Huntington's Disease Trials Surge Forward With Gene Therapy and Splicing Breakthroughs
A comprehensive October 2025 update reveals major advances across multiple HD clinical trials, including promising 36-month gene therapy data.
Summary
The October 2025 Huntington's disease clinical trials update highlights a rapidly evolving therapeutic landscape. Key developments include the launch of FALCON-HD, a phase II/III trial of SKY-0515, an mRNA splicing modulator targeting mutant huntingtin; and SPK-10001, an AAV-based gene therapy from Spark Therapeutics entering phase I/II. Most notably, uniQure's AMT-130 gene therapy reported positive topline data at 36 months, suggesting durable disease-modifying effects. Roche's tominersen programme continues in GENERATION HD2, while PTC Therapeutics advances votoplam (PTC518) in PIVOT-HD and pursues a Novartis collaboration. Pridopidine faces regulatory headwinds after the failed PROOF-HD study. The update also lists all currently registered and ongoing HD trials globally.
Detailed Summary
Huntington's disease (HD) remains one of the most challenging inherited neurodegenerative conditions, but the clinical trial landscape has never been more active or diverse. This October 2025 update from the UCL Huntington's Disease Centre synthesises the latest developments across gene therapy, splice-modulating small molecules, antisense oligonucleotides, and symptomatic treatments.
The most headline-grabbing result is positive topline data from uniQure's phase I/II AMT-130 trial (NCT04120493/NCT05243017) at 36 months of follow-up. AMT-130 is an AAV5-delivered microRNA construct (AAV5-miHTT) administered via intrastriatal infusion, designed to achieve durable, allele-non-selective silencing of huntingtin. Thirty-six-month data represent a meaningful durability milestone for a one-time gene therapy in HD and support progression toward pivotal trials.
Two newly launched trials draw significant attention. FALCON-HD (NCT06873334) is a randomised, double-blind, placebo-controlled phase II/III study of SKY-0515 from Skyhawk Therapeutics, enrolling 120 early-HD participants (UHDRS TFC ≥10) across Australia and New Zealand. SKY-0515 is an oral mRNA splicing modulator designed to simultaneously lower mutant huntingtin (mHTT) and PMS1, a DNA mismatch repair protein implicated in somatic CAG repeat expansion. Primary endpoints include blood mHTT levels, brain volumetric MRI, and UHDRS at 12 months. Separately, Spark Therapeutics has initiated a phase I/II trial of SPK-10001 (NCT06826612), an AAV-based gene therapy delivered via bilateral intraparenchymal infusion into the caudate and putamen. The randomised, sham-controlled, dose-escalation study targets HD-ISS stage 1–2 patients and prioritises UHDRS TFC change and safety as primary endpoints.
Roche's tominersen (RG6042) programme in GENERATION HD2 (NCT05686551) continues to enrol, representing a redesigned attempt to deliver efficacy after the early termination of GENERATION HD1 due to safety and futility signals. The new trial applies stricter patient selection and revised dosing schedules informed by post-hoc analyses. PTC Therapeutics' votoplam (PTC518) programme in PIVOT-HD progresses, with the oral splicing modifier having demonstrated huntingtin lowering in earlier phases; the extension study (NCT06254482) continues to evaluate long-term safety and biomarker effects. A collaborative PTC Therapeutics/Novartis programme is also noted as advancing, though specific compound details remain limited.
On the regulatory front, pridopidine faces an uncertain future following the negative PROOF-HD study (NCT04556656), which failed to meet its primary endpoint. Regulatory discussions are ongoing, underscoring the difficulty of translating mechanistic rationale into clinical benefit in HD. The update also notes the launch of NAD-HD (NCT06853743), a Norwegian single-centre randomised trial of nicotinamide riboside targeting NAD+ metabolism in early-to-moderate HD over 24 months.
Key Findings
- AMT-130 gene therapy reported positive topline data at 36 months, suggesting durable huntingtin lowering in HD patients.
- FALCON-HD launches as a phase II/III trial of oral splicing modulator SKY-0515 targeting both mHTT and somatic repeat expansion via PMS1.
- Spark Therapeutics begins phase I/II trial of SPK-10001, an AAV gene therapy delivered bilaterally into the caudate and putamen.
- Tominersen continues in the redesigned GENERATION HD2 trial with stricter patient selection after GENERATION HD1 failure.
- Pridopidine faces regulatory uncertainty after the PROOF-HD trial failed to meet its primary endpoint.
Methodology
This is a narrative clinical trials update review, not a primary research study. Data are drawn from trial registrations, press releases, and conference disclosures as of October 2025. The authors compile and synthesise publicly available information on registered and ongoing HD trials globally.
Study Limitations
As a narrative update rather than a systematic review or meta-analysis, this article does not critically appraise individual trial quality or risk of bias. Many results are topline or press-release data not yet peer-reviewed. The rapidly evolving landscape means some data may be superseded quickly.
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