{{Short description|Chemical compound}} {{Use dmy dates|date=February 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = Risdiplam.svg | image_class = skin-invert-image | width = | alt = | caption =
<!-- Clinical data --> | pronounce = | tradename = Evrysdi | Drugs.com = {{drugs.com|monograph|risdiplam}} | MedlinePlus = | DailyMedID = Risdiplam | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Evrysdi APM summary" /><ref name="AusPAR: Risdiplam" /> | pregnancy_category= | routes_of_administration = By mouth | class = | ATC_prefix = M09 | ATC_suffix = AX10 | ATC_supplemental =
<!-- Legal status --> | legal_AU = S4 | legal_AU_comment = <ref name="Evrysdi APM summary">{{cite web | title=Evrysdi | website=Therapeutic Goods Administration (TGA) | date=11 June 2021 | url=https://www.tga.gov.au/apm-summary/evrysdi | access-date=6 September 2021}}</ref><ref name="AusPAR: Risdiplam">{{cite web | title=AusPAR: Risdiplam | website=Therapeutic Goods Administration (TGA) | date=13 September 2021 | url=https://www.tga.gov.au/auspar/auspar-risdiplam | access-date=13 September 2021}}</ref> | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Summary Basis of Decision (SBD) for Evrysdi | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00544&lang=en | access-date=29 May 2022}}</ref><ref>{{cite web | title=Health product highlights 2021: Annexes of products approved in 2021 | website=Health Canada | date=3 August 2022 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html | access-date=25 March 2024}}</ref> | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Evrysdi label" /><ref name="FDA PR" /> | legal_EU = Rx-only | legal_EU_comment = <ref name="Evrysdi EPAR">{{cite web | title=Evrysdi EPAR | website=European Medicines Agency | date=24 February 2021 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/evrysdi | access-date=4 March 2023}}</ref><ref>{{cite web | title=Evrysdi Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1531.htm | access-date=3 March 2023}}</ref> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = <!-- For countries not listed above -->
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =
<!-- Identifiers --> | CAS_number_Ref = | CAS_number = 1825352-65-5 | CAS_supplemental = | PubChem = 118513932 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = DB15305 | ChemSpiderID_Ref = | ChemSpiderID = 67886354 | UNII_Ref = | UNII = 76RS4S2ET1 | KEGG_Ref = | KEGG = D11406 | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = | ChEMBL = 4297528 | NIAID_ChemDB = | PDB_ligand = | synonyms = RG7916; RO7034067
<!-- Chemical and physical data --> | 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 | StdInChI_comment = | StdInChIKey = ASKZRYGFUPSJPN-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}
'''Risdiplam''', sold under the brand name '''Evrysdi''', is a medication used to treat spinal muscular atrophy (SMA)<ref name="FDA PR">{{cite press release |title=FDA Approves Oral Treatment for Spinal Muscular Atrophy |publisher=U.S. Food and Drug Administration (FDA) |date=7 August 2020 |url=https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy |access-date=7 August 2020 |archive-date=11 August 2020 |archive-url=https://web.archive.org/web/20200811220128/https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy}} {{PD-notice}}</ref><ref name="SMA News Today">{{cite news |access-date=9 June 2021 |url=https://www.smanewstoday.com/evrysdi-risdiplam |archive-url=https://web.archive.org/web/20210127163559/https://smanewstoday.com/evrysdi-risdiplam |archive-date=27 January 2021 |work=SMA News Today|date=7 August 2020 |title=Evrysdi (Risdiplam) for Spinal Muscular Atrophy | url-status=unfit }}</ref> and is the first oral medication approved to treat this disease by the US Food and Drug Administration (FDA).<ref name="FDA PR" />
Risdiplam is a survival of motor neuron 2-directed RNA splicing modifier.<ref name="FDA PR" /><ref name="Evrysdi label" /><ref name="Zhao"/>
In clinical trials, the most common adverse events included fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections.<ref name="FDA PR" /><ref name="Evrysdi label" /> Additional adverse events observed in the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting.<ref name="FDA PR" /><ref name="Evrysdi label" />
Risdiplam was approved for medical use in the United States in August 2020.<ref name="FDA PR" /><ref name="Genentech PR">{{cite press release |date=7 August 2020 |title=FDA Approves Genentech's Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older |url=https://www.gene.com/media/press-releases/14866/2020-08-07/fda-approves-genentechs-evrysdi-risdipla |access-date=7 August 2020 |publisher=Genentech |archive-date=18 August 2020 |archive-url=https://web.archive.org/web/20200818182824/https://www.gene.com/media/press-releases/14866/2020-08-07/fda-approves-genentechs-evrysdi-risdipla }}</ref> Developed by Roche in Basel, Switzerland,<ref name="Ratni Ebeling Baird Bendels pp. 6501–6517" /> in association with PTC Therapeutics and the SMA Foundation,<ref name="SMA News Today"/><ref name="Genentech PR" /> it is marketed in the US by Genentech,<ref name="FDA PR" /> a subsidiary of Roche.<ref name="Genentech PR" /> In February 2025, the FDA approved a new tablet formulation of risdiplam.<ref>{{cite press release | title=FDA approves Roche's Evrysdi tablet as first and only tablet for Spinal Muscular Atrophy (SMA) | publisher=Roche | date=12 February 2025 | url=https://www.roche.com/media/releases/med-cor-2025-02-12 | access-date=14 February 2025}}</ref><ref>{{cite web |date=2025-02-12 |title=FDA Approves New Tablet Form of Evrysdi for Treatment of Spinal Muscular Atrophy |url=https://www.mda.org/press-releases/2025/fda-approves-new-tablet-form-of-evrysdi-for-treatment-of-spinal-muscular-atrophy |access-date=2025-02-13 |website=Muscular Dystrophy Association }}</ref>
== Medical uses == In the United States, risdiplam is indicated to treat people with spinal muscular atrophy.<ref name="FDA PR" /><ref name="Evrysdi label">{{cite web | title=Evrysdi- risdiplam powder, for solution | website=DailyMed | date=26 September 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eceb9a99-7191-4be5-87c3-0102707cf98e | access-date=14 February 2025}}</ref>
It has been used to treat a baby ''in utero''.<ref>Risdiplam for prenatal therapy of spinal muscular atrophy (2025) ''New Eng J Med'' 392:8</ref> The parents had previously suffered the death of a child due to spinal muscular atropy. The FDA approved the use of this agent in pregnancy 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.<ref name="FDA PR" /><ref name="Evrysdi label" /> Additional adverse events for the infantile-onset population included upper respiratory tract infection, pneumonia, constipation and vomiting.<ref name="FDA PR" /><ref name="Evrysdi label" />
Risdiplam may increase the plasma concentrations of medications that are multidrug and toxin extrusion (MATE) substrates.<ref name="FDA PR" /><ref name="Evrysdi label" />
== 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.<ref name="SMA News Today"/><ref name="Ramdas Servais pp. 307-315">{{cite journal | vauthors = Ramdas S, Servais L | title = New treatments in spinal muscular atrophy: an overview of currently available data | journal = Expert Opinion on Pharmacotherapy | volume = 21 | issue = 3 | pages = 307–315 | date = February 2020 | pmid = 31973611 | doi = 10.1080/14656566.2019.1704732 | veditors = Grech D, Mikhailidis D, Abdollahi M | s2cid = 210880199 | oclc = 57378019 }}</ref>
The compound is a pyridazine derivative that modifies the splicing of ''SMN2'' messenger RNA to include exon 7,<ref name="SMA News Today" /><ref name="Zhao">{{cite journal | vauthors = 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 | title = Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 25 | issue = 10 | pages = 1885–1899 | date = May 2016 | pmid = 26931466 | pmc = 5062580 | doi = 10.1093/hmg/ddw062 }}</ref><ref name=":0">{{cite journal | vauthors = 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 | title = Risdiplam in Type 1 Spinal Muscular Atrophy | journal = The New England Journal of Medicine | volume = 384 | issue = 10 | pages = 915–923 | date = March 2021 | pmid = 33626251 | doi = 10.1056/NEJMoa2009965 | lccn = 20020456 | s2cid = 232047598 | doi-access = free | title-link = doi | oclc = 231027780 }}</ref> resulting in an increase in the concentration of the functional SMN protein ''in vivo''.<ref name="Ratni Ebeling Baird Bendels pp. 6501–6517">{{cite journal | vauthors = 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 | title = Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA) | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 15 | pages = 6501–6517 | date = August 2018 | pmid = 30044619 | doi = 10.1021/acs.jmedchem.8b00741 | lccn = a63000643 | doi-access = free | title-link = doi | oclc = 39480771 }}</ref>
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''.<ref name = "Zanetta">{{cite journal | vauthors = Zanetta C, Nizzardo M, Simone C, Monguzzi E, Bresolin N, Comi GP, Corti S | title = Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials | journal = Clinical Therapeutics | volume = 36 | issue = 1 | pages = 128–140 | date = January 2014 | pmid = 24360800 | doi = 10.1016/j.clinthera.2013.11.006 | doi-access = free | title-link = doi }}</ref>
Risdiplam is classified as an aminocyclopropane.<ref>{{cite journal | vauthors = Bertus P, Caillé J | title = Advances in the Synthesis of Cyclopropylamines | journal = Chemical Reviews | volume = 125 | issue = 6 | pages = 3242–3377 | date = March 2025 | pmid = 40048498 | doi = 10.1021/acs.chemrev.4c00674 }}</ref>
== Efficacy == The safety and efficacy of risdiplam in infantile-onset and later-onset SMA has been evaluated in ongoing clinical trials.<ref name="SMA News Today"/><ref name="FIREFISH">{{cite journal | vauthors = 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 | title = P.353FIREFISH Part 1: 16-month safety and exploratory outcomes of risdiplam (RG7916) treatment in infants with type 1 spinal muscular atrophy | volume = 29 | issue = Supplement 1 | doi = 10.1016/j.nmd.2019.06.515 | doi-access = free | title-link = doi | date = October 2019 | journal = Neuromuscular Disorders |pages=S184 | oclc = 24318845 }}</ref><ref name="SUNFISH">{{cite journal | vauthors = 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 |title=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) |journal=Neurology |date=April 2019 |volume=92 |issue=15 (Supplement) |issn=0028-3878 | doi = 10.1212/WNL.92.15_supplement.S25.007 |lccn=55043902 |oclc=960771045 }}</ref>
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.<ref name="FIREFISH"/><ref name="FDA PR" />
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.<ref name="SUNFISH"/><ref name="FDA PR" /><ref name="SMA News Today"/>
==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.<ref name="FDA PR" /><ref name="SMA News Today"/><ref name="Genentech PR" /> Genentech was also awarded a rare pediatric disease priority review voucher.<ref name="FDA PR" />
The European Medicines Agency (EMA) awarded risdiplam a priority medicine designation in 2018<ref name="Genentech PR" /><ref>{{cite web |work=SMA News Today | vauthors = Inacio P |date=21 December 2018 |title=Risdiplam Granted EMA's PRIME Designation for Potential in Spinal Muscular Atrophy |url=https://smanewstoday.com/news/risdiplam-granted-ema-prime-designation/ |access-date=9 June 2021 |url-status=live |archive-url=https://web.archive.org/web/20210126185434/https://smanewstoday.com/news-posts/2018/12/21/risdiplam-granted-ema-prime-designation |archive-date=26 January 2021 }}</ref><ref>{{cite press release | title=PRIME designation granted by European Medicines Agency for Roche's risdiplam for treatment of spinal muscular atrophy (SMA) | publisher=F. Hoffmann-La Roche | via=GlobeNewswire | date=17 December 2018 | url=https://www.globenewswire.com/news-release/2018/12/17/1667599/0/en/PRIME-designation-granted-by-European-Medicines-Agency-for-Roche-s-risdiplam-for-treatment-of-spinal-muscular-atrophy-SMA.html | access-date=14 February 2025}}</ref> and an orphan drug designation in 2019.<ref name="Genentech PR" /><ref>{{cite report |title=Public summary of opinion on orphan designation: Risdiplam for the treatment of spinal muscular atrophy |date=26 February 2019 |publisher=European Medicines Agency (EMA) |url=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 |archive-url=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 |archive-date=6 May 2020 |archive-format=PDF |url-status=live }}</ref>
=== Names === Risdiplam is the international nonproprietary name (INN).<ref>{{cite journal | year=2018 | title=International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80 | journal=WHO Drug Information | volume=32 | issue=3 | page=482 | hdl=10665/330907 | hdl-access=free }}</ref>
=== Compassionate use === Since 2019, Roche has been offering the drug globally for free to some eligible people through an expanded access program.<ref>{{cite press release |title=Roche announces global compassionate use programme for Risdiplam |date=13 January 2020 |access-date=9 June 2021 |agency=Roche Global SMA Team (F. Hoffmann-La Roche Ltd) |vauthors = Petridis F |publisher=Spinal Muscular Atrophy UK ltd |url=https://smauk.org.uk/blog/treatments-research/roche-announces-global-compassionate-use-programme-for-risdiplam }}</ref>
== References == {{reflist}}
== Further reading == {{refbegin}} * {{cite journal | vauthors = Dhillon S | title = Risdiplam: First Approval | journal = Drugs | volume = 80 | issue = 17 | pages = 1853–1858 | date = November 2020 | pmid = 33044711 | doi = 10.1007/s40265-020-01410-z | s2cid = 222279898 | oclc = 01566990 }} * {{cite journal | vauthors = Ratni H, Scalco RS, Stephan AH | title = Risdiplam, the First Approved Small Molecule Splicing Modifier Drug as a Blueprint for Future Transformative Medicines | journal = ACS Medicinal Chemistry Letters | volume = 12 | issue = 6 | pages = 874–877 | date = June 2021 | pmid = 34141064 | pmc = 8201486 | doi = 10.1021/acsmedchemlett.0c00659 | oclc = 643819990 }} {{refend}}
== External links == * {{ClinicalTrialsGov|NCT02913482|Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (FIREFISH)}} * {{ClinicalTrialsGov|NCT02908685|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)}}
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Category:Drugs developed by Genentech Category:Drugs developed by Hoffmann-La Roche Category:Orphan drugs Category:Spinal muscular atrophy