Researchers are finally making headway in the search for Huntington’s disease treatments after a series of demoralizing setbacks. Three new drugs with the potential to slow the progression of the devastating inherited brain disorder have chalked up clinical wins, including medicines from UniQure, Prilenia, Wave, Roche and Ionis.
Newer contenders have also taken the stage, including Vico Therapeutics, a company testing an antisense oligonucleotide, VO659, for Huntington’s in an early trial.
“We have learned a lot from others before us in the field and other clinical trials of RNA-targeting therapies that have laid a strong foundation for future next-generation therapies and give hope to the Huntington’s disease community,” said Vico CEO Micah Mackison in an email.
Some treatments now making progress faced white-knuckle moments early on. The one-and-done gene therapy AMT-130 from uniQure faced a setback in 2022 when the company temporarily paused a phase 1/2 trial after reporting serious adverse events. However, new trial results released in July showed signs the treatment is safe and might slow Huntington’s destructive march.
“We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration,” the company’s chief medical officer Dr. Walid Abi-Saab said in a written release. The company plans to explore expedited clinical development pathways and accelerated approval with the FDA and will likely release more trial data in mid-2025.
Prilena Therapeutics similarly faced adversity before announcing last week that the EMA accepted its marketing authorization application for pridopidine, a sigma-1 receptor agonist designed to protect brain neurons by clearing toxic proteins and reducing inflammation. Neuron damage triggers Huntington’s cognitive, motor and psychiatric symptoms.
The EMA acceptance came after the drug missed the primary endpoint in a phase 3 trial but showed evidence of slightly better results in patients who were not taking antipsychotics or chorea treatments at the same time. The drug could hit the European market in late 2025.
Not long ago, failures were just a way of life for drugmakers in Huntington’s. Wave Life Sciences suffered two crushing high-profile failures with its antisense drugs WVE-120101 and WVE-120102, before turning around positive data from an ongoing phase 1b/2a trial of WVE-003, a first-in-class allele-selective antisense oligonucleotide. The drug targets the toxic mutant huntingtin protein that drives the condition while preserving the healthy form.
WVE-003 appeared safe and reduced mutant protein levels 44% compared with placebo at 28 weeks while maintaining healthy protein levels. The drug also seemed to slow the rate of caudate atrophy, a type of brain damage linked with Huntington’s symptoms. Based on the results, company leaders plan to seek accelerated FDA approval.
Tominersen, from Roche and Ionis Pharmaceuticals, may also claw its way back into contention after a phase 3 trial failure in 2021. The drug didn’t improve Huntington’s symptoms and appeared to worsen them in patients who took the most frequent doses, leading the partners to yank the trial.
However, tominersen earned a second chance by showing promise in a subset of patients with early-stage disease, and Roche is testing the treatment in that group in an ongoing phase 2 trial.
A deep pipeline
Other drugs in the Huntington’s pipeline include ANX005, a humanized monoclonal antibody from Annexon Biosciences, three early-stage candidates from Medesis Pharma and the small-molecule phase 2 drug PTC-518 from PTC Therapeutics.
The biotech Vaccinex also has a drug, pepinemab, in development after a setback. Although it missed its target in phase 2, pepinemab showed signs of promise in patients who had more advanced disease at the start of the trial.
While there has been some good news, not all recent Huntington’s trial results have been favorable. Sage Therapeutics’ dalzanemdor (SAGE-718), which targets the cognitive symptoms associated with Huntington’s and other neurological diseases, has produced “underwhelming” results. The drug showed a “small numerical difference” between cognitive scores for Huntington’s patients treated with the drug versus those who took the placebo.
The company is also facing a class action lawsuit for allegedly misleading investors about the efficacy of several of its investigational treatments, including dalzanemdor, as a treatment for mild cognitive impairment for Parkinson’s Disease, but not Huntington’s.
While the search for Huntington’s treatments has faced its share of stumbling blocks, there’s still progress being made.
“Based on the work our team at Vico is doing and the research we are seeing from others in the field, the Huntington’s disease landscape looks more hopeful today than ever,” Mackison said. “Drug development is constantly a learning process, and both significant advances and setbacks provide key insights that others can incorporate into their research efforts, whether in terms of clinical trial design, endpoint development or other areas.”
