In a highly anticipated article, FDA officials Vinay Prasad, M.D., and Martin Makary, M.D., outlined a novel regulatory pathway that could trigger a seismic shift in how bespoke gene editing therapies are developed and approved.
The new program, called the “plausible mechanism pathway,” is designed to offer a new way to market for personalized therapies, Prasad and Makary said at the beginning of a New England Journal of Medicine article.
The pathway is expected to significantly scale the recent success of a single-patient treatment for a patient known as “baby KJ” into a widely available regulatory approach and offer new hope for accessible treatments among the estimated 300 million patients with rare genetic disorders.
The article is “light on specifics,” Kiran Musunuru, M.D., Ph.D., who was part of baby KJ’s care team and is a co-founder of gene editing biotech Verve Therapeutics, said in an emailed statement to Fierce Biotech. But its publication is important, “because it opens the door for us to request meetings with the FDA to discuss the specifics of how the new pathway might impact the development of our phenylketonuria and urea cycle disorder platforms.”
While the FDA will prioritize rare diseases—especially those that are fatal or associated with severe childhood disabilities—the pathway will also be available for common diseases, particularly those for which there’s no alternative treatments or where considerable unmet need exists, the two officials wrote. One of the guiding principles, according to the FDA leaders, is that only diseases for which the biological cause is known will be eligible for the pathway.
Health officials including FDA Commissioner Makary and Center for Biologics Evaluation and Research Director Prasad have openly voiced support for the development of novel cell and gene therapies. However, several recent negative FDA decisions have put a damper on optimism in the field. The new pathway represents a major move that may boost enthusiasm in developing these novel therapies.
“The FDA will work as a partner and guide in ushering these therapies to market, and our regulatory strategies will evolve to match the pace of scientific advances,” Prasad and Makary said at the end of the article.
In a nutshell, the pathway will enable marketing approvals for individualized therapies that have established a plausible biological mechanism.
The case of baby KJ offered justification for the pathway, the FDA officials noted.
Baby KJ, a male newborn, was diagnosed with a severe form of carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an inherited rare disorder that causes an inability to process protein during digestion, potentially leading to serious brain damage and death. In baby KJ’s case, mutations in CPS1 were identified as the cause of the disease, thereby offering what the FDA officials called a “specific molecular or cellular abnormality.”
To address the underlying cause, researchers at the Children’s Hospital of Philadelphia and the University of Pennsylvania developed a customized therapy with CRISPR gene editing technology.
To get an FDA go-ahead to treat baby KJ, the care team “relied on a well-characterized natural history of the disease in the untreated population,” Prasad and Makary noted in their article.
Using baby KJ as an example, the two FDA leaders suggested an approval under the “plausible mechanism pathway” must provide some confirmation that the drug successfully addressed its target. In baby KJ’s case, the agency relied on mouse models showing successful editing in 42% of liver cells.
The FDA said it will embrace “nonanimal models” where possible after acknowledging that sometimes a human biopsy may not be appropriate.
“The FDA is open to considering successful target editing for a subset of patients and, in select cases, simply the first-in-class subject dosed,” according to the article.
Finally, an improvement in clinical outcomes is required, and that means strong enough data to “exclude regression to the mean,” the officials said. Prior experience will serve as the benchmark, and the FDA may also accept patients as their own controls in some cases.
“Once a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, the FDA will move toward granting marketing authorization for the product,” the article reads. “Manufacturers will then be able to leverage platform data from such personalized products to gain marketing approval for similar products in additional conditions.”
Depending on the specific evidence provided, the FDA may offer either an accelerated approval or the regular approval.
Once approved, the drugmaker will be asked to perform post-marketing collection of real-world evidence to confirm efficacy and the absence of off-target edits or other unexpected safety signals.
The FDA is rolling out the pathway after realizing that the traditional model of drug development, in which a single drug is tested in a large patient population through a randomized clinical trial, is not feasible to accommodate individualized gene editing therapies.
Besides, pursuing one-off compassionate-use single-patient applications such as that for baby KJ “would be a disservice to the rare disease community,” Musunuru and his collaborator Rebecca Ahrens-Nicklas, M.D., Ph.D., said in a recent article in the American Journal of Human Genetics detailing their interactions with the FDA on baby KJ’s treatment.
With this new approach, the agency is essentially shifting the regulatory focus from approving each individual drug to clearing the therapeutic platform for some individualized treatments based on the same technology. The FDA is also moving from parsing over onerous efficacy studies to assessing the treatment’s underlying science and its immediate biological effect, thereby significantly reducing the burden to provide evidence for each product.
In Prasad and Makary’s words, the agency will grant approvals where “pharmacologic effect is aligned with biologic plausibility and congruent with observed clinical outcomes.”
In a statement, the Alliance for Regenerative Medicine said the cell and gene therapy association “enthusiastically welcomes the FDA’s new pathway,” saying the modernization of the FDA’s regulatory approach will benefit patients and help the U.S. biotech sector keep pace with growing competition from China.
“We encourage the FDA to drive the execution of this vision with formal guidance that will enable its implementation with consistency, clarity and appropriate oversight so that the story of baby KJ becomes commonplace rather than extraordinary,” the organization said.
“FDA intends to issue joint CBER-CDER guidance for the plausible mechanism pathway,” a Department of Health & Human Services spokesperson said in a statement to Fierce Biotech, referring to the FDA’s two drug-reviewing bodies.
While acknowledging in their article that the policy was designed from the perspective of cell and gene therapies, which fall within CBER's domain, Prasad and Makary said there’s “no reason that such principles will not also extend to other drugs over time.” However, based on the above criteria, it’s difficult to envision any other existing therapies being eligible for the pathway.
Baby KJ’s care team and ARM aren’t the only ones looking for more guidance from the agency about the new pathway. In a Thursday note to clients, William Blair analysts also suggested that “the application of the pathway, particularly beyond rare and ultra-rare diseases is a bit more unclear.”
The analysts raised the example of CAR-T therapies being developed for autoimmune diseases, suggesting that developers in this space could pursue the pathway if the FDA considers pathogenic B-cells the underlying cause of disease. However, patients may present different autoantibodies, and it’s unclear if different autoantibodies would be considered as different underlying biological causes of disease, the team noted.
What’s more, the principles of the pathway for individualized therapies seems to run against the FDA’s apparent about-face with uniQure’s Huntington’s disease gene therapy candidate. In a recent shock to the gene therapy world, uniQure recently said that the FDA no longer agrees that data from a phase 1/2 study of the gene therapy, coded AMT-130, based on an external control comparison are enough to support a regulatory application for an accelerated approval.
The investigational therapy is meant for a rare indication with a high unmet need and is designed to target the defined biological cause of the disease, namely, to silence the HTT gene.
“It has shared natural history data demonstrating the natural course of the disease untreated, confirmed target engagement in animal models, and demonstrated clinical benefit in several consecutive patients, seemingly meeting all the criteria of the plausible mechanism pathway,” the William Blair analysts noted.
“[W]hile we view the development positively overall and anticipate near-term effects to include faster de-risking of cell and gene platforms,” the team wrote, “we look forward to more detailed guidance on the pathway to better determine its impact on the cell and gene therapy names under our coverage.”
Editor's Note: The story was updated Nov. 13 at noon ET to include a statement from HHS and information from a note by analysts with William Blair.
Join us at the “Cell & Gene’s Turning Point: Lessons Learned & the Road Ahead” virtual event on Thursday, November 20. In one of the sessions, Fierce Pharma Deputy Editor Angus Liu will host industry experts from the Alliance for Regenerative Medicine, Bristol Myers Squibb, Cellares, and Epicrispr Biotechnologies to discuss how the new FDA views cell and gene therapies and expectations for the future.