A fatal, highly hereditary illness with no disease-modifying treatments, Huntington’s is long overdue for a therapeutic win. Here, BioSpace looks at five candidates that could change the trajectory for patients.
Huntington’s disease has perplexed researchers for decades. Despite being one of the first genetic neurodegenerative illnesses for which science was able to pinpoint the causative gene, modern medicine is still searching for a disease-modifying treatment for this formidable foe.
“Here we are, decades later, and we still don’t know what to do with that information to prevent people from having decline from all the different functions of the brain and ultimately dying from the illness,” David Shprecher, movement disorder director at Banner Sun Health Research Institute, told BioSpace.
Huntington’s, which is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene, generates a triad of symptoms: motor, cognitive and behavioral. While patients can develop severe issues with anxiety and obsessive-compulsive disorder, it is complications from the motor symptoms—including difficulty swallowing and falls—that are usually the cause of death, according to Shprecher.
“The problem is we don’t fully understand why the gene mutation causes damage to the brain,” he said.
Clinical trials are another challenge, he continued, with only about 41,000 symptomatic patients in the U.S. and many not at a stage where they’re eligible to participate. Geographic barriers are also significant as most trials are conducted at major academic centers and require in-person assessments.
“There’s been a real push to use a lot more telehealth and biometric remote technology” to allow more access to these important trials, Shprecher said.
While the Huntington’s community has experienced multiple letdowns over the last four years, biopharma is not giving up. Several companies, including Prilenia Therapeutics, uniQure and Sage Therapeutics are hopeful that their approaches can make a tangible difference for patients.
Here, BioSpace reviews five investigational drugs that could change the trajectory for patients with Huntington’s disease.
Prilenia Therapeutics
Pridopidine
Prilenia Therapeutics announced in September that the European Medicines Agency has accepted its Marketing Authorisation Application for pridopidine, a “highly selective and potent” agonist of the sigma-1 receptor.
Topline results reported in April 2023 from the Phase III PROOF-HD study revealed a miss for pridopidine, which failed to meet the primary and key secondary endpoints. However, further analysis of the data showed that the candidate elicited clinically meaningful efficacy in patients not taking anti-dopaminergic and chorea medications.
The Huntington’s community had been hopeful of pridopidine’s potential to treat Parkinsonian symptoms experienced by patients, Shprecher said, as these are not addressed by any current treatments. However, he added, “there would be very few Huntington’s disease patients eligible for a trial if it excludes both of those types of medications.”
Sage Therapeutics
Dalzanemdor
Sage Therapeutics is developing dalzanemdor, a potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s. The Cambridge, Mass.–based biotech reported data in June from a small, Phase II trial in which there was a “small numerical difference” between dalzanemdor and the placebo as measured by the HD-Cognitive Assessment Battery composite score on day 28, with the company also noting that other “prespecified analyses” showed potential positive signals.
Huntington’s watchers, however, were not impressed. In a note to investors at the time, William Blair analysts called the results “underwhelming” and said they “remain cautious” on dalzanemdor and “do not view the small numerical changes as definitive” based on the results of this study.
Sage is gearing up to report data from the Phase II DIMENSION study of dalzanemdor in Huntington’s later this year, a win it needs after the drug failed to show efficacy in Alzheimer’s and Parkinson’s.
uniQure
AMT-130
Dutch biotech uniQure is developing a microRNA gene therapy, AMT-130, which is delivered deep inside the brain to inhibit the production of the mutant HTT (mHTT) protein. In July 2024, the company reported 24-month interim data from its Phase I/II trial of AMT-130 in 29 patients showing a dose-dependent slowing of disease progression.
“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,” Walid Abi-Saab, chief medical officer of uniQure, said in the press release at the time.
AMT-130 has been granted orphan drug, Fast Track and Regenerative Medicine Advanced Therapy designations from the FDA, and uniQure has scheduled a Type B meeting with the regulator for later this month to discuss the potential for an accelerated development pathway, according to its Q3 earnings report.
Wave Life Sciences
WVE-003
Wave Life Sciences is developing the first allele-specific silencing therapy for Huntington’s. An antisense oligonucleotide, WVE-003 targets a nucleotide polymorphism present on the mHTT mRNA while leaving healthy huntingtin intact.
In June 2024, Wave reported that the candidate significantly and selectively reduced levels of the mHTT protein in a Phase Ib/IIa trial. After 24 weeks, treatment with WVE-003 led to a 46% drop in mHTT levels in patients’ cerebrospinal fluid versus placebo.
While the program was initially partnered with Takeda, the larger pharma stepped back from the collaboration last month. Now taking WVE-003 forward itself, CEO Paul Bolno told BioSpace that Wave has “initiated engagement” with regulators regarding a clinical development path that could support accelerated approval.
Roche and Ionis
Tominersen
Roche and Ionis Pharmaceuticals are partnered on the development of tominersen, which is currently being studied in a Phase II clinical trial of patients with prodromal and early manifest Huntington’s disease.
In previous clinical trials, tominersen was shown to lower levels of toxic mHTT by blocking its production. The antisense oligonucleotide is administered through a lumbar puncture into the cerebrospinal fluid.
Tominersen’s development journey has not been without challenges. In March 2021, Roche discontinued a Phase III trial of the candidate in manifest Huntington’s disease after a pre-planned data review by an unblinded Independent Data Monitoring Committee. The recommendation was related to tominersen’s potential benefit/risk profile for patients, Ionis said at the time.
Roche and Ionis are going all in on Huntington’s. In addition to the mid-stage tominersen trial, Roche paid its longtime partner last year for two RNA-targeting programs targeting Huntington’s and Alzheimer’s disease.
