As the reportedly dysfunctional U.S. Food and Drug Administration (FDA) faces demands for greater clarity in the wake of rare-disease drug denials, uniQure continues to seek a path to get AMT-130, its historically efficacious Huntington’s disease gene therapy, approved.
On March 2, after having surprisingly reneged last year on its promise to allow uniQure to apply for AMT-130 approval in 2026, the FDA “strongly recommended” that the firm conduct a new, full Phase III clinical trial.
In March, Wisconsin Sen. Ron Johnson, a Republican, launched an investigation of the FDA’s rejections of rare disease drugs. He described the FDA’s request for a new AMT-130 trial, which would include a deeply invasive sham surgery for participants not getting the actual drug, as “bureaucratic idiocy.”
In an April 1 letter, the Rare Disease Advocacy, Biotechnology, and Investor Coalition urged President Trump and top administration health officials to restore regulatory clarity at the FDA.
A new way to win approval?
A possible avenue to AMT-130 approval opened on April 14. Teresa Buracchio, M.D., head of the FDA’s Office of Neuroscience, said at the National Organization for Rare Disorders (NORD) symposium in Arlington, VA, that the agency’s “plausible mechanism framework” for approval of bespoke gene therapies might be applied “to approve other therapies.” The news site Fierce Biotech reported on the symposium.
A bespoke therapy is given to a single individual, such as “Baby KJ,” the world’s first individual to be treated with a personalized (customized) CRISPR gene editing therapy, in 2025. KJ was born with a rare metabolic disease, severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. The child is now thriving.
After FDA leaders raised the topic of individualized therapies in a November 2025 The New England Journal of Medicine article, the FDA in February issued a draft guidance for a new path to such treatments, calling it the “plausible mechanism framework.”
Dr. Buracchio observed that the framework is not specifically an approval pathway but a set of regulatory principles being applied to customized therapies for the first time, Fierce Biotech reported.
The special challenges of HD science
The Fierce Biotech article noted that Dr. Buracchio’s comments “offered some clarity to a confused rare disease sector rattled by high-profile regulatory drama.” That drama has resulted in part from uniQure’s use of patient registry data (also known as a natural history study) to analyze AMT-130, which was rejected by the FDA “even as such methods are part of the criteria that could enable approvals for tailored gene-editing therapies under the plausible mechanism framework.”
In March, the FDA had pointed out that AMT-130 is not an individualized therapy.
However, Dr. Buracchio said that the plausible mechanism framework “shouldn’t be a disadvantage” to non-individualized therapies.
Dr. Buracchio stated that the FDA is open to applying the plausible mechanism framework “conceptually” to Huntington’s disease broadly, or other diseases of comparably-sized populations.
A therapy needs to show “substantial evidence of effectiveness and a substantial improvement that’s clear and distinct from the natural history of the disease,” she said, noting that KJ demonstrated marked improvement in symptoms and reached developmental milestones.
By comparison, a slowly progressive neurodegenerative disease like HD “is going to be a harder case to make,” Dr. Buracchio said. “That’s because slowing the rate of decline is much harder. So, to me, this is less of a number issue and more of a nature of the disease issue.”
Presenting AMT-130 to the rare disease symposium
At the NORD symposium, David Margolin, M.D., Ph.D., uniQure’s vice president for clinical development, gave a presentation on AMT-130, addressing the FDA’s concerns.
As reported by Fierce Biotech, in response to the FDA’s requirement that the company run a Phase III trial and Dr. Buracchio’s point about the slowness of HD, Dr. Margolin stated that this slow progression makes it nearly impossible to show clear efficacy over a short period. This creates an “ethical challenge” when giving some patients a placebo or having them undergo the sham surgery.
As presented by Dr. Margolin at numerous conferences, including the key 21st Annual HD Therapeutics Conference in February, AMT-130 demonstrated a 75 percent slowing of HD progression over three years. (The conference is sponsored by CHDI Foundation, Inc., the largest private funder of HD research.) This was the first time that a drug has delayed HD.
Dr. David Margolin at the 2026 HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)
Enroll-HD in place of a placebo
A second Fierce Biotech article on the NORD symposium focused on how academics and biopharma leaders are breaking the mold of traditional clinical trials with creative methodologies, aiming to garner interest and support from peers and regulators.
A common approach in rare disease drug development is the use of an external control or comparator, which replaces the placebo in a classic clinical trial. As noted, instead of a sham trial, uniQure took this approach by using data from the HD patient registry, called Enroll-HD.
With more than 22,000 participants, Enroll-HD is “one of the most remarkable prospective registry trials that's ever been run,” according to CHDI Chief Scientific Officer Robert Pacifici, Ph.D.
Tracy Beth Høeg, M.D., Ph.D., the acting director of the FDA’s Center for Drug Evaluation and Research, stated at the NORD event that the agency is finalizing guidance on external controls. This, she added, will hopefully “give clarity to sponsors about what sort of evidence we would be looking for and willing to accept for approval of rare disease drugs.”
As reported by Fierce Biotech, Dr. Margolin spent much of his NORD talk on uniQure’s use of a statistical technique known as “propensity score matching.” As he explained at the Therapeutics Conference, this involves finding in Enroll-HD individuals similar to those in the uniQure trial and including them as controls. At the NORD meeting, he pointed out that the difference between AMT-130 clinical trial participants and the individuals uniQure selected from Enroll-HD was negligible.
Dr. Margolin also responded to the FDA’s criticism that one of the clinical trial measurements uniQure used for AMT-130 was too subjective, leaving the participants susceptible to a placebo effect that could not be detected when using Enroll-HD.
An ongoing dialogue with the FDA
“I know there’s active dialogue with FDA and the Huntington’s disease organizations regarding how to interpret and best utilize these clinical scored measures, and that’s an ongoing process,” Dr. Margolin stated.
Meanwhile, the HD community and its allies continue to pressure Congress and public officials to focus on HD and bring AMT-130 a fair hearing at the FDA.
Or, in the current political and business climate, perhaps the HD community also needs a vast stroke of good luck, celebrity connections, and publicity, as biotech observers have noted with dark humor.
Joe Rogan to the rescue?
On April 18, Pearl Freier, president of Cambridge Biopartners, Inc., asked on the social media platform X how the HD community could overcome an FDA rejection based on the “personal negative opinion” of FDA Commissioner Marty Makary and/or U.S. Secretary of Health and Human Services Secretary Robert F. Kennedy Jr.
She added: can the HD community make a deal with growth stage venture capital firm and prediction market company “Kalshi and/or Polymarket?”
Adam Feuerstein, the senior writer covering biotech at the essential STAT, responded to Freier’s post: “I guess people living and dying with Huntington’s disease need an influencer/podcaster to text Trump. That’s how the FDA works these days.”
Feuerstein linked to an X post detailing how popular podcaster Joe Rogan revealed how the president “IMMEDIATELY offered FDA approval for a psychedelic treatment in a text chain Because the data was SO CONVINCING and STUNNING.” The treatment is for depression and other conditions.
Finding comfort in Pope Francis’ embrace of the HD community
These are trying times for the world, with the U.S. again in a major war and world peace once again at risk. For the HD community, it is distressing that AMT-130 is rejected after seven years of clinical study by uniQure.
For comfort I remember highlights of the HD cause such as Pope Francis’ 2017 audience with HD families, declaring that the disease should be “hidden no more” and HD families respected and loved. I also look with hope to the first American head of the Church, Pope Leo XIV, who has continued Francis’ emphasis on mercy.
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