RegulationFast Track (US), Orphan Drug (EU), PRIME (EU), Priority Review (CN), Orphan Drug (KR), Orphan Drug (AU), Priority Review (AU), Accelerated assessment (EU), Special Review Project (CN), Orphan Drug (US)

Structure

Molecular FormulaC22H23N7O

InChIKeyASKZRYGFUPSJPN-UHFFFAOYSA-N

CAS Registry1825352-65-5

Clinical Trials associated with Risdiplam

NCT05861999 / RecruitingPhase 4

A Phase IV Open-Label Study Evaluating the Effectiveness and Safety of Risdiplam Administered in Pediatric Patients With Spinal Muscular Atrophy Who Experienced a Plateau or Decline in Function After Gene Therapy

This is an open-label, single-arm, multicenter clinical study to evaluate the effectiveness and safety of risdiplam administered in pediatric participants with SMA and 2 SMN2 copies who previously received onasemnogene abeparvovec and experience a plateau or decline in function. Participants to be enrolled are children <2 years of age genetically diagnosed with SMA.

Start Date14 Aug 2024

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT05861986 / RecruitingPhase 4

A Phase IV Open-Label Study Evaluating the Effectiveness and Safety of Risdiplam Administered as an Early Intervention in Pediatric Patients With Spinal Muscular Atrophy After Gene Therapy

This is an open-label, single-arm, multicenter clinical study to evaluate the effectiveness and safety of risdiplam administered as an early intervention in pediatric participants with spinal muscular atrophy (SMA) and 2 SMN2 copies who have previously received onasemnogene abeparvovec. Participants are children < 2 years of age genetically diagnosed with SMA.

Start Date30 May 2024

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT05808764 / RecruitingPhase 2

A Phase II, Open-label Study to Investigate the Pharmacokinetics and Safety of Risdiplam in Infants With Spinal Muscular Atrophy

This study will evaluate the pharmacokinetics (PK) and safety of risdiplam in participants with spinal muscular atrophy (SMA) under 20 days of age at first dose.

Start Date26 Apr 2024

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with Risdiplam

100 Translational Medicine associated with Risdiplam

100 Patents (Medical) associated with Risdiplam

165

Literatures (Medical) associated with Risdiplam

01 Dec 2024·MUSCLE & NERVE

Outcomes of early‐treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study

Article

Author: Lee, Bo Hoon ; Hamid, Omer Abdul ; Herbert, Karen ; Farah, Hiba ; King, Kiana ; Kuntz, Nancy L. ; Zaidman, Craig M. ; Fisher, Mark ; Gibbons, Melissa ; Lakhotia, Arpita ; Parsons, Julie ; Rehborg, Rebecca ; Goedeker, Natalie L. ; Rogers, Amanda ; Kichula, Elizabeth ; Harmelink, Matthew ; Brandsema, John F. ; Veerapaniyan, Aravindhan ; Felker, Marcia V. ; Farrar, Michelle A. ; Arya, Kapil

Abstract:

Introduction/Aims:

While prompt identification and treatment of infants with spinal muscular atrophy (SMA) can ameliorate outcomes, variability persists. This study assessed management and outcomes of early‐treated infants with SMA.

Methods:

We analyzed retrospective data at 12 centers on infants with SMA treated at age ≤6 weeks from August 2018 to December 2023.

Results:

Sixty‐six patients, 35 with two SMN2 copies and 31 with ≥3 SMN2 copies, were included. Twenty‐five (38%, 22 with two SMN2 copies), had SMA findings before initial treatment which was onasemnogene abeparvovec in 47 (71%) and nusinersen in 19 (29%). Thirty‐two received sequential or combination treatments, including 16 adding nusinersen or risdiplam due to SMA findings following onasemnogene abeparvovec. All sat independently. Compared to children with ≥3 SMN2 copies, those with two SMN2 copies were less likely to walk (23/34 [68%] vs. 31/31 [100%], p < .001) and less likely to walk on time (9/34 [26%] vs. 29/31 [94%], p < .001); one non‐ambulatory child was <18 months old and was excluded from this analysis. No patients required permanent ventilation or exclusively enteral nutrition; six required nocturnal non‐invasive ventilation and four utilized supplemental enteral nutrition, all with two SMN2 copies.

Discussion:

Early treatment of infants with SMA can improve outcomes as indicated by our cohort, all of whom sat independently and are without permanent ventilation. However, our study demonstrates ongoing disability in most children with two SMN2 copies despite early monotherapy and emphasizes the need for additional research, including earlier monotherapy, initial combination therapy, prenatal treatment, and non‐SMN modifying treatments.

01 Dec 2024·Lancet Regional Health-Europe

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Article

Background:

Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH).

Methods:

This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status.

Findings:

343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups.

Interpretation:

Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio.

Funding:

The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

01 Nov 2024·MUSCLE & NERVE

Nutrition outcomes of disease modifying therapies in spinal muscular atrophy: A systematic review

Review

Author: O'Brien, Katie ; Woodcock, Ian R. ; Nguo, Kay ; Yiu, Eppie M. ; Billich, Natassja ; Davidson, Zoe E.

Abstract:

The nutritional implications of spinal muscular atrophy (SMA) are profound. Disease modifying therapies (DMT) have improved clinical outcomes. This review describes the impact of DMT on nutrition outcomes. A systematic search strategy was applied across seven databases until May 2023. Eligible studies measured nutrition outcomes in individuals with SMA on DMT (nusinersen, risdiplam or onasemnogene abeparvovec [OA]) compared to untreated comparators. Nutrition outcomes included anthropometry, feeding route, swallowing dysfunction, dietary intake, dietetic intervention, nutritional biochemistry, metabolism, gastrointestinal issues and energy expenditure. Articles retrieved were screened in duplicate, data were extracted and appraised systematically. Sixty three articles from 54 studies were included; 41% (n = 22) investigated nusinersen in pediatric participants with SMA type 1. Anthropometry (n = 18), feeding route (n = 39), and swallowing dysfunction (n = 18) were the most commonly reported outcomes. In combined pediatric and adult cohorts, BMI z‐score remained stable post nusinersen therapy. The proportion of children with SMA requiring enteral nutrition was stable post nusinersen therapy. Ability to thrive at age 1.5 years was higher in children treated in early infancy with OA compared to historical controls. Significant heterogeneity existed across study population characteristics and outcome measures. Nusinersen may prevent deterioration in some nutrition outcomes; and OA in early infancy may be associated with improved nutrition outcomes. Timing of DMT initiation is an important consideration for future nutrition research. Studies investigating nutrition as a primary outcome of DMT, using consistent outcome measures are required for nutritional management strategies for this cohort to be appropriately tailored.

133

News (Medical) associated with Risdiplam

02 Dec 2024

·www.prnewswire.com

PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program

- PTC to receive $1.0B in cash at closing - - PTC is eligible to receive up to $1.9B in development, regulatory and sales milestones - - PTC to share profits in the U.S. and tiered double-digit royalties on ex-U.S. net sales - - Novartis will assume global development, manufacturing and commercial responsibilities following completion of placebo-controlled portion of ongoing PIVOT-HD study - - PTC will host a conference call on Dec. 2, 2024, at 8:30 am EST- WARREN, N.J., Dec. 2, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) announced today the signing of an exclusive global license and collaboration agreement with Novartis Pharmaceuticals Corporation, a subsidiary of Novartis AG (NYSE: NVS), for its PTC518 Huntington's disease program, which includes related molecules. Under the agreement, PTC will receive an upfront payment of $1.0 billion, up to $1.9 billion in development, regulatory and sales milestones, a profit share in the U.S., and double-digit tiered royalties on ex-U.S. sales. "PTC518 is the leading oral disease-modifying therapy in development for Huntington's disease and the economics of this agreement are consistent with the promise of this treatment," said Matthew B. Klein, M.D., Chief Executive Officer, PTC Therapeutics. "This collaboration combines PTC's expertise in developing small molecule splicing therapies with Novartis's expertise in global development and commercialization of neuroscience therapies. We are excited to collaborate with Novartis to accelerate the potential of PTC518 for the hundreds of thousands of HD patients worldwide in need of a therapy designed to be well-tolerated and an effective disease-modifying therapy. PTC will use the proceeds of this transaction to expand our splicing platform as well as to support commercial and development portfolio activities." "Huntington's Disease is a devastating, fatal, familial disease. This agreement with PTC is intended to bolster our neuroscience pipeline and reflects our strategic focus and commitment to explore new and potentially transformative approaches for neurodegenerative diseases with high unmet needs," said Vas Narasimhan, CEO of Novartis. "We look forward to building on our expertise in neurodegenerative diseases and experience in HD with the intention to advance this potential first in class oral therapy for the HD community." PTC518 was discovered from PTC's validated splicing platform and is currently being studied in the ongoing Phase 2 PIVOT-HD trial. Interim results reported in June 2024 demonstrated that PTC518 treatment resulted in durable, dose-dependent reduction in blood and cerebrospinal fluid (CSF) mutant Huntingtin protein (HTT) levels as well as early signals of dose-dependent benefit on key clinical measurements at 12 months.1 Importantly, PTC518 continues to demonstrate a favorable safety and tolerability profile.1 Novartis will assume responsibility for PTC518's development, manufacturing and commercialization, following the completion of the on-going placebo-controlled portion of PIVOT-HD, which is expected to occur in H1 2025. The companies will share U.S. profits and losses, on a 40/60 basis (40% PTC and 60% Novartis). The closing of the transaction is subject to customary closing conditions, including regulatory clearance. The parties anticipate that the agreement will close in the first quarter of 2025. Conference Call and Webcast Details: PTC will hold a conference call at 8:30 am EST today to discuss this news. To access the call by phone, please click here to register and you will be provided with dial-in details. To avoid delays, we recommend participants dial in to the conference call 15 minutes prior to the start of the call. The webcast conference call can be accessed on the Investor section of the PTC website at . A replay of the call will be available approximately two hours after completion of the call and will be archived on the company's website for 30 days following the call. About Huntington's Disease Huntington's disease (HD) is a fatal, hereditary, genetic disorder of the central nervous system.2 It is caused by a defective gene. This gene produces a protein, called Huntingtin, which is involved in the functioning of the nerve cells in the brain (neurons). When the gene is defective, it produces an abnormal (or mutated) Huntingtin protein that is toxic and causes neuron damage and neuron death.3 HD usually presents in people who are in their 30s or 40s. Symptoms can present earlier in life, and this is called the Juvenile HD.3,4 There are also cases of infantile HD, when symptoms develop in children who are younger than 10 years old.3 While symptoms vary from person to person, the disease primarily affects the brain and results in abnormal movements, difficulties with speech, swallowing and walking, as well as a number of other symptoms including behavioral, cognitive and motor symptoms.5,6 While there are therapies approved for specific disease symptoms, currently, there is no cure for HD and there are no approved drugs that delay the onset or slow disease progression. About PTC's Splicing Platform PTC has pioneered the use of advanced alternative splicing technology to identify small molecules that affect mRNA splicing for the treatment of disease of high unmet need. PTC's validated splicing platform identified the first-ever approved small molecule splicing modifier - Evrysdi® (risdiplam), and PTC has leveraged the extensive learnings from the SMA program to broaden the platform to support discovery programs across numerous therapeutic areas including neurodegenerative disease, oncology and metabolism. PTC has also developed a powerful high-throughput drug discovery platform (PTSeek™) that identifies small molecules that modulate pre-mRNA splicing to upregulate or down regulate targeted protein production, accelerating the discovery and early preclinical development process for candidate small molecule splicing agents. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to children and adults living with rare disorders. PTC's ability to innovate to identify new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC's mission is to provide access to best-in-class treatments for patients who have little to no treatment options. PTC's strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients. PTC believes this allows it to maximize value for all its stakeholders. To learn more about PTC, please visit us at and follow us on Facebook, Instagram, LinkedIn and X. For More Information: Investors: Ellen Cavaleri +1 (615) 618-6228 [email protected] Media: Jeanine Clemente +1 (908) 912-9406 [email protected] Forward-Looking Statement: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this press release, other than statements of historic fact, are forward-looking statements, including statements with respect to the future expectations, plans and prospects for PTC, including with respect to PTC's right to receive any upfront payment from Novartis; PTC's right to receive development, regulatory and sales milestones, profit sharing and royalty payments from Novartis; the continued development of PTC518; future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward -looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; the expected benefits and opportunities related to the licensing agreement may not be realized or may take longer to realize than expected due to a variety of reasons, including any inability of the parties to perform their commitments and obligations under the agreement, challenges and uncertainties inherent in development; success in early clinical trials, especially if based on a small patient sample, does not ensure that later clinical trials will be successful, and early results from a clinical trial do not necessarily predict final results; data for PTC518 may not be sufficient for obtaining regulatory approval; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's most recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. References: PTC Therapeutics, "Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients," news release, June 20, 2024, World Health Organization, 2020. 8A01.10 Huntington disease. Available at: Accessed October 2021. Gatto EM, González Rojas N, Persi G, et al. Clin Parkinsonism Rel Disord 2020;3:100056. Tabrizi SJ, Flower MD, Ross CA, et al. Nat Rev Neurol 2020;16(10):529–546. Roos RAC. Orphanet J Rare Dis 2010;5:40. Kirkwood SC, Su JL, Conneally P, et al. Arch Neurol 2001;58(2):273–278. SOURCE PTC Therapeutics, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

License out/inClinical ResultPhase 2

02 Dec 2024

·medcitynews.com

Novartis Tries Again in Huntington’s, Putting Up $1B to Partner on a PTC Therapeutics Drug - MedCity News

Nearly six months ago, PTC Therapeutics reported positive interim data for a drug in mid-stage development for Huntington’s disease, an inherited neurological disorder with limited treatment options and a history of stymied drug research efforts. The PTC drug’s data readout prompted another company to make an unsolicited bid for the program. Rather than jump at the offer, PTC decided to see if others might also be interested in the asset. Novartis has won this competitive process. On Monday, the companies announced the Swiss pharma giant is paying $1 billion up front to license global rights to the PTC Huntington’s drug, PTC518. PTC is still responsible for completing the ongoing placebo-controlled portion of the Phase 2 test of PTC518, and the Warren, New Jersey-based biotech will lead planned discussions with the FDA later this month to discuss the Phase 3 clinical trial. Novartis will take over the program for its pivotal study and is also responsible for the drug’s manufacturing and commercialization, though the deal calls for the companies to share profits from U.S. sales of an approved product — 60% to Novartis and 40% to PTC. The biotech is in line for up to $1.9 billion in milestone payments from Novartis plus royalties from sales of the drug in other markets. This deal is expected to close in the first quarter of 2025. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News Huntington’s stems from a genetic mutation that leads to defective versions of huntingtin, a protein key to neuronal function. Mutated huntingtin causes neuronal damage and cell death that affects movement, speech, and swallowing. The disease also leads to behavioral, cognitive, and motor symptoms. Drugs used to treat Huntington’s address certain disease symptoms. There are no approved therapies that delay Huntington’s onset or slow its progression. PTC518 is a small molecule that affects the splicing of messenger RNA in order to reduce levels of a target protein. The drug comes from the same PTC technology that yielded Evrysdi, an mRNA-splicing drug that won FDA approval in 2020 as a treatment for the rare muscle disease spinal muscular atrophy (Evyrsdi is marketed by Roche under a partnership). The PTC518 data that prompted deal interest from other companies are interim results from a Phase 2 test showing the once-daily tablet led to dose-dependent lowering of mutant huntingtin protein in the blood and cerebrospinal fluid. The company also reported favorable trends on several clinical assessments of Huntington’s. PTC said the drug was safe and well tolerated by study participants. Additional Phase 2 data are expected in the second quarter of 2025. Huntington’s drug research has yielded many disappointments. In 2021, Roche halted a Phase 3 test of tominersen at the recommendation of the trial’s independent data monitoring committee. The drug candidate, an antisense oligonucleotide from Roche’s partnership with Ionis Pharmaceuticals, is designed to bind to mRNA in order to prevent production of mutant huntingtin. Roche has not given up on this drug entirely. In 2022, the pharma giant revealed plans for a new Phase 2 trial in younger Huntington’s patients with less severe disease. More recently, Sage Therapeutics reported it would stop dosing of dalzanemdor, a small molecule that had reached Phase 2 testing in Huntington’s. The November decision was based on the recommendation of independent observers of the clinical trial. Novartis has also experienced disappointment in Huntington’s. Its internally discovered drug candidate, branaplam, was initially developed as a treatment for spinal muscular atrophy before the company changed the small molecule’s focus to Huntington’s. In 2022, Novartis suspended dosing of branaplam after findings suggested the experimental drug may have caused peripheral neuropathy in some study participants. The mid-stage study was subsequently discontinued. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions In a note sent to investors, Leerink Partners analyst Joseph Schwartz said Novartis seems like a logical partner for PTC518, as branaplam’s approach to Huntington’s was similar to the PTC drug. In a Monday conference call, PTC executives said besides Novartis’s competitive financial offer, the pharma giant was selected because of its experience developing neuroscience drugs. William Blair analyst Sami Corwin wrote in an investor note that the deal makes financial sense for PTC, which last week struck a $150 million deal to sell the priority review voucher (PRV) it received for the recent FDA approval of gene therapy Kebilidi for an inherited enzyme deficiency. She said PTC now has additional funds to support its drug portfolio without needing to also pay for a pivotal clinical trial. “We see the $1 billion upfront payment, in addition to the $150 million PRV sale, as providing the company with sufficient financial funds to reach cash flow break even in the future without the need to raise additional funds,” Corwin said. “In addition, the deal provides PTC with a strategic partner that has experience developing drugs for CNS-based diseases, which could accelerate the clinical development and bolster the commercialization of PTC518, in our view. We also see the deal as validating PTC518 and PTC’s splicing platform.” In the hands of a big pharma company with neuroscience experience, William Blair gives PTC518 a 50% probability of success, modeling peak revenue of $5 billion, about $1.43 billion of which would go to PTC. In the nearer term, PTC is preparing to meet with the FDA later this month to discuss the design of the Phase 3 study. Schwartz noted that PTC is seeking alignment with the regulator on using lowering of huntingtin levels as a potential surrogate endpoint to support accelerated approval. This endpoint could also serve as the primary endpoint of a Phase 3 study supporting a traditional approval.

Phase 2Phase 3Clinical ResultPhase 1

28 Nov 2024

·pipelinereview.com

Biohaven Provides Update on Taldefgrobep Alfa Development Program for Spinal Muscular Atrophy and Obesity

NEW HAVEN, CT, USA I November 25, 2024 I Biohaven Ltd. (NYSE: BHVN ) (Biohaven), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies to treat a broad range of rare and common diseases, provided an update today regarding the taldefgrobep alfa development programs in SMA and obesity. Figure 1: MFM-32 Total Score Change from Baseline in Caucasian Subjects with Measurable Free Myostatin Levels Present at Baseline In the RESILIENT SMA study, taldefgrobep showed clinically meaningful improvements in motor function at all timepoints on the Motor Function Measurement-32 scale (MFM-32) but the treatment arm did not statistically separate on the primary outcome at 48 weeks compared to the placebo+standard of care (SOC) group. Signals of efficacy were observed in clinically relevant and biomarker-defined subgroups including those related to age, ambulatory status, background therapy, and presence of myostatin at baseline. Notably, there was an unexpectedly large subgroup (35%) of subjects without measurable levels of myostatin at baseline and imbalances in some genetic factors (SMN2 copy number, race) across treatment arms. Diverse populations are affected by SMA, but its genetic epidemiology and carrier rates vary with race or ethnicity, with more than a 2-fold higher prevalence in Caucasian compared to non-Caucasian populations 1 . Analyses of prespecified subgroups by race and ethnicity demonstrated that the largest study population (87% Caucasian; n=180) showed a 2.2-point change-from-baseline improvement with taldefgrobep treatment on the MFM-32 at Week 48 compared to a 1.1-point change-from-baseline improvement in the corresponding placebo+SOC group (p < 0.039). The improvement associated with taldefgrobep in this subgroup was further increased to a 1.4-point placebo adjusted change-from-baseline (p=0.02) when analyzed by subjects who had measurable myostatin levels at baseline (see Figure 1). These benefits on the MFM-32 continued to increase in the open-label extension period based on preliminary data through Extension Week 24. Moreover, a responder analysis of this myostatin-positive subgroup, with response defined as ≥ 3-point change from baseline improvement on the MFM-32 at Week 48, showed that 50% of taldefgrobep-treated subjects responded compared to 30% in the placebo+SOC arm. Non-Caucasian subjects (n=26) had a higher than expected placebo response and did not separate from placebo on the MFM-32 at Week 48 (p=0.24). Significant enrichment of known, common genetic polymorphisms in non-Caucasian subjects, considered likely to confer myostatin-inhibitory independence for myostatin therapies, are probable in explaining this ethnic separation of responsiveness to therapy. This provides a potentially facile biomarker for identifying SMA patients likely to benefit from taldefgrobep and other myostatin therapies. Further analysis is ongoing to better understand the likely potential impact of these readily monitorable biomarker and genetic factors, including myostatin allele frequencies, in both the potential lower overall response in treated subjects and the overall higher response observed in placebo subjects. In the overall study population, and relevant to activity of taldefgrobep on muscle and fat, prespecified outcome measures analyzing the change from baseline in body composition at Week 48 demonstrated a greater reduction in the percent change in total body fat mass in the taldefgrobep arm compared to the placebo+SOC arm (p=0.008) as measured by dual energy x-ray absorptiometry (DXA). The taldefgrobep arm also showed numerically larger increases in lean muscle mass and bone density compared to the placebo+SOC arm. Importantly, variables such as race or baseline myostatin levels did not alter the impact of taldefgrobep on the favorable effects on fat mass over the course of the study. These results suggest that the body composition changes observed in subjects treated with taldefgrobep, including lower fat mass, are not solely mediated by taldefgrobep’s effects on myostatin but also through its effects on other targets such as activin A. The favorable effects observed on overall body composition (fat and lean mass) is consistent with nonclinical data showing that taldefgrobep has direct effects on adipose tissue mediated by activin receptor signaling through multiple ligands, including activin A, myostatin and others. Notably, taldefgrobep is the first and only myostatin blocking agent that has shown the ability to favorably change fat mass in people with SMA. This finding has important implications for the potential of taldefgrobep as a treatment for obesity in a broad population. Based upon data from this study demonstrating target engagement (i.e., myostatin reduction) and taldefgrobep-associated changes in body composition (i.e., fat mass, lean muscle mass and bone density), Biohaven intends to accelerate taldefgrobep clinical plans in 4Q24, advancing a user-friendly, self-administered autoinjector in adults living with overweight and obesity, medical conditions defined by excess, abnormal body fat. Biomarker analyses demonstrated that taldefgrobep achieved robust target engagement, reducing myostatin levels in all treated subjects below the level of detection at all time points measured through Week 48. Post hoc efficacy analyses in subjects with measurable baseline myostatin (the pharmacological target of taldefgrobep) showed an improved efficacy signal in this myostatin-positive population. Cliff Bechtold, Taldefgrobep Development Lead and President of Biohaven Ireland, commented, “SMA is a devastating rare disease and although we are disappointed that taldefgrobep did not achieve a statistically significant difference in the broad study population on the MFM-32, we are encouraged that a majority subgroup did show a treatment benefit compared to the placebo arm. The observed treatment effect on motor function, which had a similar magnitude on the MFM-32 after 1 year of treatment as approved therapies (i.e., risdiplam), along with the strong biomarker evidence of target engagement, suggests that taldefgrobep may play a potentially beneficial role in a majority subgroup population of SMA patients. Additionally, taldefgrobep demonstrated an important beneficial effect on body composition which supports our plans to accelerate development in broader populations with obesity.” Taldefgrobep was well-tolerated in the RESILIENT trial with 97% of subjects continuing into the optional long-term extension, which will remain open and ongoing pending discussion with FDA. There were no taldefgrobep treatment-related SAEs. Evaluation of additional RESILIENT clinical and biomarker data is ongoing, and Biohaven plans to engage with FDA regarding these emerging data to discuss a path forward. Full topline data will be presented at an upcoming scientific meeting. Lindsey Lair, MD, MBA, Vice President of Neurology and Clinical Lead for SMA at Biohaven added, “Biohaven remains committed to fighting rare diseases and will engage SMA experts and regulatory authorities regarding the full dataset from the RESILIENT study. We are extremely grateful to the international SMA community – especially the participants and their families, investigators and their teams, and patient advocacy groups who made the trial possible.” About Taldefgrobep alfa Taldefgrobep alfa is a fully human recombinant protein specifically designed to inhibit both myostatin and activin receptor signaling. By blocking the formation of the myostatin-activin receptor complex, taldefgrobep prevents downstream activity that leads to muscle atrophy and accumulation of fat mass. More information about taldefgrobep alfa can be found at the Biohaven website . About SMA SMA is a rare genetic neurodegenerative disorder characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk and progressive muscle weakness that is often fatal and typically diagnosed in young children. The underlying pathology of SMA is caused by insufficient production of the SMN (survival of motor neuron) protein, essential for the survival of motor neurons, and is encoded by two genes, SMN1 and SMN2. Globally, SMA affects approximately 1 in 10,000 births, and about 1 in every 50 individuals is a genetic carrier. About Biohaven Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology. The company is advancing its innovative portfolio of therapeutics, leveraging its proven drug development experience and multiple proprietary drug development platforms. Biohaven’s extensive clinical and preclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders; extracellular protein degradation for immunological diseases; TRPM3 antagonism for migraine and neuropathic pain; TYK2/JAK1 inhibition for neuroinflammatory disorders; glutamate modulation for OCD and SCA (spinocerebellar ataxia); myostatin inhibition for neuromuscular and metabolic diseases, including SMA and obesity; antibody recruiting bispecific molecules and antibody drug conjugates for cancer. For more information, visit www.biohaven.com . (1: https://www.ncbi.nlm.nih.gov/books/NBK1352/ ) SOURCE: Biohaven

Clinical Result

100 Deals associated with Risdiplam

External Link

KEGG	Wiki	ATC	Drug Bank
D11406	Risdiplam	M09A	DB15305

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Spinal Muscular Atrophy	US	Genentech, Inc.	07 Aug 2020

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	US	Roche China Holding Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	US	F. Hoffmann-La Roche Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	JP	Roche China Holding Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	JP	F. Hoffmann-La Roche Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	BE	Roche China Holding Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	BE	F. Hoffmann-La Roche Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	BR	F. Hoffmann-La Roche Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	BR	Roche China Holding Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	HR	Roche China Holding Ltd.	19 Dec 2016
HMN (Hereditary Motor Neuropathy) Proximal Type I	Phase 2	HR	F. Hoffmann-La Roche Ltd.	19 Dec 2016

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03779334 (RAINBOWFISH, GlobeNewswire) Manual	Phase 2	Spinal Muscular Atrophy SMN2 copies	23	Evrysdi	alhmuvlooo(voixwjqsll) = All of the children treated with Evrysdi who had three or more SMN2 copies (n=18), achieved standing and walking (100%). gzezkeuxql (htsxfklbbc ) Met View more	Positive	14 Oct 2024
EAN	Not Applicable	Spinal Muscular Atrophy	-	Risdiplam	farzzpzbta(xsnuyxbtqb) = jjlwklpzei udrqzfgwny (ntrqypwumj )	-	28 Jun 2024
FIREFISH (NEWS) Manual	Not Applicable	Spinal Muscular Atrophy	-	Evrysdi	bdzvtshbxx(naxmknwgmc) = owwfyapbbf ribqacpkau (ctwvdafuot ) View more	Positive	14 Jun 2024
NCT03779334 (RAINBOWFISH, AAN2024)	Phase 2	Spinal Muscular Atrophy ulnar CMAP amplitude	26	Risdiplam	zxksoajjby(xvfiwfgmsc) = ytqfwdlgme dmhphvpkqj (jwyfisfewp ) View more	Positive	09 Apr 2024
NCT03779334 (RAINBOWFISH, MDA2024) Manual	Phase 3	Spinal Muscular Atrophy SMN2 copies \| ulnar CMAP amplitude	26	Risdiplam	hpzkctfrfk(labozdudci) = ntjzbvyktf uexudihqxb (zyupdgbygz ) View more	Positive	03 Mar 2024
MDA2024	Not Applicable	Spinal Muscular Atrophy SMN2 copies	-	Risdiplam	pirbdlhmhp(uoogbmjici) = One infant had a single overdose 10x intended dosing without related sequelae exygcfwxxu (iebjvsbrgx ) View more	Positive	03 Mar 2024
MDA2024	Not Applicable	Spinal Muscular Atrophy	-	Onasemnogene abeparvovec (OA)	noohriyjdz(nyduxuinee) = xrpihowblt hcmlqwjkjy (sswbwopwau )	-	03 Mar 2024
MDA2024	Not Applicable	Spinal Muscular Atrophy	-	Risdiplam (EVRYSDI)	noohriyjdz(nyduxuinee) = scuumgfkec hcmlqwjkjy (sswbwopwau )	-	03 Mar 2024
EAN	Not Applicable	SMN2 gene transcription	56	Nusinersen	fbmyydtqum(aqbdnhnawt) = 6 patients had transient diarrhea, but we observed no significant side effects ehenhnizqk (itztvnswqs ) View more	Positive	28 Jun 2023
EAN	Not Applicable	SMN2 gene transcription	56	Risdiplam		Positive	28 Jun 2023
MDA2023	Not Applicable	Spinal Muscular Atrophy	-	Risdiplam-treated patients	dhiwiuomdu(dsovvmkpch) = cgvqiiaimi qhcpsphjxu (iozodnfaue ) View more	-	19 Mar 2023
MDA2023	Not Applicable	Spinal Muscular Atrophy	-	Risdiplam	ncxuywmtvg(syxjgkeqoo) = imdctgaata anycfucaju (ktkearmnge, 22) View more	-	19 Mar 2023

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