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 the first oral medication approved to treat this disease. [6] [9]

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 by the US Food and Drug Administration (FDA) in August 2020, for the treatment of adults and children two months of age or older. [6] [11] Developed 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]

Medical uses

In the United States, risdiplam is indicated to treat people two months of age and older with spinal muscular atrophy. [6] [5]

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. [6] [5] Additional adverse events for the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting. [6] [5]

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. [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] [12]

The compound is a pyridazine derivative that modifies the splicing of SMN2 messenger RNA to include exon 7, [13] [10] [14] resulting in an increase in the concentration of the functional SMN protein in vivo. [15]

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. [16]

Efficacy

The safety and efficacy of risdiplam in infantile-onset and later-onset SMA has been evaluated in ongoing clinical trials. [9] [17] [18]

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. [17] [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. [18] [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] [19] [20] and an orphan drug designation in 2019. [11] [21]

As of August 2020, Roche has applied for marketing authorisation in Brazil, Chile, China, the European Union, Indonesia, Russia, South Korea and Taiwan. [11] [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]

Related Research Articles

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<span class="mw-page-title-main">Spinal muscular atrophy</span> Rare congenital neuromuscular disorder

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.

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<span class="mw-page-title-main">X-linked spinal muscular atrophy type 2</span> Medical condition

X-linked spinal muscular atrophy type 2, also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons.

<i>SMN2</i> Protein-coding gene in the species Homo sapiens

Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.

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References

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  2. 1 2 "AusPAR: Risdiplam". Therapeutic Goods Administration (TGA). 13 September 2021. Retrieved 13 September 2021.
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  20. Roche Group Media Relations Division (17 December 2018). "PRIME designation granted by European Medicines Agency for Roche's risdiplam for treatment of spinal muscular atrophy (SMA)" (Press release). Basel, Switzerland: F. Hoffmann-La Roche Ltd. Group Communications Department (Roche Group Media Relations Division). pp. 1–5. Archived from the original (PDF) on 18 August 2020. Retrieved 9 June 2021.
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  22. PTC Therapeutics (17 August 2020). "PTC Announces the Acceptance of the European Marketing Authorization Application for Evrysdi™ (risdiplam) for the Treatment of Spinal Muscular Atrophy" (Press release). Albuquerque, New Mexico, United States of America: PR Newswire. PTC Therapeutics. Archived from the original on 18 August 2020. Retrieved 9 June 2021.
  23. World Health Organization (2018). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80". WHO Drug Information. 32 (3): 482. hdl: 10665/330907 .
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Further reading