Adam Lee, MS
Thermo Fisher Scientific
United States

Kevin Bosse, PhD
Nationwide Children’s Hospital
United States

A Look at the FDA's New Plausible Mechanism Pathway for Bespoke Therapies

Top FDA officials, Vinay Prasad and Martin Makary, authored an article in the New England Journal of Medicine discussing a new plausible mechanism pathway for bespoke, personalized therapies. Inspired by the recent case study of Baby K.J., a male neonate with carbamoyl-phosphate synthetase 1 (CPS1) deficiency, and the first patient to receive a personalized CRISPR gene-editing therapy, the FDA aims to facilitate the development and approval of future single-patient medicine.

The paper states that “…the FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view.” This direction is an applicable step to the modernization of the FDA’s regulatory approach and shows the appropriate adaptability sometimes needed for cell and gene therapies.  An optimistic viewpoint of the article would suggest that this can only streamline specific therapies for certain patients and heavily implies that the FDA is openly willing to work with sponsors on personalized therapies.

While the paper was written by FDA officials, there is still no timeline for a draft guidance that outlines specifics regarding this new pathway. Still, several aspects of Baby K.J.’s story are highlighted to illustrate the tenets of the FDA’s novel plausible mechanism pathway: Identification of the specific biological cause, the therapy addresses the root cause, the disease is well characterized, and the tolerance of the risk by regulators being dependent on the disease severity and the therapeutic benefit.  In the article’s context, mechanistic plausibility, target engagement, and natural-history anchoring provide the evidentiary structure for FDA decision-making. These aspects potentially foreshadow what a future guidance document might require for this kind of pathway. Importantly, platform designation is only offered to companies with approved products. The article suggests that that may not be necessary for the plausible mechanism described.

An interesting section of the article suggests that this pathway can also be leveraged for sponsors’ future platform approval by gaining real-world proof-of-concept models for additional indications. The paper states that the plausible mechanism pathway would ideally fit in a scenario where a “single disease with 150 different genetic mutations with the same functional implication may require 150 different therapies”. Baby K.J. highlights that while individual mutations require individual therapies, the same technology can address multiple genetic mutations.

While exciting, the plausible mechanism pathway, as described, is highly specific for sequence-targeted therapies that involve a distinct mutation where each intervention is tailored to a single patient and thus built on a common technological backbone (LNPs, CRISPR). The pathway does not describe or address the broader universe of non-individualized biologics, such as autologous or allogeneic cell therapies, viral-vector gene therapies, or small-population academic biologics that are fixed products rather than bespoke constructs. These products face a different set of challenges yet to be addressed, and further development of this new pathway or additional new pathways may serve those needs. Although the pathway is narrow in scope, it still provides an opportunity to leverage data to streamline the development of new drugs that target different mutations.

Today, the story of Baby K.J. is a unique one where scientists and regulators were able to quickly address the root cause of a rare disease. However, with the implementation of the new plausible mechanism pathway proposed by top FDA officials, the hope is that such stories can become commonplace. The plausible mechanism pathway represents an exciting advance for individualized medicine and a meaningful signal of regulatory flexibility. As we look forward to the development of a formal guidance, there is hope that this pathway will pave the way for applicable, timely, and lifesaving treatments for patients with rare and complex conditions that will potentially change the landscape of cell and gene therapy.

References

Prasad, V., & Makary, M. A. (2025). FDA’s new plausible mechanism pathway. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMsb2512695