Risdiplam

Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA)[1][2] and the first oral medication approved to treat this disease.[1][2]

Risdiplam
Clinical data
Trade namesEvrysdi
Other namesRG7916; RO7034067
AHFS/Drugs.comEvrysdi
License data
Routes of
administration		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC22H23N7O
Molar mass401.474 g·mol−1
3D model (JSmol)

Risdiplam is a survival of motor neuron 2-directed RNA splicing modifier.[1][3][4]

The most common side effects include fever, diarrhoea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections.[1][3] Additional side effects for the infantile-onset population include upper respiratory tract infection, pneumonia, constipation and vomiting.[1][3]

It 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.[1] Developed in association with PTC Therapeutics and the SMA Foundation,[2] it is marketed in the US by Genentech,[1] a subsidiary of Roche.[5]

Medical uses

In the United States, risdiplam is indicated to treat people two months of age and older with spinal muscular atrophy, a rare and often fatal genetic disease affecting muscle strength and movement.[1][3]

Adverse effects

The most common side effects include fever, diarrhoea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections.[1][3] Additional side effects for the infantile-onset population include upper respiratory tract infection, pneumonia, constipation and vomiting.[1][3]

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.[1][3]

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.[2]

The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA, resulting in a larger quantity of the functional SMN protein.[6][4] Nusinersen, the first drug approved to treat SMA, works in a similar way.[7]

Efficacy

The safety and efficacy of risdiplam in infantile-onset and later-onset SMA has been evaluated in two ongoing clinical trials.[8][9]

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.[8][1]

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.[9][1][2]

Two further clinical studies are underway.[2]

Society and culture

The US Food and Drug Administration (FDA) awarded marketing approval to Genentech on August 7, 2020. The FDA earlier granted the application for risdiplam fast track, priority review, and orphan drug designations.[1][2][5] Genentech was also awarded a rare pediatric disease priority review voucher.[1]

As of August 2020, Roche has applied for marketing authorisation in Brazil, Chile, China, Indonesia, Russia, South Korea and Taiwan, and an application in the European Union is imminent.[5]

In 2018, the European Medicines Agency (EMA) awarded risdiplam a priority medicine designation for its potential to treat SMA.[5][10][11]

In 2019, risdiplam was awarded orphan drug designation by the EMA.[12][5]

Compassionate use

Since late 2019, Roche has been offering the drug globally for free for eligible people through an expanded access program.[13]

References
  1. "FDA Approves Oral Treatment for Spinal Muscular Atrophy". U.S. Food and Drug Administration (FDA) (Press release). 7 August 2020. Retrieved 7 August 2020. This article incorporates text from this source, which is in the public domain.
  2. "Evrysdi (Risdiplam)". smanewstoday.com. 7 August 2020. Retrieved 8 August 2020.
  3. "Evrysdi (risdiplam) for oral solution" (PDF). Genentech. Retrieved 8 August 2020.
  4. 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): 1885–99. doi:10.1093/hmg/ddw062. PMC 5062580. PMID 26931466.
  5. "FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older". Genentech (Press release). 7 August 2020. Retrieved 7 August 2020.
  6. Maria Joao Almeida (2016-09-08). "RG7916". BioNews Services. Retrieved 2017-10-08.
  7. 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): 128–40. doi:10.1016/j.clinthera.2013.11.006. PMID 24360800.
  8. 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: S184. doi:10.1016/j.nmd.2019.06.515. ISSN 0960-8966.
  9. 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). ISSN 0028-3878.
  10. Inacio P (2018-12-21). "Risdiplam Granted EMA's PRIME Designation for Potential in Spinal Muscular Atrophy". SMA News Today. Retrieved 8 August 2020.
  11. "PRIME designation granted by European Medicines Agency for Roche's risdiplam for treatment of spinal muscular atrophy (SMA)". Roche (Press release). 17 December 2018. Retrieved 12 August 2020.
  12. "EU/3/19/2145". European Medicines Agency (EMA). 9 April 2019. Retrieved 12 August 2020.
  13. "Roche announces global compassionate use programme for risdiplam". Spinal Muscular Atrophy UK. Retrieved 2020-04-08.
  • "Risdiplam". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02913482 for "Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (FIREFISH)" at ClinicalTrials.gov
  • Clinical trial number NCT02908685 for "A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants (SUNFISH)" at ClinicalTrials.gov


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