Risdiplam

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Risdiplam
Risdiplam.svg
Clinical data
Trade names Evrysdi
Other namesRG7916; RO7034067
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.278.103 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H23N7O
Molar mass 401.474 g·mol−1
3D model (JSmol)
  • CC1=CC(=NN2C1=NC(=C2)C)C3=CC(=O)N4C=C(C=CC4=N3)N5CCNC6(C5)CC6
  • 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
  • Key:ASKZRYGFUPSJPN-UHFFFAOYSA-N

Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA) [6] [9] and is the first oral medication approved to treat this disease by the US Food and Drug Administration (FDA). [6]

Contents

Risdiplam is a survival of motor neuron 2-directed RNA splicing modifier. [6] [5] [10]

In clinical trials, the most common adverse events included fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. [6] [5] Additional adverse events observed in the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting. [6] [5]

Risdiplam was approved for medical use in the United States in August 2020. [6] [11] Developed by Roche in Basel, Switzerland, [12] in association with PTC Therapeutics and the SMA Foundation, [9] [11] it is marketed in the US by Genentech, [6] a subsidiary of Roche. [11] In February 2025, the FDA approved a new tablet formulation of risdiplam. [13] [14]

Medical uses

In the United States, risdiplam is indicated to treat people with spinal muscular atrophy. [6] [5]

It has been used to treat a baby in utero. [15] The parents had previously suffered the death of a child due to spinal muscular atropy. The FDA approved the use of this agent in pregnency and it was started at 32 weeks gestation. The baby was delivered at 38 weeks gestation and has continued on this agent until the age of 2.5 years. During this period there have been no signs of spinal muscle atrophy.

Adverse effects

In two clinical trials, the following adverse events occurred at least 5% more frequently in participants treated with risdiplam than in the placebo group: fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. [6] [5] Additional adverse events for the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting. [6] [5]

Risdiplam may increase the plasma concentrations of medications that are multidrug and toxin extrusion (MATE) substrates. [6] [5]

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. [9] [16]

The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA to include exon 7, [9] [10] [17] resulting in an increase in the concentration of the functional SMN protein in vivo. [12]

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. [18]

Efficacy

The safety and efficacy of risdiplam in infantile-onset and later-onset SMA has been evaluated in ongoing clinical trials. [9] [19] [20]

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. [19] [6]

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. [20] [6] [9]

Society and culture

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. [6] [9] [11] Genentech was also awarded a rare pediatric disease priority review voucher. [6]

The European Medicines Agency (EMA) awarded risdiplam a priority medicine designation in 2018 [11] [21] [22] and an orphan drug designation in 2019. [11] [23]

Names

Risdiplam is the international nonproprietary name (INN). [24]

Compassionate use

Since 2019, Roche has been offering the drug globally for free to some eligible people through an expanded access program. [25]

References

  1. 1 2 "Evrysdi". Therapeutic Goods Administration (TGA). 11 June 2021. Retrieved 6 September 2021.
  2. 1 2 "AusPAR: Risdiplam". Therapeutic Goods Administration (TGA). 13 September 2021. Retrieved 13 September 2021.
  3. ↑ "Summary Basis of Decision (SBD) for Evrysdi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ↑ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada . 3 August 2022. Retrieved 25 March 2024.
  5. 1 2 3 4 5 6 7 8 "Evrysdi- risdiplam powder, for solution". DailyMed. 26 September 2024. Retrieved 14 February 2025.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "FDA Approves Oral Treatment for Spinal Muscular Atrophy" (Press release). U.S. Food and Drug Administration (FDA). 7 August 2020. Archived from the original on 11 August 2020. Retrieved 7 August 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ "Evrysdi EPAR". European Medicines Agency. 24 February 2021. Retrieved 4 March 2023.
  8. ↑ "Evrysdi Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  9. 1 2 3 4 5 6 7 "Evrysdi (Risdiplam) for Spinal Muscular Atrophy". SMA News Today. 7 August 2020. Archived from the original on 27 January 2021. Retrieved 9 June 2021.
  10. 1 2 Zhao X, Feng Z, Ling KK, Mollin A, Sheedy J, Yeh S, et al. (May 2016). "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. doi:10.1093/hmg/ddw062. PMC   5062580 . PMID   26931466.
  11. 1 2 3 4 5 6 "FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older" (Press release). Genentech. 7 August 2020. Archived from the original on 18 August 2020. Retrieved 7 August 2020.
  12. 1 2 Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, et al. (August 2018). "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. doi: 10.1021/acs.jmedchem.8b00741 . LCCN   a63000643. OCLC   39480771. PMID   30044619.
  13. ↑ "FDA approves Roche's Evrysdi tablet as first and only tablet for Spinal Muscular Atrophy (SMA)" (Press release). Roche. 12 February 2025. Retrieved 14 February 2025.
  14. ↑ "FDA Approves New Tablet Form of Evrysdi for Treatment of Spinal Muscular Atrophy". Muscular Dystrophy Association. 12 February 2025. Retrieved 13 February 2025.
  15. ↑ Risdiplam for prenatal therapy of spinal muscular atrophy (2025) New Eng J Med 392:8
  16. ↑ Ramdas S, Servais L (February 2020). Grech D, Mikhailidis D, Abdollahi M (eds.). "New treatments in spinal muscular atrophy: an overview of currently available data". Expert Opinion on Pharmacotherapy. 21 (3): 307–315. doi:10.1080/14656566.2019.1704732. OCLC   57378019. PMID   31973611. S2CID   210880199.
  17. ↑ Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, et al. (March 2021). "Risdiplam in Type 1 Spinal Muscular Atrophy". The New England Journal of Medicine. 384 (10): 915–923. doi: 10.1056/NEJMoa2009965 . LCCN   20020456. OCLC   231027780. PMID   33626251. S2CID   232047598.
  18. ↑ Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, et al. (January 2014). "Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials". Clinical Therapeutics. 36 (1): 128–140. doi: 10.1016/j.clinthera.2013.11.006 . PMID   24360800.
  19. 1 2 Baranello G, Servais L, Day J, Deconinck N, Mercuri E, Klein A, et al. (October 2019). "P.353FIREFISH Part 1: 16-month safety and exploratory outcomes of risdiplam (RG7916) treatment in infants with type 1 spinal muscular atrophy". Neuromuscular Disorders. 29 (Supplement 1): S184. doi: 10.1016/j.nmd.2019.06.515 . OCLC   24318845.
  20. 1 2 Mercuri E, Baranello G, Kirschner J, Servais L, Goemans N, Pera MC, et al. (April 2019). "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)". Neurology . 92 (15 (Supplement)). doi:10.1212/WNL.92.15_supplement.S25.007. ISSN   0028-3878. LCCN   55043902. OCLC   960771045.
  21. ↑ Inacio P (21 December 2018). "Risdiplam Granted EMA's PRIME Designation for Potential in Spinal Muscular Atrophy". SMA News Today. Archived from the original on 26 January 2021. Retrieved 9 June 2021.
  22. ↑ "PRIME designation granted by European Medicines Agency for Roche's risdiplam for treatment of spinal muscular atrophy (SMA)" (Press release). F. Hoffmann-La Roche. 17 December 2018. Retrieved 14 February 2025– via GlobeNewswire.
  23. ↑ Public summary of opinion on orphan designation: Risdiplam for the treatment of spinal muscular atrophy (PDF) (Report). European Medicines Agency (EMA). 26 February 2019. Archived (PDF) from the original on 6 May 2020.
  24. ↑ World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80". WHO Drug Information. 32 (3): 482. hdl: 10665/330907 .
  25. ↑ Petridis F (13 January 2020). "Roche announces global compassionate use programme for Risdiplam" (Press release). Spinal Muscular Atrophy UK ltd. Roche Global SMA Team (F. Hoffmann-La Roche Ltd). Retrieved 9 June 2021.

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