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“But wouldn’t sharing your data help you find a cure sooner?”

When explaining the nature of scientific publishing to a cancer patient, you realize how difficult it is to rationalize the protection of novelty. The speakers in the “Targeted Protein Degradation Therapeutics: Opportunities and Challenges” Workshop Session should be commended for taking the risk to present confidential, early data. Listening to their strategies for improving safety assessments of targeted protein degraders, I appreciated the novelty of the different approaches. Out of respect for the presenters, who requested their data remain confidential, I’ll share just a few of these strategies in the broadest terms. I'll also provide definitions of key terms for those unfamiliar with this field.

Targeted protein degraders (TPDs) are a rapidly evolving class of drugs that can target difficult-to-drug targets by using endogenous protein degradation processes. In this session, speakers provided an overview of the different types of TPDs in development and the risks associated with this exciting class of therapeutics.

From a regulatory perspective, TBPs are considered small molecules, though key differences do exist. TPDs, which function through induced protein proximity, can be a bit larger than traditional small molecules and have two targets rather than a single known target. Specific factors to consider for the assessment of efficacy and safety are noted in the table and discussed in the following paragraphs.

Multiple speakers identified off-target toxicity as a risk associated with TPDs. As the term implies, off-target toxicity occurs when another target is modulated; it may be biologically relevant or totally unrelated. In the case of TPDs, degraders may bind to proteins other than the intended target, leading to unwanted side effects. A safety strategy to mitigate this risk—EARLY in drug development—is to prioritize a list of proteins that may be impactful to vital organs when degraded. Then, you can establish a “knock-down threshold” for these proteins in an in vitro system and screen degraders early in development. There are challenges associated with this strategy, including narrowing the list of candidate proteins and identifying how much off-target degradation is too much to advance a therapeutic molecule.

A second highlight of the session was the discussion of species selection. Data were presented to show that substrate degradation is sequence-dependent and that humanization of mouse targets by reciprocal mutations can modulate degradation. To improve toxicity prediction across species, complementary methods of assessing risk can be used: literature assessment, predictive assessment (based on binding and structure), in vitro assessment in cell lines, ex vivo assessment of mRNA/protein expression in tissues, and ex vivo assessment of expression and degradation following in vivo treatment.

Taken together, this session illustrates the evolving nature of early safety evaluation for TPDs. As our understanding of these molecules deepens and more clinical data is gathered, it will be interesting to see how well our existing models have predicted adverse outcomes.

Want to learn more? Check out these resources:

AstraZeneca. 2022. “PROTACs and Molecular Glues—Drugging the ‘Undruggable.’” Last modified January 2022. https://www.astrazeneca.com/r-d/next-generation-therapeutics/protacs.html

Bristol Myers Squibb. n.d. “Protein Degradation and Resources.” Accessed March 26, 2023. https://www.bms.com/media/media-library/scientific-media-resources/understanding-protein-degradation-and-resources.html.

Chirnomas, Deborah, Keith R. Hornberger, and Craig M. Crews. 2023. “Protein Degraders Enter the Clinic—A New Approach to Cancer Therapy.” Nature Reviews Clinical Oncology 20, no. 4 (April): 265–278. https://doi.org/10.1038/s41571-023-00736-3.

Key regulatory guidance documents: 21 CFR 312, ICH M3(R2), and ICH S9

Liu, Xin, Ye Zhang, Lucas D. Ward, Qinghong Yan, Tanggis Bohnuud, Rocio Hernandez, Socheata Lao, Jing Yuan & Fan Fan. 2021. “A Proteomic Platform to Identify Off-Target Proteins Associated with Therapeutic Modalities That Induce Protein Degradation or Gene Silencing.” Scientific Reports 11: 15856. https://doi.org/10.1038/s41598-021-95354-3.

Glossary

This blog reports on the Workshop Session titled “Targeted Protein Degradation Therapeutics: Opportunities and Challenges” that was held during the 2023 SOT Annual Meeting and ToxExpo. An on-demand recording of this session is available for meeting registrants on the SOT Online Planner and SOT Event App.

This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email SOT Headquarters.