additional adverse events observed in the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting.

Risdiplam was approved by the US Food and Drug Administration (FDA) in August 2020, for the treatment of adults and children two months of age or older. Developed by Roche in Basel, Switzerland, in association with PTC Therapeutics and the SMA Foundation,[8] it is marketed in the US by Genentech, a subsidiary of Roche.

Medical uses

In the United States, risdiplam is indicated to treat people two months of age and older with spinal muscular atrophy.[9]

Adverse effects

In two clinical trials, the following adverse events occurred at least 5% more frequently in patients treated with risdiplam than in the placebo group: fever, diarrhoea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. Additional adverse events for the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting.

Risdiplam should not be taken together with medications that are multidrug and toxin extrusion (MATE) substrates because risdiplam may increase plasma concentrations of these drugs.

Pharmacology

Mechanism of action

Risdiplam addresses the underlying cause of SMA: a reduced amount of survival motor neuron (SMN) protein. The protein is encoded by the SMN1 and SMN2 genes. SMA is caused by mutations in SMN1 that code for inactive forms of the protein. The activity of the SMN2 gene, which produces much smaller quantities of SMN, tends to determine the severity of disease.[8] [10]

The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA to include exon 7,[11] [12] [13] resulting in an increase in the concentration of the functional SMN protein in vivo.[14]

Nusinersen, the first drug approved to treat SMA, an anti-sense oligonucleotide targeting intronic splicing silencer N1 (ISS-N1), also alters mRNA splicing of SMN2.[15]

Efficacy

The safety and efficacy of risdiplam in infantile-onset and later-onset SMA has been evaluated in ongoing clinical trials.[8] [16] [17]

In the infantile-onset SMA study, an open-label trial with 41 participants, efficacy was established based on the ability to sit without support for at least five seconds. After 12 months of treatment, 29% of participants were able to sit independently for more than five seconds. After 23 or more months of treatment, 81% of participants were alive without permanent ventilation. Although the study did not perform direct comparisons against children receiving a placebo (inactive treatment), these results compare favourably with the typical course of the untreated disease.[16]

The study of later-onset SMA was a randomised controlled trial that enrolled 180 participants, aged between 2 and 25 years, with less severe forms of the disease. Participants treated with risdiplam for 12 months showed improvements in motor function compared to participants given a placebo.[17] [8]

Society and culture

Legal status

The US Food and Drug Administration (FDA) awarded marketing approval to Genentech in August 2020. The FDA earlier granted the application for risdiplam fast track, priority review, and orphan drug designations.[8] Genentech was also awarded a rare pediatric disease priority review voucher.

The European Medicines Agency (EMA) awarded risdiplam a priority medicine designation in 2018[18] [19] and an orphan drug designation in 2019.[20]

, Roche has applied for marketing authorisation in Brazil, Chile, China, the European Union, Indonesia, Russia, South Korea and Taiwan.[21] [22]

Names

Risdiplam is the International nonproprietary name (INN).[23]

Compassionate use

Since late 2019, Roche has been offering the drug globally for free to some eligible people through an expanded access program.[24]

Further reading

Notes and References

  1. Web site: Evrysdi . Therapeutic Goods Administration (TGA) . 11 June 2021 . 6 September 2021.
  2. Web site: AusPAR: Risdiplam . Therapeutic Goods Administration (TGA) . 13 September 2021 . 13 September 2021.
  3. Web site: Summary Basis of Decision (SBD) for Evrysdi . Health Canada . 23 October 2014 . 29 May 2022.
  4. Web site: Health product highlights 2021: Annexes of products approved in 2021 . . 3 August 2022 . 25 March 2024.
  5. Web site: Evrysdi EPAR . European Medicines Agency . 24 February 2021 . 4 March 2023.
  6. Web site: Evrysdi Product information . Union Register of medicinal products . 3 March 2023.
  7. Silver Spring, Maryland, United States of America . O'Keefe L . FDA Approves Oral Treatment for Spinal Muscular Atrophy . . FDA Newsroom Department . 7 August 2020 . 7 August 2020 . 11 August 2020 . https://web.archive.org/web/20200811220128/https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy.
  8. News: BioNews Services (BioNews Services, LLC.) . Pensacola, Florida, United States . 9 June 2021 . Evrysdi (Risdiplam) for Spinal Muscular Atrophy . https://web.archive.org/web/20210127163559/https://smanewstoday.com/evrysdi-risdiplam . 27 January 2021 . SMA News Today. . 7 August 2020 .
  9. Web site: Evrysdi- risdiplam powder, for solution . DailyMed . . . Bethesda, Maryland, United States . 18 August 2020 . 24 September 2020.
  10. Ramdas S, Servais L . New treatments in spinal muscular atrophy: an overview of currently available data . Expert Opinion on Pharmacotherapy . 21 . 3 . 307–315 . February 2020 . 31973611 . 10.1080/14656566.2019.1704732 . Taylor & Francis (Informa UK Ltd) . London, England, United Kingdom of Great Britain . Grech D, Mikhailidis D, Abdollahi M . 210880199 . 57378019 .
  11. Web site: https://web.archive.org/web/20200424213701/https://smanewstoday.com/rg7916-rg7800-roche-ptc-smaf . 8 November 2016 . 24 April 2020 . 9 June 2021 . RG7916 . BioNews Services (BioNews Services, LLC.) . Pensacola, Florida, United States .
  12. Zhao X, Feng Z, Ling KK, Mollin A, Sheedy J, Yeh S, Petruska J, Narasimhan J, Dakka A, Welch EM, Karp G, Chen KS, Metzger F, Ratni H, Lotti F, Tisdale S, Naryshkin NA, Pellizzoni L, Paushkin S, Ko CP, Weetall M . 6 . Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy . Human Molecular Genetics . 25 . 10 . 1885–1899 . May 2016 . 26931466 . 5062580 . 10.1093/hmg/ddw062 . . Oxford, United Kingdom of Great Britain .
  13. Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Seabrook T, Fontoura P, Servais L . 6 . Risdiplam in Type 1 Spinal Muscular Atrophy . The New England Journal of Medicine . 384 . 10 . 915–923 . March 2021 . 33626251 . 10.1056/NEJMoa2009965 . NEJM Group (Massachusetts Medical Society) . Boston, Massachusetts, United States of America . 20020456 . 232047598 . free . 231027780 .
  14. Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, Denk N, Feng Z, Green L, Guerard M, Jablonski P, Jacobsen B, Khwaja O, Kletzl H, Ko CP, Kustermann S, Marquet A, Metzger F, Mueller B, Naryshkin NA, Paushkin SV, Pinard E, Poirier A, Reutlinger M, Weetall M, Zeller A, Zhao X, Mueller L . 6 . Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA) . Journal of Medicinal Chemistry . 61 . 15 . 6501–6517 . August 2018 . 30044619 . 10.1021/acs.jmedchem.8b00741 . . a63000643 . free . 39480771 .
  15. Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S . Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials . Clinical Therapeutics . 36 . 1 . 128–140 . January 2014 . 24360800 . 10.1016/j.clinthera.2013.11.006 . Elsevier . Philadelphia, Pennsylvania, United States of America . free .
  16. Baranello G, Servais L, Day J, Deconinck N, Mercuri E, Klein A, Darras B, Masson R, Kletzl H, Cleary Y, El-Khairi M, Seabrook T, Czech C, Gerber M, Nguyen C, Gelblin K, Gorni K . 6 . P.353FIREFISH Part 1: 16-month safety and exploratory outcomes of risdiplam (RG7916) treatment in infants with type 1 spinal muscular atrophy . 29 . Supplement 1 . 10.1016/j.nmd.2019.06.515 . free . 1 October 2019 . Neuromuscular Disorders . S184 . World Muscle Society (WMS)/Elsevier Inc. . London, United Kingdom of Great Britain . 0960-8966 . 24318845 .
  17. Mercuri E, Baranello G, Kirschner J, Servais L, Goemans N, Pera MC, Buchbjerg J, Yeung WY, Kletzl H, Gerber M, Czech C, Cleary Y, Gorni K, Khwaja O . 6 . Update from SUNFISH Part 1: Safety, Tolerability and PK/PD from the Dose-Finding Study, Including Exploratory Efficacy Data in Patients with Type 2 or 3 Spinal Muscular Atrophy (SMA) Treated with Risdiplam (RG7916) (S25.007) . . 16 April 2019 . 92 . 15 (Supplement) . 0028-3878 . . 10.1212/WNL.92.15_supplement.S25.007 . Minneapolis, Minnesota, United States of America . 9 June 2021 . 55043902 . 960771045 .
  18. News: BioNews Services (BioNews Services, LLC.) . Pensacola, Florida, United States. SMA News Today . Inacio P . 21 December 2018 . Risdiplam Granted EMA's PRIME Designation for Potential in Spinal Muscular Atrophy . 9 June 2021 . live . English . https://web.archive.org/web/20210126185434/https://smanewstoday.com/news-posts/2018/12/21/risdiplam-granted-ema-prime-designation . 26 January 2021 .
  19. F. Hoffmann-La Roche Ltd . 17 December 2018 . PRIME designation granted by European Medicines Agency for Roche's risdiplam for treatment of spinal muscular atrophy (SMA) . . English . Group Communications Department (Roche Group Media Relations Division) . 1–5 . 18 August 2020 . 9 June 2021 . https://web.archive.org/web/20200818182553/https://www.roche.com/media/releases/med-cor-2018-12-17.htm . Roche Group Media Relations Division .
  20. Public summary of opinion on orphan designation: Risdiplam for the treatment of spinal muscular atrophy . 26 February 2019 . Amsterdam, the Netherlands . 1–4 . European Medicines Agency (EMA Committee for Orphan Medicinal Products) . English . Stoyanova-Beninska V, Schwarzer-Daum B . https://web.archive.org/web/20200506191834/https://www.ema.europa.eu/en/documents/orphan-review/eu/3/19/2145-public-summary-opinion-orphan-designation-risdiplam-treatment-spinal-muscular-atrophy_en.pdf . 6 May 2020 . PDF . live . EMA Committee for Orphan Medicinal Products (COMP) .
  21. 7 August 2020 . FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older. 7 August 2020 . Genentech. San Francisco, California, United States of America . Genentech, Inc. (Roche Group) . Genentech Global Product Development Division . 18 August 2020 . https://web.archive.org/web/20200818182824/https://www.gene.com/media/press-releases/14866/2020-08-07/fda-approves-genentechs-evrysdi-risdipla . English .
  22. PR Newswire . PTC Therapeutics . PTC Announces the Acceptance of the European Marketing Authorization Application for Evrysdi™ (risdiplam) for the Treatment of Spinal Muscular Atrophy. https://web.archive.org/web/20200818182239/https://www.prnewswire.com/news-releases/ptc-announces-the-acceptance-of-the-european-marketing-authorization-application-for-evrysdi-risdiplam-for-the-treatment-of-spinal-muscular-atrophy-301113095.html . 18 August 2020 . 17 August 2020 . 9 June 2021 . PTC Therapeutics . Albuquerque, New Mexico, United States of America .
  23. ((World Health Organization)) . 2018 . International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80 . WHO Drug Information . 32 . 3 . 482 . 10665/330907 . free .
  24. Roche announces global compassionate use programme for Risdiplam . 13 January 2020 . 9 June 2021 . English . Roche Global SMA Team (F. Hoffmann-La Roche Ltd) . Petridis F . Stratford-upon-Avon, England, United Kingdom of Great Britain . Spinal Muscular Atrophy UK ltd .

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