Pridopidine

iStock, wildpixel Analysts reacted positively to the news that uniQure is in alignment with the FDA on an accelerated approval pathway and on target for a Q1 2026 submission for its one-time gene therapy for Huntington’s disease—but patients have been here before. When uniQure CEO Matt Kapusta speaks to patients with Huntington’s disease, he hears a sense of “deep desperation.” Currently, people with Huntington’s—who number around 30,000 in the U.S.—are only offered drugs that can manage symptoms, which include movement abnormalities and cognitive impairment, “and those drugs really don’t work very well,” Kapusta told BioSpace . “There’s no disease-modifying treatments for them.” uniQure is hoping to change that. Last fall, the Massachusetts-based biotech announced alignment with the FDA on “key elements” of an accelerated approval pathway for AMT-130, a one-time gene therapy for Huntington’s. These elements include the use of natural history external controls as a comparator and change in the composite Unified Huntington’s Disease Rating Scale (cUHDRS) as an intermediate clinical endpoint. The cUHDRS measures the cognitive, motorial, psychiatric and behavioral symptoms of Huntington’s disease, Kapusta explained. For AMT-130, which is currently in Phase I/II studies, this would negate the need for another trial before uniQue can approval, and Stifel analysts at the time called the alignment “a best case scenario” for the company. On Monday, uniQure shared another regulatory update , communicating that it has “reached alignment with the FDA on several key components of the statistical analysis plan and chemistry, manufacturing and controls [CMC] information that will support” a biologics license application (BLA) in the first quarter of 2026. If successful, uniQure plans to launch the product before the end of next year. AMT 130 represents “the first potentially disease modifying treatment that could be available for [patients],” Kapusta said. Much of this, however, could hinge on three-year topline data which Kapusta expects to read out in September. At 24-months, a higher dose of AMT 130 slowed disease progression by 80% versus external controls, uniQure reported last July. The BLA will be based on this higher dose cohort, and the company will also analyze changes in neurofilament light—an accepted neurodegenerative biomarker—as supporting evidence. In September, Kapusta said the company will be seeking “consistency” with the two-year data. “If we’re able to demonstrate in treated patients at three years after a one-time administration of AMT 130 that there’s meaningful slowing of disease progression compared to this very closely matched external control cohort, I think that would be immensely powerful, and I think potentially supportive of a conditional approval,” he said. Typically, Kapusta said, early manifest patients—like those enrolled in uniQure’s study—lose around half a point on the cUHDRS scale per year. At two years, external controls in uniQure’s Phase I/II study had lost around one point, while patients treated with AMT 130 lost only 0.2 points. “If you extrapolate these things, what you’re really doing is you’re giving back to patients potentially years of their life, years of career development, years of weddings with their children, or birth of grandchildren, bar mitzvahs, sweet sixteens,” he said, “That’s what we’re hoping we can demonstrate in the third quarter.” uniQure’s news generated some buzz on Wall Street, with H.C. Wainwright assigning AMT-130 a 75% probability of success, “with anticipated approval in 2026E.” William Blair, meanwhile, called the regulatory update “favorable” both for uniQure and the broader gene therapy space, “as it demonstrates the FDA’s continued flexibility regarding registrational pathways for transformative therapies for rare diseases with a high unmet need.” Kapusta echoed this sentiment, saying that uniQure has not noticed a difference in terms of the company’s FDA interactions occurring before and after the administration turnover this year. “There’s still senior people that are attending our meetings from [CBER’s] office of therapeutic products . . . and we continue to see significant engagement and productive, constructive interactions with the FDA,” he added. While Kapusta said there has been a “knee jerk” reaction to past comments made by new Center for Biologics Evaluation and Research director Vinay Prasad regarding accelerated approvals, “It definitely seems that in comments he’s made to his own FDA staff, and comments that he’s made in other interactions, that he appears to be making it clear that he supports regulatory flexibility as it relates to innovative medicines in very high needs in rare diseases.” Indeed, on Tuesday, Prasad said the FDA plans to “rapidly make available” rare disease drugs, making use of surrogate endpoints to get promising medicines to patients before they clear the traditional efficacy bar for authorization. He made these remarks during a keynote speech organized by the National Organization for Rare Disorders. Prasad’s comments largely echo those of his boss. In April, during an interview with former Fox News journalist Megyn Kelly, FDA Commissioner Marty Makary introduced plans for a “conditional pathway” that would potentially allow for the approval of rare disease drugs based on a “plausible mechanism.” A Precedent of Disappointment As uniQure and analysts express optimism—albeit gaurded—the Huntington’s space has been here before, with myriad late-stage assets nearing the regulatory finish line only to falter. Five years ago, the community pinned its hopes on Roche’s antisense oligonucleotide tominersen . The ASO was designed to lower levels of the huntingtin ( HTT ) gene, particularly mutant HTT, which plays a crucial role in the development of the disease. Tominersen had shown great promise in Phase II, but in March 2021, Roche discontinued a Phase III trial of the drug after it ultimately failed to elicit higher efficacy than placebo, and actually led to worse outcomes when given more frequently. 2021 was a particularly bad year for the Huntington’s space, as Wave Life Sciences likewise shelved its two lead ASOs after they failed to elicit a therapeutic effect. But Huntington’s-focused companies aren’t giving up. Wave is back with a next-gen ASO, WVE-003, that targets a single-nucleotide polymorphism found on mutant HTT mRNA. Like uniQure, Wave is targeting accelerated approval for its candidate, having “initiated engagement” with regulators regarding a clinical development path, CEO Paul Bolno told BioSpace in November 2024. And at least on a global scale, uniQure has some competition to bring the first disease-modifying drug for Huntington’s to the market. In September 2024, Prilenia Therapeutics announced that the European Medicines Agency had accepted its marketing authorization application for pridopidine, 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. Prilenia expects an opinion from the European regulator in the second half of this year, a company spokesperson told BioSpace in November 2024. A breakthrough can’t come soon enough for patients. Huntington’s is a dominantly transmitted neurodegenerative disorder and children of HD gene carriers have a 50% chance of inheriting the disease. Kapusta described a situation in which an individual has watched the degeneration of their parent—and possibly even acted as a caregiver. “If this is a patient that has been genetically confirmed, they know it’s 100% penetrative; they’re going to develop the disease, and they’re going to have to relive that movie as the main actor,” he said. “So right now, anything for them would give them hope.”

iStock, BeritK The biotech’s Huntingtin-targeting molecule lowered blood levels of the protein and elicited functional improvements in earlier-stage patients, but results were not as robust in other biomarkers or with patients at later stages of the disease. PTC Therapeutics announced new data Monday from a Phase II trial showing that Huntington’s hopeful PTC518 could modify a key disease indicator of the disease. The data received mixed reviews, however, and shares of the biotech nose-dived. In a Monday afternoon note to investors, William Blair analysts said that a “question regarding correlation between [huntingtin] reductions and clinical benefit remains,” but added that the 24-month data should aid FDA dialogue. In the Phase II PIVOT-HD trial , PTC518 lowered blood huntingtin (HTT) protein levels by 23% at the lowest dose (5 mg) for patients with both earlier- and later-stage disease, meeting the trial’s primary endpoint. At a higher 10mg dose, patients at the early stage saw a 39% reduction, with patients at a later stage seeing a 36% drop. Patients with early-stage disease also saw functional improvements and slow-down in disease progression. PTC trumpeted the data as a huge win. “We look forward to discussions on the next development and regulatory steps including the potential for accelerated approval as we work to potentially bring the first disease-modifying therapy to those affected by Huntington’s disease,” CEO Matthew Klein said in a statement . William Blair analysts, citing data presented on the company’s follow-up call Monday, were intrigued but less enthusiastic, noting that patients with later-stage disease did not show any functional benefit on PTC518 and protein reduction in cerebrospinal fluid (CSF) was less robust in these patients. Despite the mixed results, the analysts wrote that they “believe the biomarker and clinical outcomes data at 12 and 24 months in the [earlier stage] patients are likely sufficient for productive conversations with the FDA regarding a registrational path in patients with less advanced disease.” Either way, Wall Street does not seem to be buying PTC’s new data, as the company’s stock slid about 17% by Monday afternoon after the morning announcement. Novartis, for one, appears to believe in PTC518. PTC signed a deal with the Swiss pharma late last year worth up to $2.9 billion. Under the terms of the agreement, PTC would be responsible for development through Phase II, at which point Novartis would take over. If the drug is successfully brought to market, PTC will be entitled to 40% of U.S. profits while Novartis would take 60%. PTC518 is a small molecule that includes a premature stop codon in the Huntingtin mRNA, inducing degradation by cells and lower levels of HTT protein in the cell. Mutations in this protein are thought to be the largest culprit in Huntington’s disease. Regardless of the market reaction, these biomarker data are welcome news for the Huntington’s space, which in the past five years has been beset by disappointments as Roche, Wave Life Sciences and NeuBase Therapeutics have all seen clinical failures or ceased work altogether. There have also been glimmers of light, however, with Prilenia Therapeutics’ pridopidine being accepted in November for European Marketing Authorisation Review. And Wave bounced back last summer with data showing that its next-generation antisense oligonucleotide, WVE-003, lowered HTT levels by 46% in patients’ CSF.