Former biologics boss Peter Marks had a vision. With the FDA’s latest draft guidance, it’s coming to fruition. Speaking with BioSpace, current CBER leader Karim Mikhail said the “adapted pathway” is designed to develop personalized gene therapies more quickly.
With new draft guidance for the regulation of gene-edited therapies, the FDA has taken a concrete step toward delivering on its promise to expedite the approval of individualized genetic medicines—a promise that has been a long time coming. In fact, it was a vision described by former biologics boss Peter Marks in 2024.
Speaking at the American Society of Gene & Cell Therapy’s 27th annual conference in May of that year, Marks said that one advantage of CRISPR-based therapies is that companies could make many different products that all target different mutations in the same gene, and the FDA could theoretically come up with regulatory processes to simplify the approvals for such groups of therapies.
“There are a lot of nucleotides that can go wrong in the genome. I don’t think we can have three billion visits to the FDA a year,” he joked. “So we’ll have to figure this out.”
“CRISPR constructs can target the liver for a range of conditions, which would be “99.9% identical,” said Marks, who served as director of the Center for Biologics Evaluation and Research (CBER) until he was ousted from the role less than a year after speaking at the conference. That means, he said, you could create a platform that allows you to manufacture CRISPR-based therapies “in a much more facile way.”
Two and a half years later, the FDA has released draft guidance to do just that—streamline biologics license applications (BLAs) to bring personalized gene therapies to patients faster.
“It offers a path for an adapted pathway for these approvals to happen in a more expeditious way,” current CBER Director Karim Mikhail told BioSpace on Friday. Mikhail officially took the top spot at the FDA’s biologics unit in September after serving in the role in an acting capacity for the previous several months.
H.C. Wainwright described it as the FDA turning its plausible mechanism pathway into a “BLA blueprint.” Specifically, the guidance outlines how one regulatory application could cover gene-editing therapies addressing various disease-causing mutations, with the goal of enabling faster access for patients in need.
“Think of the human genome as a massive instruction manual with three billion letters,” Andrew Byrnes, director of the Division of Gene Therapy 1 at CBER, said during an FDA webinar discussing the new guidance. “A genetic disease can be caused by a single typo in these instructions, and different patients with that disease may have different typos.”
The draft guidance proposes the use of a new concept called the individualized feature space (IFS), which describes the parameters for variations on a product to be lumped together as part of a set of customized products.
“The core premise is to create a faster and more efficient access with a consistent ‘individualized feature space’ (IFS) that serves as an anchor for a single BLA . . . that is present across all variations, where each additional variant would need to produce predictable safety and activity,” BMO Capital Markets analysts said in a note to investors on Thursday.
At least two biotechs already have products in development that could benefit from this regulatory approach: Beam Therapeutics and Prime Medicine.
Early beneficiaries of the plug-and-play model
Located in Cambridge, Mass., Beam leverages base editing technology, which allows therapies to change single DNA letters directly without cutting through both strands of the double helix, avoiding potentially harmful mutations and cell stress. Beam is using this approach to develop precision genetic medicines for diseases including alpha-1 antitrypsin deficiency (AATD), glycogen storage disease Ia and phenylketonuria (PKU).
The new draft guidance “converts the individualized ‘product variant’ concept into an operational licensing framework, with base editing the template modality,” H.C. Wainwright said in a Wednesday note to investors.
For PKU, Beam is developing BEAM-304, currently in a Phase 1/2 trial and designed to correct mutations in the phenylalanine hydroxylase (PAH) gene that cause the disease. In most Northern European populations, there are four specific mutations that cause PKU.
H.C. Wainwright sees the “potential permutations of BEAM-304’s suite of guide molecules” as fitting within the FDA’s draft guidance. “We view the design of the Phase 1/2 study encompassing multiple PKU-causing mutations as a landmark development for the field and prudent for Beam’s base editing therapeutics development in diseases with multiple disease-causing mutations,” the analysts wrote.
Another potential beneficiary of the FDA’s new framework is Prime Medicine, BMO said on Thursday. The biotech is developing genetic medicines based on prime editing, which, like base editing, avoid double-strand breaks cuts to enable high-precision changes to the DNA.
Prime’s platform-based approach “is poised to benefit,” the analysts continued, particularly in Wilson disease, for which the company is developing PM577a for variants of the disease caused by an H1069Q mutation in the ATP7B gene—the most common causative mutation of the progressive genetic disorder in North America and Europe, according to Prime. The asset, which is intended as a one-time treatment to correct this mutation, is currently in a Phase 1/2 trial.
“PM577a targets H1069Q and follow-on editors could address other ATP7B variants using largely common delivery and editing components,” BMO said. “FDA’s draft guidance could provide an important regulatory tailwind for Prime Medicine by allowing subsequent mutation-specific editors to rely primarily on laboratory evidence once a shared platform and clinically predictive acceptance criteria are established.”
The FDA’s concept could extend much further than Beam and Prime in the future. As Mikhail noted, researchers are uncovering new mutations every day.
“The pace of the innovation in the science is incredible,” Mikhail said. “In gene therapy, you have eight to 10 mutations being discovered a week.”
A unified rare disease journey
Over the last two years, through unprecedented FDA turnover, rare disease has been a primary focus at CBER. Marks had long championed regulatory innovation to support the advancement of gene therapies, overseeing the approvals of Novartis’ spinal muscular atrophy gene therapy Zolgensma, Sarepta’s Duchenne muscular dystrophy gene therapy Elevidys and Vertex and CRISPR Therapeutics’ Casgevy for sickle cell disease.
After Marks resigned in March 2025, Vinay Prasad took the reins in May, and alongside then FDA Commissioner Marty Makary, developed a new regulatory pathway for rare disease drugs, allowing for their conditional approval based on a “scientifically plausible mechanism.” This initiative moved down the field another yard in November last year, when Makary and Prasad further elucidated the pathway in an article in The New England Journal of Medicine.
Makary and Prasad both left the agency in the spring, and a new set of leaders have picked up the torch. Acting commissioner Kyle Diamantas alongside Mikhail and Michael Davis as director of the Center for Drug Evaluation and Research introduced the Rare Disease Framework Initiative, aimed at standardizing the agency’s approach to scientific evidence in this space.
“We’ll be standing up the work streams pretty aggressively on a rapid timeline,” Davis told BioSpace on Friday, adding that time is of the essence. During a public meeting this week to discuss the framework, he added, “you could hear from patients and families that they can’t wait.”
