Development of peptide therapeutics: A nonclinical safety assessment perspective.

Novel peptide drugs continue to gain interest as effective modalities against previously undruggable targets. As with any other technology, development and safety assessment of peptides presents with various complex challenges. Additionally, there is a lack of specific regulatory guidance for peptide development, with the industry relying mainly on associating existing small molecule [ICH M3(R2)] and biologic [ICH S6(R1)] guidance. To gain insights into regulatory requirements for therapeutic peptides, we developed a dataset of peptides approved in the United States from 1998 through 2019 for which the summary basis of approval (SBA) packages are publicly available. The dataset comprises a total of 47 peptides (22 chemically synthesized, 6 semi-synthetic, 18 recombinant, and 1 natural). This article summarizes our learnings from the dataset in regards to the development paradigm, guidances followed, strategies for selection of toxicology species; requirements and/or value of genotoxicity and immunogenicity assessment; impurity, metabolite, and safety pharmacology assessment; and safety assessment of peptides containing non-proteogenic amino acids. In the context of the learnings from the dataset, the authors provide their recommendations for improvement of strategies to develop peptide drugs.