Synthetic Peptide Therapeutics: Not-So-Sweet Spot between Large and Small Molecule


With the advent of new technology supporting high-throughput discovery platforms, synthetic peptides as a therapeutic modality have increasingly gained popularity for previously considered difficult or undruggable targets. Although peptides, such as insulin and glucagon, have played an important role in modern medicine over several decades, development of peptide therapeutics is a gray area between small molecule and biologic, with an array of complex challenges and lack of specific regulatory guidance. The well-received Symposium Session “Consideration for Safety Assessment of Chemically Synthesized Therapeutic Peptides: A Drug Development Paradigm between the Large and Small” during the SOT 58th Annual Meeting and ToxExpo in Baltimore, Maryland, focused on navigating the unique challenges associated with peptide development, such as short plasma half-life and rapid clearance, presence of non-natural amino acids, and immunogenicity and genotoxicity assessment.

Dr. Evan Thackaberry kicked off the Symposium, laying a strong foundation by presenting an overview of peptide development and how advances in science have been instrumental in changing the chemically synthesized peptide landscape. The fascinating peptide journey from hormone analogs to synthetic peptides is further strengthened by the fact that hundreds of peptides under development are probing novel binding mechanism. The intrinsic properties of peptides due to their size; molecular flexibility; and high-target selectivity, affinity, and specificity make them a promising and effective treatment modality.

Dr. Mayur Mitra discussed the general nonclinical toxicity assessment strategy for development of therapeutic peptides leveraging the existing small molecule [ICH M3(R2)] and biologic [ICH S6(R1)] guidances. This talk also emphasized the lack of peptide-specific regulatory guidances around immunogenicity assessment or considerations for issues such as safety of non‑natural amino acids that are part of chemically synthesized peptides. In addition to general toxicology and safety, presence of impurities precipitated from the chemical synthesis and manufacturing process (e.g., residual reagents such as chemical linkers or non-natural amino acids) poses a unique challenge in development of peptides. Subsequent talks by Dr. Laura Custer and Dr. Stephanie Leuenroth-Quinn addressed the genotoxicity/carcinogenicity testing for peptides and impurity qualification approaches, respectively. In addition, Dr. Custer presented several case studies and a decision tree for protocol design that may be followed to perform genetic toxicology assessment and minimize false positive genotoxic liability. Because of the lack of peptide‑specific regulatory guidances, current standard practices follow principles recommended for small and large molecule impurity assessment and qualification.

The icing on the cake for the audience was an opportunity to review the nonclinical safety strategy of a late-stage clinical peptide under development, Dasiglucagon, which is a glucagon analog intended for long-term clinical use. The presentation highlighted the scope of chronic toxicity studies supporting intended clinical regimen, including but not limited to species selection, immunogenicity assessment, and comparative study with native glucagon. Overall, active audience participation during the Symposium and the panel discussion that followed aptly recognized the uniqueness of development of synthetic peptides as well as reinforced the interest and need for an open dialogue between stakeholders (industry, regulatory bodies, and academia).

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.

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