Regulatory Considerations for Deuterated Products

Deuteration is the act of substituting a hydrogen atom with its heavy isotope, deuterium, resulting in a more stable chemical bond. This structural modification can improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts¹. Deuterated drugs are also considered by FDA to be a different active moiety from the non-deuterated analogue because deuteration changes the nature of a covalent bond; thus, these products are eligible for five-year new chemical entity exclusivity.

In total, four deuterated drugs have been approved by the FDA, with many more in clinical development. While some developers apply deuteration in novel drug discovery (e.g., deucravacitinib [SOTYKTU; Bristol-Myers Squibb Company], approved in 2022), others have used a “deuterium switch” approach to bring deuterated analogues of existing drugs to market (e.g., deuruxolitinib [LEQSELVI; Sun Pharma] and deutivacaftor, one component of ALYFTREK [Vertex Pharmaceuticals Inc.], a triple combination therapy product; both approved in 2024).

One notable benefit in the development of a deuterium switch product is the ability to utilize nonclinical and clinical data obtained for the non-deuterated compound to support the safety and/or efficacy of the deuterated compound. FDA has permitted this in at least one example, deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017 via the 505(b)(2) pathway¹. For a deuterium switch, a sponsor must provide evidence to support that reliance on findings of safety and effectiveness for the approved product is scientifically justified. This may involve, for example: in vitro and in vivo studies in animals and humans to characterize any potential differences in metabolism between products, bridging toxicity studies, relative bioavailability and other pharmacokinetic (PK) studies, and/or population PK or PK-PD modeling. Assuming an appropriate bridge can be established, sponsors may benefit from a reduced development program (from both a nonclinical and clinical perspective), leading to lower overall costs and faster timelines to approval. This, combined with the five-year exclusivity mentioned above, is clearly an advantage for many companies.

Salamandra has extensive experience with 505(b)(2) development programs, inclusive of working with sponsors to design creative and strategic bridging approaches, that can be expertly leveraged in support of deuterium switch products. If you have further questions regarding regulatory challenges for deuterated products or are curious about how we can support your development program, reach out to Salamandra at hello@salamandra.net to learn more.