Huntington's disease (HD), a formidable neurodegenerative illness caused by a CAG repeat in the huntingtin (HTT) gene, continues to challenge researchers despite decades of investigation. While the causative gene was identified early, disease-modifying treatments remain elusive. Several companies are actively pursuing innovative therapies to address the motor, cognitive, and behavioral symptoms of HD.
Prilenia Therapeutics: Pridopidine and Sigma-1 Receptor Modulation
Prilenia Therapeutics is advancing pridopidine, a highly selective and potent agonist of the sigma-1 receptor. The European Medicines Agency is currently reviewing its Marketing Authorisation Application. While Phase III PROOF-HD study results missed primary and key secondary endpoints, further analysis revealed clinically meaningful efficacy in patients not taking anti-dopaminergic and chorea medications. According to David Shprecher, movement disorder director at Banner Sun Health Research Institute, the Huntington’s community hoped pridopidine could treat Parkinsonian symptoms, which current treatments do not address. However, he noted that excluding patients on anti-dopaminergic and chorea medications would significantly limit trial eligibility.
Sage Therapeutics: Dalzanemdor Targeting Cognitive Impairment
Sage Therapeutics is developing dalzanemdor, a potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s disease. Phase II trial data showed a small numerical difference between dalzanemdor and placebo in the HD-Cognitive Assessment Battery composite score on day 28. William Blair analysts described the results as "underwhelming" and remain cautious about dalzanemdor. Sage is preparing to report data from the Phase II DIMENSION study in Huntington’s later this year, following previous failures in Alzheimer’s and Parkinson’s disease.
uniQure: AMT-130 Gene Therapy for Mutant HTT Silencing
uniQure, a Dutch biotech company, is developing AMT-130, a microRNA gene therapy designed to inhibit the production of the mutant HTT (mHTT) protein. Interim 24-month data from its Phase I/II trial in 29 patients demonstrated a dose-dependent slowing of disease progression. Walid Abi-Saab, chief medical officer of uniQure, stated that this is the first clinical trial to show evidence of potential long-term clinical benefit and reduction of a key marker of neurodegeneration. The FDA has granted AMT-130 orphan drug, Fast Track, and Regenerative Medicine Advanced Therapy designations. uniQure is scheduled to meet with the FDA to discuss the potential for an accelerated development pathway.
Wave Life Sciences: WVE-003 Allele-Specific Silencing
Wave Life Sciences is developing WVE-003, the first allele-specific silencing therapy for Huntington’s disease. This antisense oligonucleotide targets a nucleotide polymorphism present on the mHTT mRNA while sparing healthy huntingtin. Phase Ib/IIa trial data showed that WVE-003 led to a 46% reduction in mHTT levels in patients’ cerebrospinal fluid after 24 weeks compared to placebo. While Takeda stepped back from the collaboration, Wave Life Sciences CEO Paul Bolno stated that the company has initiated engagement with regulators regarding a clinical development path that could support accelerated approval.
Roche and Ionis: Tominersen and RNA-Targeting Programs
Roche and Ionis Pharmaceuticals are collaborating on the development of tominersen, currently in a Phase II clinical trial for patients with prodromal and early manifest Huntington’s disease. Tominersen has been shown to lower levels of toxic mHTT by blocking its production. The antisense oligonucleotide is administered via lumbar puncture into the cerebrospinal fluid. In March 2021, a Phase III trial of tominersen in manifest Huntington’s disease was discontinued due to its potential benefit/risk profile. Roche and Ionis are also working on two RNA-targeting programs for Huntington’s and Alzheimer’s disease.
