The FDA’s recently unveiled plausible mechanism framework may have been forged with individualized therapies in mind, but its principles are not confined to the bespoke.
Teresa Buracchio, M.D., head of the FDA’s Office of Neuroscience, told Fierce that while the framework was designed to shepherd individualized therapies toward approval, its concepts are applicable to other therapies as well. Buracchio was a co-lead for writing the FDA’s draft guidance on the new regulatory framework.
“Plausible mechanism framework and individualized therapies are not interchangeable,” Buracchio said in an interview on the sidelines of the National Organization for Rare Disorders (NORD) symposium in Arlington, Virginia on Tuesday.
“We’re talking about how you can use the principles of the plausible mechanism framework to support an approval of an individualized therapy,” she added. “But you might be able to use the principles of the plausible mechanism framework to approve other therapies.”
Originally coined as a “pathway” by FDA Commissioner Martin Makary, M.D., and outgoing FDA director of the Center for Biologics Evaluation and Research (CBER) Vinay Prasad, M.D., the term was later tweaked to a “plausible mechanism framework.” The agency made the shift because it isn’t a new designation or approval pathway that companies can apply for, but rather a set of regulatory principles being applied to reviewing customized therapies for the first time, Buracchio explained.
Her comments to Fierce offered some clarity to a confused rare disease sector rattled by high-profile regulatory drama. Prasad’s CBER recently rejected uniQure’s plan of using a natural history comparison to seek an approval for its Huntington’s disease gene therapy, AMT-130, even as such methods are part of the criteria that could enable approvals for tailored gene-editing therapies under the plausible mechanism framework.
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UniQure’s candidate targets a defined genetic cause, in the form of the HTT gene, and has shown clinical benefit in several patients—criteria that seemingly also match the requirements of the new framework.
However, during a press call in March about the rejection, a senior FDA official pointed out that AMT-130 is not a bespoke therapy, suggesting that the regulatory flexibility under the plausible mechanism policy is unique to customized therapies. The official further dismissed uniQure’s one-year randomized trial data as “stone-cold and negative,” arguing that uniQure’s comparison against external control is not trustworthy because it did not factor in potential placebo effects.
The snub raised concerns that the FDA’s policy lacks consistency and that the agency is favoring one type of therapeutic technology over the others.
The high bar for ‘large effect sizes’
The plausible mechanism framework “shouldn’t be a disadvantage” to non-individualized therapies, Buracchio said. Still, her description suggests the new framework comes with a high regulatory bar that could make drug development in certain disease areas more challenging than the others.
“We anticipate this is a situation where there’s going to be a very small number of patients, [where] you understand the disease pathophysiology very well, you know what you’re targeting in a causal pathway of the disease, that you see substantial improvements—these are going to be large effect sizes—and you’re not able to do a randomized, controlled trial,” Buracchio explained of the plausible mechanism considerations.
Because a randomized study is not feasible in this scenario, it removes the possibility that a drug developer can leverage data from just a couple of patients to get an approval to treat a population in the high thousands and hence the concern that individualized therapies might gain an unfair regulatory edge over other modalities, Buracchio argued.
Applying the same principles to uniQure, the FDA and the company disagree on whether a randomized study is feasible for AMT-130.
The slow progression of Huntington’s makes showing clear efficacy in a short window nearly impossible, creating an “ethical challenge” for keeping patients on a sham or placebo arm, David Margolin, M.D., Ph.D., uniQure’s VP of clinical development, contended during a presentation at the NORD rare disease event.
However, during the March press call, the senior FDA official maintained that the heterogeneity of Huntington’s patients and the need to filter out placebo effects demand sham controls.
A disease-data dilemma
The FDA is open to applying the plausible mechanism framework “conceptually” to Huntington’s disease broadly, or other diseases of comparable size, Buracchio said. But there’s a catch.
“I think we still need to be sure that they can meet our standards for substantial evidence of effectiveness and a substantial improvement that’s clear and distinct from the natural history of the disease,” she said.
Buracchio pointed to the case of “baby KJ,” which paved the way for the plausible mechanism framework. After receiving a bespoke CRISPR base-editing therapy for an otherwise potentially fatal metabolic disorder called carbamoyl phosphate synthetase 1 (CPS1) deficiency, KJ showed improved dietary protein tolerance and reached developmental milestones.
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By comparison, a slowly progressive neurodegenerative disease like Huntington’s “is going to be a harder case to make,” 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.”
That is exactly the argument that uniQure is trying to make to explain the lack of a treatment effect for AMT-130 among a small group of randomized U.S. Huntington’s patients at the one-year mark. However, the FDA official on the March media call flagged a seemingly contradictory result, which showed a treatment effect for AMT-130 at one year when compared with uniQure’s external control.
“Huntington’s disease can be slowly progressive,” uniQure’s Margolin said in response to a question by Fierce at the symposium. “And seeing a trend as early as one year in a 3,000, or 30,000, patient data set is a different matter than in the n of 10 in our control. I think it was just too early to see a mean change of sufficient magnitude at that point.”
The FDA and uniQure, along with Huntington’s disease organizations, are in active dialogue regarding how to interpret AMT-130’s data, Margolin added.
