Thirty years after the discovery of the huntingtin gene, the field of Huntington's disease therapeutics is experiencing renewed momentum, with several companies vying to bring the first disease-modifying treatment to market. Despite previous high-profile failures, a new wave of therapies from companies like Wave Life Sciences, Prilenia Therapeutics, and uniQure are showing promise and charting paths toward regulatory approval.
The Long and Winding Road
Ignacio Munoz-Sanjuan, chairman of Rumi Scientific and president of Factor-H, noted the historical challenges in developing disease-modifying therapies for neurodegenerative disorders. He highlighted recent successes in genetically-driven diseases like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) with therapies like Biogen and Ionis’ Spinraza and Qalsody, and Novartis’ Zolgensma, as encouraging precedents.
Paul Bolno, president and CEO of Wave, emphasized the convergence of genetic understanding and therapeutic technology as crucial for progress. "The translation from understanding what drives pathology to ultimately developing therapeutics that interrogate that is often . . . in some ways a long road," he said.
Potential Breakthroughs on the Horizon
Prilenia Therapeutics is leading the charge with its marketing authorization application for pridopidine accepted by the European Medicines Agency (EMA). The company anticipates an opinion from the Committee for Medicinal Products for Human Use in the second half of 2025. Pridopidine, a selective sigma-1 receptor agonist, aims to modulate key processes impaired in neurodegenerative diseases.
While pridopidine missed its primary endpoint in the Phase III PROOF-HD study, a pre-specified analysis excluding patients on anti-dopaminergic drugs showed "clinically meaningful and nominally significant benefits," according to Prilenia CEO Michael Hayden. Specifically, this subgroup of patients experienced stabilization in total functional capacity and improvements in motor function and cognition.
Wave Life Sciences is also making strides with WVE-003, an antisense oligonucleotide targeting a single nucleotide polymorphism on mutant HTT mRNA. In a Phase Ib/IIa trial, WVE-003 demonstrated a 46% reduction in mutant HTT levels in patients' cerebrospinal fluid after 24 weeks, while preserving wildtype HTT levels. Wave has initiated engagement with regulators regarding a clinical development path that could support accelerated approval.
"I think [we’re having] an impressive impact on engaging the target," Bolno said, highlighting the importance of target engagement for accelerated approval. Wave also presented data showing a correlation between the reduction in mutant HTT and slowing of atrophy in the caudate nucleus, a key feature of Huntington's disease.
uniQure is advancing its gene therapy AMT-130, with a Type B meeting scheduled with the FDA to discuss the potential for an accelerated development pathway. Updated Phase I/II data revealed that AMT-130 significantly slowed the progression of Huntington's disease in a dose-dependent manner, with an 80% slowing of disease progression after 24 months at a higher dose, relative to external controls. AMT-130 also elicited an 11% reduction in neurofilament light chain levels in patients' cerebrospinal fluid, earning it the first Regenerative Medicine Advanced Therapy (RMAT) designation for Huntington's disease.
Other Promising Avenues
Beyond these frontrunners, other companies are exploring various approaches. PTC Therapeutics reported positive interim results from a Phase II study of PTC518, a small molecule based on its splicing platform. Roche and Ionis Therapeutics are collaborating on tominersen, an antisense oligonucleotide designed to reduce the production of all forms of the HTT protein. Sage Therapeutics is developing dalzanemdor, a positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington's, though its development in Alzheimer's and Parkinson's has been halted.
The Ideal Therapy
Munoz-Sanjuan emphasized the importance of preferential lowering of mutant HTT and broad distribution throughout the brain for an ideal Huntington's therapy. He noted that current modalities and routes of administration each have disadvantages compared to this ideal profile, which would be an oral drug that selectively lowers mutant huntingtin.
While supportive of leveraging the accelerated approval pathway, Munoz-Sanjuan urged caution to ensure the safety of new therapies. Bolno concurred, stating, "I do think we’re on the precipice."
