The past four years have brought disappointment for the Huntington’s community, but optimism is growing as companies including Prilenia and Wave Life Sciences eye paths to approval of therapies that could address the underlying cause of the disease.
Thirty years after the discovery of the huntingtin gene—and following several high-profile failures—a new crop of Huntington’s disease therapies is nearing the R&D finish line, all aiming to be the first disease-modifying treatment for this intractable, and ultimately fatal, disease.
While symptomatic treatments exist to treat Huntington’s, which is caused by a CAG repeat in the first exon of the huntingtin (HTT) gene, patients are still waiting for the type of breakthrough seen recently in another neurodegenerative disease, Alzheimer’s. Unfortunately, work toward this goal has hit notable potholes and dead ends, with clinical disappointments for Roche and Wave Life Sciences as well as an axed program from NeuBase Therapeutics and the shuttering of Huntington’s-focused Triplet Therapeutics.
But now, after decades of trial and error, the space appears to be gaining momentum. Wave, along with Prilenia Therapeutics and uniQure, are all charting out a pathway to regulatory approval, while PTC Therapeutics, Sage Therapeutics and Roche and Ionis are moving forward with mid-stage clinical trials.
“I think it’s very encouraging, really healthy,” Ignacio Munoz-Sanjuan, chairman of Rumi Scientific and president of the Huntington’s-focused non-profit Factor-H, said of the current R&D pipeline.
The Long Road for Huntington’s
Thirty years may sound like a long time, but Munoz-Sanjuan noted that “we haven’t been particularly successful” at developing disease-modifying therapies for neurodegenerative disorders. So the apparent lack of progress in Huntington’s, he said, is “probably true for most genetic disorders of the nervous system.”
This has only recently begun to change, he told BioSpace, pointing to the approvals of Biogen and Ionis’ Spinraza and Novartis’ Zolgensma in spinal muscular atrophy and Biogen and Ionis’ Qalsody for SOD1-amyotrophic lateral sclerosis (ALS) —both diseases with genetic underpinnings.
Paul Bolno, president and CEO of Wave, concurred, adding that “the translation from understanding what drives pathology to ultimately developing therapeutics that interrogate that is often . . . in some ways a long road. You need the convergence of the understanding of genetics, and you need the convergence of the technology with which to interrogate that.”
A Pathway to Approval
In September, Prilenia announced that the European Medicines Agency had accepted its marketing authorization application for pridopidine in Huntington’s disease. Prilenia’s submission is the first for an investigational drug with the potential to impact Huntington’s measures of clinical disease progression, according to the company’s press release. Prilenia expects an opinion from the Committee for Medicinal Products for Human Use in the second half of 2025, according to a company spokesperson.
As for the FDA, the spokesperson told BioSpace in an email that the company “remain[s] in an ongoing dialogue with them and hope to be meeting with them in the near future to understand how they view the potential pathways forward.”
Pridopidine is a “highly selective and potent” agonist of the sigma-1 receptor, which is highly expressed in the brain and spinal cord and regulates several key processes that are commonly impaired in neurodegenerative diseases.
In April 2023, Prilenia shared that pridopidine missed the primary endpoint in the Phase III PROOF-HD study, failing to reach statistical significance on the Unified Huntington Disease Rating Scale-Total Functional Capacity scale. However, a prespecified analysis that excluded participants taking anti-dopaminergic drugs and chorea medications showed “clinically meaningful and nominally significant benefits” with pridopidine.
“When we looked then at those off of anti-dopaminergics, then we got a very different picture,” Prilenia CEO Michael Hayden previously told BioSpace. In terms of total functional capacity, this subgroup of patients remained stable for at least a year, and as for motor function and cognition, “we saw improvement,” he said. “That was exciting because no [Huntington’s] drug had ever shown improvement in any of these functions.”
Munoz-Sanjuan suggested that the EMA might request another Phase III trial before approving pridopidine. “We’ll see how the regulatory agencies respond to such a restricted group of people,” he said.
Meanwhile, Bolno said Wave has “initiated engagement” with regulators regarding a clinical development path that could support accelerated approval for WVE-003, a potentially first-in-class antisense oligonucleotide that targets a single nucleotide polymorphism found on mutant HTT mRNA. Wave has “lean[ed] on a lot of growth in the field of oligonucleotides,” to develop the first allele specific silencing therapy for Huntington’s, he told BioSpace.
In June 2024, Wave announced that WVE-003 significantly and selectively reduced levels of the mutant HTT protein in a Phase Ib/IIa trial. After 24 weeks, the therapy elicited a 46% drop in mutant HTT levels in patients’ cerebrospinal fluid versus placebo. WVE-003 also preserved wildtype HTT levels throughout the 28-week assessment period.
“I think [we’re having] an impressive impact on engaging the target,” Bolno said. This is important because “when we think about accelerated approval, the first step is you’ve got to show that your therapeutic engages the target [mutant HTT].”
Additionally, Wave demonstrated the first-ever data showing a correlation between the reduction in mutant HTT and slowing of atrophy in the caudate nucleus, a feature of Huntington’s detected on imaging, Bolno said.
He pointed to recent data showing that “for the first time now you can look at changing caudate with clinical outcome measurements.” This type of correlation is a key factor for the FDA accelerated approval, which is granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit.
“If we could use clinical imaging as a surrogate, I think we can expedite medicines that are disease-modifying for Huntington’s patients very quickly,” Bolno said.
Like Wave, uniQure is moving forward in the regulatory process for its gene therapy AMT-130, announcing in its Q3 earnings report last week that it has scheduled a Type B meeting with FDA for later this month to discuss the potential for an accelerated development pathway.
After failing to impress investors with Phase I/II data for the candidate in December 2023, uniQure rebounded in July with updated data from the study showing that AMT-130 significantly slowed the progression of Huntington’s disease in a dose-dependent manner. After 24 months of observation, a higher dose of the gene therapy slowed disease progression by 80% relative to the external controls, according to uniQure.
AMT-130 also elicited a significant reduction level of neurofilament light chain—a key marker in neurodegenerative diseases—which dropped by 11% in patients’ cerebrospinal fluid, compared with the external controls. These results nabbed AMT-130 the first-ever Regenerative Medicine Advanced Therapy (RMAT) designation for Huntington’s disease, which comes with the opportunity for the Type B meeting with the FDA.
And the Huntington’s pipeline doesn’t end there. In June 2024, PTC Therapeutics reported positive interim results from a Phase II study of PTC518, a small molecule based on the biotech’s 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 potentially first-in-class positive allosteric modulator of the NMDA receptor, for cognitive impairment associated with Huntington’s. As the company recently halted dalzanemdor’s development in Alzheimer’s and Parkinson’s, Sage is banking on early data in Huntington’s expected later this year.
The Ideal Huntington’s Therapy
Munoz-Sanjuan said that the programs targeting the HTT protein are “receiving a lot of excitement.”
In terms of an ideal therapy for Huntington’s, he said preferential lowering of mHTT and broad distribution throughout the brain are key. “You’re going to see that each one of these modalities and routes of administration has disadvantages compared to the ideal profile,” he said. “An ideal profile will be an oral drug that lowers mutant huntingtin selectively. That doesn’t exist today.”
When it comes to leveraging the accelerated approval pathway for Huntington’s, Munoz-Sanjuan was supportive but urged caution. “We need to make sure that these therapies are really safe if we don’t want to be in a situation like some of the Alzheimer’s drugs where there’s a lot of reported side effects, including deaths that [were] maybe worse . . . than what the trials actually initially reported,” he said. Ultimately, Munoz-Sanjuan said, “I think the field has advanced a lot in the last decade.”
Bolno agreed. “I do think we’re on the precipice.”
