Risdiplam

Identification

Summary

Risdiplam is an oral mRNA splicing modifier used in the treatment of spinal muscular atrophy (SMA).

Brand Names

Evrysdi

Generic Name

Risdiplam

DrugBank Accession Number

DB15305

Background

Risdiplam is an orally bioavailable mRNA splicing modifier used for the treatment of spinal muscular atrophy (SMA).⁵ It increases systemic SMN protein concentrations by improving the efficiency of SMN2 gene transcription. This mechanism of action is similar to its predecessor nusinersen, the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy onasemnogene abeparvovec, whereas risdiplam offers the ease of oral bioavailability.^9,4

Risdiplam was approved by the FDA in August 2020 for the treatment of spinal muscular atrophy (SMA).^6,7 Set to be substantially cheaper than other available SMA therapies,⁹ risdiplam appears to provide a novel and relatively accessible treatment option for patients with SMA regardless of severity or type.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Risdiplam (DB15305)

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Weight

Average: 401.474
Monoisotopic: 401.196408389

Chemical Formula

C₂₂H₂₃N₇O

Synonyms

• Risdiplam
• Risdiplamum

External IDs

• RG-7916
• RG7916
• RO-7034067
• RO7034067
• WHO 10614

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Pharmacology

Indication

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA).¹⁰

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Spinal muscular atrophy (sma)		••••••••••••			••••••• ••• ••••••••

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Pharmacodynamics

Risdiplam helps to alleviate symptoms of spinal muscular atrophy by stimulating the production of a critical protein in which these patients are deficient. Early trials with risdiplam demonstrated up to a 2-fold increase in SMN protein concentration in SMA patients after 12 weeks of therapy.²

Mechanism of action

Spinal muscular atrophy (SMA) is a severe and progressive congenital neuromuscular disease resulting from mutations in the survival of motor neuron 1 (SMN1) gene responsible for making SMN proteins.³ Clinical features of SMA include degeneration of motor neurons in the spinal cord which ultimately leads to muscular atrophy and, in some cases, loss of physical strength.¹ SMN proteins are expressed ubiquitously throughout the body and are thought to hold diverse intracellular roles in DNA repair, cell signaling, endocytosis, and autophagy.¹ A secondary SMN gene (SMN2) can also produce SMN proteins, but a small nucleotide substitution in its sequence results in the exclusion of exon 7 during splicing in approximately 85% of the transcripts - this means that only ~15% of the SMN proteins produced by SMN2 are functional,¹ which is insufficient to compensate for the deficits caused by SMN1 mutations. Emerging evidence suggests that many cells and tissues are selectively vulnerable to reduced SMN concentrations, making this protein a desirable target in the treatment of SMA.¹

Risdiplam is an mRNA splicing modifier for SMN2 that increases the inclusion of exon 7 during splicing, which ultimately increases the amount of functional SMN protein produced by SMN2.³ It does so by binding to two sites in SMN2 pre-mRNA: the 5' splice site (5'ss) of intron 7 and the exonic splicing enhancer 2 (ESE2) of exon 7.⁴

Absorption

The T_max following oral administration is approximately 1-4 hours.^3,7 Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days.⁷ The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.⁷

Volume of distribution

Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues.¹ The apparent volume of distribution at steady-state is 6.3 L/kg.⁷

Protein binding

Risdiplam is approximately 89% protein-bound in plasma, primarily to serum albumin.⁷

Metabolism

The metabolism of risdiplam is mediated primarily by flavin monooxygenases 1 and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7.⁷ Parent drug comprises approximately 83% of circulating drug material.⁷

A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite - this M1 metabolite has been observed in vitro to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.⁷

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• Risdiplam
  • Risdiplam M1 metabolite

Route of elimination

Following the oral administration of 18mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine.⁷ Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine.⁷

Half-life

The terminal elimination half-life of risdiplam is approximately 50 hours in healthy adults.⁷

Clearance

For a 14.9kg patient, the apparent clearance of risdiplam is 6.3 L/kg.⁷

Adverse Effects

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Toxicity

Data regarding overdose of risdiplam are unavailable. Symptoms of overdose are likely to be consistent with risdiplam's adverse effect profile, and may therefore involve significant fever, diarrhea, and skin reactions.⁷

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Risdiplam.
Acyclovir	The serum concentration of Acyclovir can be increased when it is combined with Risdiplam.
Baricitinib	The serum concentration of Baricitinib can be increased when it is combined with Risdiplam.
Cefradine	The serum concentration of Cefradine can be increased when it is combined with Risdiplam.
Cephalexin	The serum concentration of Cephalexin can be increased when it is combined with Risdiplam.

Food Interactions

• Take after a meal.
• Take at the same time every day.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Evrysdi	Powder, for solution	0.75 mg / mL	Oral	Hoffmann La Roche	2021-05-19	Not applicable
Evrysdi	Powder, for solution	0.75 mg/1mL	Oral	Genentech Inc.	2020-08-07	Not applicable
Evrysdi	Powder, for solution	0.75 mg/ml	Oral	Roche Registration Gmb H	2021-05-07	Not applicable

Categories

ATC Codes

M09AX10 — Risdiplam

• M09AX — Other drugs for disorders of the musculo-skeletal system
• M09A — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M09 — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M — MUSCULO-SKELETAL SYSTEM

Drug Categories

• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A7 Substrates
• Cytochrome P-450 Substrates
• MATE 1 Inhibitors
• MATE 2 Inhibitors
• MATE inhibitors
• Musculo-Skeletal System
• Other Miscellaneous Therapeutic Agents
• P-glycoprotein substrates
• Peripheral Nervous System Agents
• Survival Motor Neuron-2-directed RNA Interaction
• Survival of Motor Neuron 2 Splicing Modifier

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

76RS4S2ET1

CAS number

1825352-65-5

InChI Key

ASKZRYGFUPSJPN-UHFFFAOYSA-N

InChI

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

IUPAC Name

7-{4,7-diazaspiro[2.5]octan-7-yl}-2-{2,8-dimethylimidazo[1,2-b]pyridazin-6-yl}-4H-pyrido[1,2-a]pyrimidin-4-one

SMILES

CC1=CN2N=C(C=C(C)C2=N1)C1=CC(=O)N2C=C(C=CC2=N1)N1CCNC2(CC2)C1

References

Synthesis Reference

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: Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Aug 9;61(15):6501-6517. doi: 10.1021/acs.jmedchem.8b00741. Epub 2018 Jul 25.

General References

1. Ramdas S, Servais L: New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother. 2020 Feb;21(3):307-315. doi: 10.1080/14656566.2019.1704732. [Article]
2. 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: Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Aug 9;61(15):6501-6517. doi: 10.1021/acs.jmedchem.8b00741. Epub 2018 Jul 25. [Article]
3. Sturm S, Gunther A, Jaber B, Jordan P, Al Kotbi N, Parkar N, Cleary Y, Frances N, Bergauer T, Heinig K, Kletzl H, Marquet A, Ratni H, Poirier A, Muller L, Czech C, Khwaja O: A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 2019 Jan;85(1):181-193. doi: 10.1111/bcp.13786. Epub 2018 Nov 16. [Article]
4. Messina S, Sframeli M: New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J Clin Med. 2020 Jul 13;9(7). pii: jcm9072222. doi: 10.3390/jcm9072222. [Article]
5. BiopharmaDive: 5 FDA Approval Decisions to Watch in the 2nd Quarter [Link]
6. BusinessWire: FDA Approves Genentech’s Evrysdi (risdiplam) for Treatment of Spinal Muscular Atrophy (SMA) in Adults and Children 2 Months and Older [Link]
7. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
8. CaymanChem: Risdiplam MSDS [Link]
9. BiopharmaDive: First oral drug for spinal muscular atrophy approved by FDA [Link]
10. FDA Approved Drug Products: EVRYSDI (risdiplam) Powder for oral solution (May 2022) [Link]

External Links

ChemSpider

67886354

RxNav

2390935

ChEMBL

CHEMBL4297528

Wikipedia

Risdiplam

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Spinal Muscular Atrophy (SMA)	1
4	Not Yet Recruiting	Treatment	Spinal Muscular Atrophy (SMA)	2
4	Recruiting	Treatment	Spinal Muscular Atrophy (SMA)	1
2	Active Not Recruiting	Treatment	Spinal Muscular Atrophy (SMA)	2
2	Completed	Treatment	Spinal Muscular Atrophy (SMA)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Powder, for solution	Oral	0.75 mg / mL
Powder, for solution	Oral	0.75 mg/1mL
Powder, for solution	Oral	0.75 MG/ML
Powder, for solution	Oral	60 mg
Powder	Oral	0.75 mg/mL
Powder, for solution	Enteral; Oral	60 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9969754	No	2018-05-15	2035-05-11
US9586955	No	2017-03-07	2033-02-08
US11534444	No	2018-10-04	2038-10-04
US11827646	No	2016-01-25	2036-01-25

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0958 mg/mL	ALOGPS
logP	1.22	ALOGPS
logP	1.18	Chemaxon
logS	-3.6	ALOGPS
pKa (Strongest Basic)	8.7	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	78.13 Å2	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	127.06 m3·mol-1	Chemaxon
Polarizability	45.12 Å3	Chemaxon
Number of Rings	6	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-0000900000-8877198e95556f902a76
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0100900000-e828d71424d108336d45
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udr-0009700000-308665b5630a1162fecd
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0udi-0006900000-af4390b95085f885ab0e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0k9i-0009100000-9e923794253e9444b7fd
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00e9-0619000000-2f76c5bf31819fc36939
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

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Drug created at May 20, 2019 15:10 / Updated at August 03, 2023 15:04