Identification

Name
Risdiplam
Accession Number
DB15305
Description

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 use in patients 2 months of age or older in 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
Thumb
Weight
Average: 401.474
Monoisotopic: 401.196408389
Chemical Formula
C22H23N7O
Synonyms
  • Risdiplam
  • Risdiplamum
External IDs
  • RG-7916
  • RG7916
  • RO-7034067
  • RO7034067
  • WHO 10614

Pharmacology

Pharmacology
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Indication

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.7

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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 Tmax 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

Hover over products below to view reaction partners

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

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Risdiplam.
AcyclovirThe serum concentration of Acyclovir can be increased when it is combined with Risdiplam.
BaricitinibThe serum concentration of Baricitinib can be increased when it is combined with Risdiplam.
CefradineThe serum concentration of Cefradine can be increased when it is combined with Risdiplam.
CephalexinThe serum concentration of Cephalexin can be increased when it is combined with Risdiplam.
CimetidineThe serum concentration of Cimetidine can be increased when it is combined with Risdiplam.
CiprofloxacinThe serum concentration of Ciprofloxacin can be increased when it is combined with Risdiplam.
EmtricitabineThe serum concentration of Emtricitabine can be increased when it is combined with Risdiplam.
Estrone sulfateThe serum concentration of Estrone sulfate can be increased when it is combined with Risdiplam.
FlecainideThe serum concentration of Flecainide can be increased when it is combined with Risdiplam.
Interactions
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Food Interactions
  • Take after a meal.
  • Take at the same time every day.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EvrysdiPowder, for solution0.75 mg/1mLOralGenentech Inc.2020-08-07Not applicableUS flag

Categories

Drug Categories
Classification
Not classified

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. [PubMed:31973611]
  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. [PubMed:30044619]
  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. [PubMed:30302786]
  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. [PubMed:32668756]
  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]
ChemSpider
67886354
RxNav
2390935
ChEMBL
CHEMBL4297528
Wikipedia
Risdiplam

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentSpinal Muscular Atrophy (SMA)1
2RecruitingTreatmentMuscular Atrophy, Spinal1
2, 3Active Not RecruitingTreatmentMuscular Atrophy, Spinal2
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentMuscular Atrophy, Spinal1
1CompletedTreatmentSpinal Muscular Atrophy (SMA)2
1RecruitingBasic ScienceMuscular Atrophy, Spinal1
Not AvailableApproved for MarketingNot AvailableMuscular Atrophy, Spinal1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionOral0.75 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9969754No2015-05-112035-05-11US flag
US9586955No2013-02-082033-02-08US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0958 mg/mLALOGPS
logP1.22ALOGPS
logP1.18ChemAxon
logS-3.6ALOGPS
pKa (Strongest Basic)8.7ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area78.13 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity127.06 m3·mol-1ChemAxon
Polarizability45.12 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Nadp binding
Specific Function
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. Form I catalyzes the N-oxygenation of secondary and tertiary amines.
Gene Name
FMO1
Uniprot ID
Q01740
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 1
Molecular Weight
60310.285 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation to all four regioisomeric cis-epoxyeicosatrienoic acids. One of the predominant enzymes responsible f...
Gene Name
CYP2J2
Uniprot ID
P51589
Uniprot Name
Cytochrome P450 2J2
Molecular Weight
57610.165 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Evrysdi (risdiplam) powder for oral solution [Link]

Drug created on May 20, 2019 15:10 / Updated on February 21, 2021 18:55