More than 1,300 researchers, clinicians, and community members gathered in Kraków, Poland, for the 2026 Clinical Research Congress of the European Huntington’s Disease Network. HDBuzz reported on new human clinical trial updates for Huntington’s disease, highlighting progress in protein-lowering therapies alongside recent setbacks in late-stage trials.
Following introductory sessions on laboratory-stage drug discovery, the European Huntington’s Disease Network (EHDN) congress turned its attention toward active human trials. Investigators weighed early-stage efficacy signals against trial failures, showing the demanding validation pathway required for neurodegenerative therapeutics.
New Drugs Aim to Reduce Toxic Huntingtin Levels
- Huntingtin Suppression: Several new drugs aim to reduce levels of the toxic huntingtin protein responsible for cellular degeneration in Huntington’s disease.
- Diverse Delivery Methods: Experimental therapies span various administration routes, including lumbar punctures into spinal fluid, oral splice-modulating pills, and direct neurosurgical gene therapy.
Advancing RNA Interference With Brezosiran
Sarah Tabrizi outlined plans from Alnylam to advance brezosiran—formerly designated as ALN-HTT02—directly into a registrational Phase 3 trial in 2027 following encouraging early clinical data, HDBuzz reported. Brezosiran utilizes RNA interference to suppress the production of both full-length huntingtin and HTT1a, a shorter RNA variant implicated in Huntington’s pathology.
Einige dieser Präparate werden durch eine Injektion in den Wirbelkanal direkt in die Liquorflüssigkeit verabreicht, welche Gehirn und Rückenmark umschließt, während andere einen operativen Eingriff erfordern, um Gentherapieansätze in das Gehirngewebe zu bringen. Initial clinical findings demonstrated reductions of the mutant huntingtin protein in cerebrospinal fluid by up to approximately 64 percent, accompanied by an encouraging safety profile.
Zu den besonders beachtenswerten Berichten zählte jener von Sarah Tabrizi, welche im Auftrage von Alnylam ankündigte, Brezosiran nach vielversprechenden ersten klinischen Daten im Jahr 2027 unmittelbar in eine zulassungsentscheidende Phase-3-Untersuchung überzuführen.
Targeting Mutant CAG Repeats With VO659
Scott Schobel presented clinical updates on VO659, an antisense oligonucleotide engineered by VICO Therapeutics to target the expanded CAG repeat sequence within the huntingtin mRNA transcript selectively. Unlike therapies that suppress both wild-type and mutant proteins, this selective strategy seeks to preserve normal huntingtin functions vital for cellular homeostasis.
The ongoing trial evaluates participants with Huntington’s disease alongside individuals with spinocerebellar ataxia types 1 and 3 (SCA1 and SCA3).
Oral Splice Modulators Alter RNA Processing
Researchers showcased two distinct oral splice modulators capable of altering RNA processing prior to protein translation. Meghan Miller presented findings on SKY-0515 from Skyhawk Therapeutics, a small-molecule drug that suppresses huntingtin alongside PMS1, a DNA repair protein involved in somatic expansion of CAG repeats over time.
Data spanning roughly 15 months revealed favorable trends compared to external participants in the Enroll-HD observational study, though researchers emphasized the small cohort size. SKY-0515 is advancing into the Phase 2/3 FALCON-HD program to establish definitive efficacy against placebo controls.
Concurrently, Beth Borowsky shared data on Novartis-developed votoplam, formerly known as PTC518. Phase 2 PIVOT-HD trial results demonstrated approximately 20 percent reduction in mutant huntingtin alongside two-year open-label extension data. However, investigators noted dose-dependent ventricular enlargement on neuroimaging, necessitating rigorous monitoring as the drug enters the Phase 3 INVEST-HD program.
| Therapeutic Candidate | Mechanism of Action | Route of Administration | Primary Clinical Status |
|---|---|---|---|
| Brezosiran (ALN-HTT02) | RNA Interference (RNAi) | Int intrathecal injection | Preparing for Phase 3 (2027) |
| VO659 | Antisense Oligonucleotide (ASO) | Intrathecal injection | Ongoing Phase 1/2 trials |
| SKY-0515 | Oral Spleice Modulator / PMS1 | Oral tablet | Entering FALCON-HD Phase 2/3 |
| Votoplam (PTC518) | Oral Splicing Modulator | Oral tablet | Advancing to INVEST-HD Phase 3 |
David Hawellek detailed results from the GENERATION HD2 Phase 2 trial of tominersen, an antisense oligonucleotide developed by Roche. The intervention achieved an approximate 30 percent reduction of mutant huntingtin in cerebrospinal fluid alongside late-stage improvements in neurofilament light (NfL) concentrations, a biological indicator of axonal injury.
Despite these favorable pharmacodynamic shifts, the study failed to demonstrate statistically significant improvements across standard functional measures, including Total Functional Capacity and the composite Unified Huntington’s Disease Rating Scale (cUHDRS).
Anhand von motorischen Testverfahren, die unter dem Sammelbegriff Q-Motor zusammengefasst werden, zeigte David Margolin ergänzende Auswertungen der Nachbeobachtung bei jenen Probanden, welche die höhere Dosierung erhalten hatten. While high-dose cohorts (N=17) displayed encouraging motor performance trends relative to external controls, investigators continue to evaluate the long-term safety and procedural variables of surgical intervention.
Consult Neurologists Regarding Clinical Trial Eligibility
As clinical programs transition into advanced regulatory phases, researchers stress that trial participation remains strictly regulated by inclusion and exclusion criteria designed to protect patient safety. Families are encouraged to consult clinical trial registries and treating neurologists to understand eligibility requirements for ongoing Phase 2 and Phase 3 evaluations.
References
- European Huntington’s Disease Network (EHDN). Clinical Research Congress 2026 Proceedings. Kraków, Poland.
- Tabrizi, S. et al. RNA interference therapeutics targeting mutant huntingtin expression in neurodegenerative disease.
- Hawellek, D. et al. GENERATION HD2 Phase 2 Clinical Trial Results on Tominersen Pharmacodynamics and Biomarkers.
