votoplam (HTT227) / PTC Therap, Novartis - LARVOL DELTA

PTC…reported progress with its drug development pipeline. (Investing.com) - "The company reached alignment with the FDA on the design of a global Phase 3 trial for votoplam in Huntington’s disease, planned to initiate in the first half of 2026. The FDA confirmed openness to a potential Accelerated Approval pathway...The company’s New Drug Application for Translarna remains under FDA review."

FDA event • New P3 trial • Duchenne Muscular Dystrophy • Huntington's Disease

PIVOT-HD: A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD) (clinicaltrials.gov) - P2 | N=159 | Completed | Sponsor: PTC Therapeutics | Active, not recruiting ➔ Completed | N=252 ➔ 159

Enrollment change • Trial completion • Genetic Disorders • Huntington's Disease • Movement Disorders

INVEST-HD: A Study to Investigate the Efficacy, Safety and Tolerability of Votoplam in Participants With Huntington's Disease (clinicaltrials.gov) - P3 | N=770 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • Genetic Disorders • Huntington's Disease • Movement Disorders

Huntington's disease clinical trials update: October 2025. (PubMed, J Huntingtons Dis) - "In this edition of the Huntington's Disease Clinical Trials Update, we expand on the launch of the phase II/III clinical trial of SKY-0515 from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 from Spark Therapeutics. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2, progress with votoplam (PTC518) in PIVOT-HD by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 after 36 months of follow-up. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease."

Journal • Huntington's Disease • Movement Disorders

Effects of High- and Low-Fat Meals on the Bioavailability and Pharmacokinetics of Votoplam, a HTT Gene Splicing Modifier. (PubMed, Clin Pharmacol Drug Dev) - "There were no relevant safety findings in any of the treatment groups. Votoplam can be administered with or without food in patients."

Journal • PK/PD data • Huntington's Disease • Movement Disorders • Rare Diseases

An Extension Study to Evaluate the Long-Term Safety and Efficacy of Votoplam in Participants With Huntington's Disease (HD) (clinicaltrials.gov) - P2 | N=144 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Enrolling by invitation ➔ Active, not recruiting | N=250 ➔ 144 | Trial completion date: Jul 2027 ➔ Jul 2029 | Trial primary completion date: Jun 2027 ➔ Jul 2029

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Genetic Disorders • Huntington's Disease • Movement Disorders

In vitro and in vivo comparison of three small molecule splicing modulators: Branaplam, PTC-518 and CHDI-113 (Neuroscience 2025) - "When orally dosed for 21 days BACHD mice, Branaplam showed the greatest peripheral tissue HTT lowering (compared to PTC-518 and CHDI-113) at doses resulting in 50% CNS mHTT lowering. The therapeutic Index (defined as the ratio of highest doses tolerated vs dose required to reach 50% mHTT lowering in CNS) was similar and very narrow (2-fold) for all three compounds"

Preclinical • CNS Disorders • Movement Disorders • FOXM1

Key Clinical and Regulatory Updates (PTC Therapeutics Press Release) - "Additional Sephience marketing authorization reviews ongoing including in Japan where decision is expected in Q4 2025; FDA meeting for votoplam Huntington's disease program planned for Q4; FDA meeting planned for vatiquinone Friedreich's ataxia program in Q4; Translarna NDA remains under FDA review."

FDA event • Japan filing • Duchenne Muscular Dystrophy • Friedreich ataxia • Huntington's Disease • Phenylketonuria

Key Clinical and Regulatory Milestones (PRNewswire) - "NDA reviews for vatiquinone (Friedreich's ataxia) and Translarna (nonsense mutation DMD) are ongoing, with regulatory action date of August 19, 2025 for vatiquinone...In May 2025, reported positive Phase 2 PIVOT-HD study results for votoplam (PTC518) in Huntington's Disease patients. PTC continues to collaborate with Novartis on next steps and aims to meet with FDA in Q4 2025 to discuss Phase 3 clinical trial design and potential accelerated approval pathway."

Clinical protocol • New P3 trial • PDUFA • Duchenne Muscular Dystrophy • Friedreich ataxia • Huntington's Disease

PTCT Stock Dips 18% Despite Positive Huntington's Disease Study Results (Gurufocus) - "PTC Therapeutics (PTCT, Financial) Phase 2 trial shows potential, but stocks fall by nearly 19%. Analysts set a one-year average price target of $63.21, suggesting significant upside potential."

Stock price • Huntington's Disease

PTC518 PIVOT-HD Study Achieves Primary Endpoint (PTC Therapeutics Press Release) - P2 | N=252 | PIVOT-HD (NCT05358717) | Sponsor: PTC Therapeutics | "Results from the full 12-month cohort demonstrate dose-dependent lowering in blood HTT levels, with 23% at the 5mg dose level for both Stage 2 and 3 patients and 39% and 36% at the 10mg dose level for Stage 2 and 3 patients, respectively. For Stage 2 patients, there were dose-dependent trends of benefit on clinical scales including the Composite Unified Huntington's Disease Rating Scale (cUHDRS) and Total Motor Score (TMS) subscale. For Stage 3 patients, there were trends favoring the 5mg dose group relative to placebo, but not the 10mg dose group, suggesting that treatment effect may differ in Stage 3 patients relative to Stage 2 patients...In addition, 24-month treatment data from the patients on whom data were shared last year (N=21) demonstrate signals of dose-dependent trends on the cUHDRS....PTC will hold a conference call at 8:00 am ET today to discuss this news."

P2 data • Huntington's Disease

PTC shares jump on FDA fast-track hopes after Huntington's drug hits mark (Firstwordpharma Press Release) - "PTC Therapeutics said its experimental Huntington's disease treatment PTC518 (votoplam) achieved the primary endpoint in a mid-stage study, sending shares up nearly 22% Monday."

Commercial • Huntington's Disease

PTC Therapeutics Provides Corporate Update and Reports Fourth Quarter and Full Year 2024 Financial Results (PRNewswire) - "PTC submitted four regulatory approval applications to FDA in 2024....Sepiapterin for children and adults with PKU, with a target regulatory action date of July 29, 2025....PTC submitted several additional marketing authorization applications outside the U.S. for sepiapterin in 2024, with CHMP opinion on sepiapterin MAA expected in Q2 2025 and a regulatory decision in Japan expected in Q4 2025....12-month results from the PIVOT-HD Phase 2 study of PTC518 expected in Q2 2025."

CHMP • Japan approval • P2 data • PDUFA • Huntington's Disease • Phenylketonuria

Huntington's Disease Clinical Trials Update: September 2024. (PubMed, J Huntingtons Dis) - "In this edition of the Huntington's Disease Clinical Trials Update, we expand on the ongoing extension study of PTC518 from PTC Therapeutics, including 12-month interim results from the parent study. We also discuss 24-month interim results from uniQure's AMT-130 program and 28-week follow-up results from Wave Life Sciences' SELECT-HD clinical trial of WVE-003. Additionally, we provide a comprehensive listing of all currently registered and ongoing clinical trials in Huntington's disease."

Journal • Review • Huntington's Disease • Movement Disorders

PTC Therapeutics Provides Update on Commercial Performance and R&D Pipeline at 43rd Annual J.P. Morgan Healthcare Conference (PRNewswire) - "PTC signed a global license and collaboration agreement with Novartis for the research, development and commercialization of PTC518 for HD, which has now closed. Key aspects of the transaction include the following: PTC to receive $1.0 billion in upfront proceeds following closing. PTC is eligible to receive up to $1.9 billion in development, regulatory and sales milestones. PTC to receive 40% profit share on U.S. sales, and double-digit tiered royalties on ex-U.S. sales. Novartis will assume global development, manufacturing and commercial responsibilities following the completion of the placebo-controlled portion of PIVOT-HD, which is expected in 1H 2025."

Licensing / partnership • Trial completion date • CNS Disorders • Huntington's Disease

PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program (PRNewswire) - "PTC Therapeutics, Inc...announced today the signing of an exclusive global license and collaboration agreement with Novartis Pharmaceuticals Corporation...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...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 parties anticipate that the agreement will close in the first quarter of 2025."

Licensing / partnership • Trial completion • CNS Disorders • Huntington's Disease

Twelve-Month Interim Data from PIVOT-HD: a Phase 2, Randomized, Placebo-Controlled Study to Evaluate the Safety and Efficacy of PTC518 in Participants with Huntington's Disease (HSG 2024) - P2 | "These interim results continue to demonstrate that PTC518 is a potential therapeutic benefit in patients with HD."

Clinical • P2 data • Huntington's Disease • Movement Disorders • NEFL • Plasma NfL

PIVOT-LTE: a Phase 2, Double-Blind, Randomized Extension Study to Evaluate the Long-Term Safety and Efficacy of PTC518 in Participants with Huntington's Disease (HSG 2024) - P2 | "Early data from PIVOT-HD indicate PTC518 treatment saw a dose-dependent reduction of mHTT in blood and CSF and was well tolerated. Enrollment of participants for PIVOT-LTE is ongoing and data will be presented at a later timepoint."

Clinical • P2 data • Huntington's Disease • Movement Disorders

PIVOT-HD: A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD) (clinicaltrials.gov) - P2 | N=252 | Active, not recruiting | Sponsor: PTC Therapeutics | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2024 ➔ Aug 2025 | Trial primary completion date: Mar 2024 ➔ Feb 2025

Enrollment closed • Trial completion date • Trial primary completion date • Genetic Disorders • Huntington's Disease • Movement Disorders

FDA Grants Fast Track Designation to PTC518 Huntington’s Disease Program (PRNewswire) - "PTC Therapeutics...announced today that the FDA has granted Fast Track designation to the PTC518 program for the treatment of Huntington's disease...'The granting of Fast Track designation to the PTC518 program further supports the potential of PTC518 to provide a disease modifying therapy to Huntington's disease patients'...'We look forward to working collaboratively with FDA to continue to advance the program as efficiently as possible.'"

Fast track • CNS Disorders • Huntington's Disease

Pharmacokinetics and pharmacodynamics of PTC518, an oral huntingtin lowering splicing modifier: A first-in-human study. (PubMed, Br J Clin Pharmacol) - "PTC518 was well tolerated, and proof of mechanism of this novel splicing modifier was demonstrated by the dose-dependent decrease in systemic HTT mRNA and HTT protein levels. Results from this first-in-human study support further studies in patients with HD and demonstrate the potential for PTC518 as a breakthrough treatment for HD."

Journal • P1 data • PK/PD data • Genetic Disorders • Huntington's Disease • Movement Disorders

An Extension Study to Evaluate the Long-Term Safety and Efficacy of PTC518 in Participants With Huntington's Disease (HD) (clinicaltrials.gov) - P2 | N=250 | Enrolling by invitation | Sponsor: PTC Therapeutics | Recruiting ➔ Enrolling by invitation

Enrollment status • Genetic Disorders • Huntington's Disease • Movement Disorders

Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients (PRNewswire) - P2a | N=252 | PIVOT-HD (NCT05358717) | Sponsor: PTC Therapeutics | "PTC Therapeutics, Inc...today shared interim results from the Phase 2 PIVOT-HD study of PTC518 in Huntington's disease (HD) patients...Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated...At Month 12, durability of dose-dependent mHTT lowering in the blood was demonstrated with lowering of 22% and 43% for 5mg and 10mg dose levels, respectively. In the CSF, dose dependent mHTT lowering was also demonstrated with lowering of 21% and 43%, for 5mg and 10mg dose levels, respectively...In addition, PTC announced that the FDA has lifted the partial clinical hold on the program based on review of the PIVOT-HD data."

FDA event • P2a data • CNS Disorders • Huntington's Disease

Understanding Pharmacy Costs and the Changing Treatment Landscape in Huntington's Disease (HD) in the US: A Systematic Literature Review (SLR) and Database Review for Disease-Modifying Therapies (DMT) in Development (ISPOR 2024) - "Motor symptoms incur the greatest annual drug cost, with high median costs per patient (2019) for tetrabenazine ($24,996), deutetrabenazine ($69,972), and valbenazine ($76,908). Ten clinical trials are investigating potential future DMTs: two-antisense oligonucleotides (n=5; Tominersen [RO7234292, ISIS 443139], WVE-003), two-RNA-targeting small molecules (n=2; PTC518, Branaplam), monoclonal antibodies (n=2; ANX005, VX15/2503), and gene therapy (n=1; rAAV5-miHTT). Pharmacy costs for symptomatic treatment are substantial in HD, with these costs increasing as HD progresses and symptom severity increases. This significant burden illustrates the importance of developing new DMTs that can prevent or slow disease progression for patients with HD."

Review • CNS Disorders • Depression • Gene Therapies • Huntington's Disease • Mood Disorders • Movement Disorders • Psychiatry

Huntington's Disease Clinical Trials Update: February 2024. (PubMed, J Huntingtons Dis) - "In this edition of the Huntington's Disease Clinical Trials Update, we expand on the ongoing program from VICO Therapeutics and on the recently terminated VIBRANT-HD clinical trials. We also discuss updates from uniQure's AMT-130 program and PTC therapeutics' trial of PTC518 and list all currently registered and ongoing clinical trials in Huntington's disease."

Journal • Genetic Disorders • Huntington's Disease • Movement Disorders