FDA draft guidance proposes single BLA for gene-editing therapies targeting different mutations

One application, many mutations

The draft guidance proposes an individualized feature space, or IFS, which describes the parameters for grouping variations on a product into a set of customized therapies, BioSpace reported. BMO Capital Markets analysts said in a note to investors on Thursday that the IFS would anchor a single biologics license application, or BLA, that is present across all variations, while each additional variant would need to produce predictable safety and activity.

In practice, one application could cover gene-editing therapies that address different disease-causing mutations, rather than a separate BLA for every mutation. H.C. Wainwright said in a Wednesday note that the proposal turns the FDA's plausible mechanism pathway into a "BLA blueprint." The analysts said it "converts the individualized 'product variant' concept into an operational licensing framework, with base editing the template modality."

The document is draft guidance, so the framework is not final.

Where the idea came from

Peter Marks, then director of the Center for Biologics Evaluation and Research, made the case at the American Society of Gene & Cell Therapy's 27th annual conference in May 2024. "There are a lot of nucleotides that can go wrong in the genome," he said. "I don't think we can have three billion visits to the FDA a year."

Marks said CRISPR constructs targeting the liver for a range of conditions would be "99.9% identical," which could let companies build a manufacturing platform and make therapies "in a much more facile way." Andrew Byrnes, director of the Division of Gene Therapy 1 at CBER, used a simpler image during an FDA webinar: the human genome is "a massive instruction manual with three billion letters," and a genetic disease can be caused by "a single typo" that differs between patients.

Karim Mikhail, the current CBER director, told BioSpace the guidance offers "a path for an adapted pathway for these approvals to happen in a more expeditious way."

Which companies could use it

At least two biotechs already have products in development that could benefit, BioSpace reported: Beam Therapeutics and Prime Medicine. Beam, based in Cambridge, Massachusetts, uses base editing, which changes single DNA letters without cutting through both strands of the double helix. The company is developing precision genetic medicines for diseases including alpha-1 antitrypsin deficiency, glycogen storage disease Ia and phenylketonuria, or PKU.

For PKU, Beam is developing BEAM-304 in a Phase 1/2 trial. The therapy is designed to correct mutations in the phenylalanine hydroxylase, or PAH, gene. In most Northern European populations, four specific mutations cause PKU. H.C. Wainwright sees the "potential permutations of BEAM-304's suite of guide molecules" as fitting within the draft guidance. The firm called the Phase 1/2 study's design, which covers multiple PKU-causing mutations, "a landmark development for the field."

Prime Medicine, which BMO named as another potential beneficiary, is developing genetic medicines based on prime editing.

Why platformization matters

Sadik Kassim, chief technology officer of Genomic Medicines at Danaher, said personalized therapies do not fit traditional drug-development models. Companies are seeking "platformization," he said, with common manufacturing processes standardized and limited elements such as guide RNAs customized for each patient.

Ajay Gannerkote, president of Integrated DNA Technologies, said many CRISPR therapies remain bespoke. Their manufacturing is not standardized or easily repeatable, which produces long timelines and high costs.