Risdiplam

Last updated

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

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<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.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis (MS). It is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and is an immunosuppressive drug. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

<span class="mw-page-title-main">PTC Therapeutics</span> Pharmaceutical company

PTC Therapeutics, Inc. is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan diseases.

<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.

<span class="mw-page-title-main">Olesoxime</span> Chemical compound

Olesoxime (TRO19622) is an experimental drug formerly under development by the now-defunct French company Trophos as a treatment for a range of neuromuscular disorders. It has a cholesterol-like structure and belongs to the cholesterol-oxime family of mitochondrial pore modulators.

Polatuzumab vedotin, sold under the brand name Polivy, is a CD79b-directed antibody-drug conjugate medication used for the treatment of diffuse large B-cell lymphoma (cancer). It was developed by the Genentech subsidiary of Roche.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Nusinersen</span> Medication used for spinal muscular atrophy

Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder.

<span class="mw-page-title-main">Branaplam</span> Chemical compound

Branaplam is a pyridazine derivative that is being studied as an experimental drug. It was originally developed by Novartis to treat spinal muscular atrophy (SMA); since 2020 it was being developed to treat Huntington's disease but the trial ended in 2023 due to toxicity concerns.

<span class="mw-page-title-main">Faricimab</span> Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

Satralizumab, sold under the brand name Enspryng, is a humanized monoclonal antibody medication that is used for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease. The drug is being developed by Chugai Pharmaceutical, a subsidiary of Roche.

Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy used to treat spinal muscular atrophy (SMA), a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. It works by providing a new copy of the SMN gene that produces the SMN protein.

Novartis Gene Therapies, until 2020 known as AveXis, is a biotechnology company that develops treatments for rare neurological genetic disorders. It was founded in Dallas, Texas, United States in 2012 by John Carbona after reorganizing a company called BioLife Cell Bank founded by David Genecov and John Harkey. Work done at Nationwide Children's Hospital in the laboratory of Brian Kaspar was licensed to AveXis in October 2013. Unusual for the time, Nationwide Children's Hospital, in addition to upfront and milestone payments, also took an equity position in AveXis. Kaspar became paid consultant pari passu with the license agreement in 2013. The company was built specifically around a discovery of a novel method of treating spinal muscular atrophy using gene therapy. AveXis was acquired by Novartis in 2018 for USD 8.7 billion.

<span class="mw-page-title-main">Casirivimab/imdevimab</span> Antiviral combination medication

Casirivimab/imdevimab, sold under the brand name REGEN‑COV among others, is a combination medicine used for the treatment and prevention of COVID‑19. It consists of two human monoclonal antibodies, casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection. The combination of two antibodies is intended to prevent mutational escape. It is also available as a co-formulated product. It was developed by the American biotechnology company Regeneron Pharmaceuticals.

<span class="mw-page-title-main">Alberto Kornblihtt</span> Argentine molecular biologist

Alberto Kornblihtt is an Argentine molecular biologist who specializes in alternative ribonucleic acid splicing. During his postdoctoral training with Francisco Baralle in Oxford, Kornblihtt documented one of the first cases of alternative splicing, explaining how a single transcribed gene can generate multiple protein variants. Kornblihtt was elected as a foreign associate of the National Academy of Sciences of the United States in 2011, received the Diamond Award for the most relevant scientist of Argentina of the decade, alongside physicist Juan Martin Maldacena, in 2013, and was incorporated to the Académie des Sciences of France in 2022.

Avalglucosidase alfa, sold under the brand name Nexviazyme, is an enzyme replacement therapy medication used for the treatment of glycogen storage disease type II.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

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 Food and Drugs Administration (FDA) (18 August 2020). "Evrysdi- risdiplam powder, for solution". DailyMed. Bethesda, Maryland, United States: MedLine by the National Library of Medicine (NLM) of the United States National Institutes of Health (NIH) . Retrieved 24 September 2020.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 O'Keefe L (7 August 2020). "FDA Approves Oral Treatment for Spinal Muscular Atrophy" (Press release). Silver Spring, Maryland, United States of America: United States Food and Drug Administration (FDA). FDA Newsroom Department. 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 Food and Drugs Administration (FDA) (7 August 2020). "Evrysdi (Risdiplam) for Spinal Muscular Atrophy". SMA News Today. Pensacola, Florida, United States: BioNews Services (BioNews Services, LLC.). 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). Oxford, United Kingdom of Great Britain: Oxford University Press (OUP): 1885–1899. doi:10.1093/hmg/ddw062. PMC   5062580 . PMID   26931466.
  11. 1 2 3 4 5 6 7 "FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older". Genentech (Press release). San Francisco, California, United States of America: Genentech, Inc. (Roche Group). Genentech Global Product Development Division. 7 August 2020. Archived from the original on 18 August 2020. Retrieved 7 August 2020.
  12. ↑ 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). London, England, United Kingdom of Great Britain: Taylor & Francis (Informa UK Ltd): 307–315. doi:10.1080/14656566.2019.1704732. OCLC   57378019. PMID   31973611. S2CID   210880199.
  13. ↑ "RG7916". Pensacola, Florida, United States: BioNews Services (BioNews Services, LLC.). 8 November 2016. Archived from the original on 24 April 2020. Retrieved 9 June 2021.
  14. ↑ 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). Boston, Massachusetts, United States of America: NEJM Group (Massachusetts Medical Society): 915–923. doi: 10.1056/NEJMoa2009965 . LCCN   20020456. OCLC   231027780. PMID   33626251. S2CID   232047598.
  15. ↑ 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). Washington, D.C.: 6501–6517. doi: 10.1021/acs.jmedchem.8b00741 . LCCN   a63000643. OCLC   39480771. PMID   30044619.
  16. ↑ Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S (January 2014). "Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials". Clinical Therapeutics. 36 (1). Philadelphia, Pennsylvania, United States of America: Elsevier: 128–140. doi: 10.1016/j.clinthera.2013.11.006 . PMID   24360800.
  17. 1 2 Baranello G, Servais L, Day J, Deconinck N, Mercuri E, Klein A, et al. (1 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). London, United Kingdom of Great Britain: World Muscle Society (WMS)/Elsevier Inc.: S184. doi: 10.1016/j.nmd.2019.06.515 . ISSN   0960-8966. OCLC   24318845.
  18. 1 2 Mercuri E, Baranello G, Kirschner J, Servais L, Goemans N, Pera MC, et al. (16 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)). Minneapolis, Minnesota, United States of America: American Academy of Neurology/Wolters Kluwer. doi:10.1212/WNL.92.15_supplement.S25.007. ISSN   0028-3878. LCCN   55043902. OCLC   960771045 . Retrieved 9 June 2021.
  19. ↑ Inacio P (21 December 2018). "Risdiplam Granted EMA's PRIME Designation for Potential in Spinal Muscular Atrophy". SMA News Today. Pensacola, Florida, United States: BioNews Services (BioNews Services, LLC.). Archived from the original on 26 January 2021. Retrieved 9 June 2021.
  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.
  21. ↑ Stoyanova-Beninska V, Schwarzer-Daum B (26 February 2019). Public summary of opinion on orphan designation: Risdiplam for the treatment of spinal muscular atrophy (PDF). EMA Committee for Orphan Medicinal Products (COMP) (Report). Amsterdam, the Netherlands: European Medicines Agency (EMA Committee for Orphan Medicinal Products). pp. 1–4. Archived (PDF) from the original on 6 May 2020.
  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 .
  24. ↑ Petridis F (13 January 2020). "Roche announces global compassionate use programme for Risdiplam" (Press release). Stratford-upon-Avon, England, United Kingdom of Great Britain: Spinal Muscular Atrophy UK ltd. Roche Global SMA Team (F. Hoffmann-La Roche Ltd). Retrieved 9 June 2021.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.