Profoundly Expanding the Target Space: A Primer on TPD

THE COWEN INSIGHT

Targeted protein degradation (TPD) is an emerging new therapeutic modality that harnesses existing cellular machinery to tag diseased-linked proteins for disposal. TPD has the potential to expand the target space beyond small molecule inhibitors. First-generation degraders are showing clinical proof of concept with their success, leading to a flywheel effect & a growing next-gen class.

With TPD in its infancy, much learning on all aspects of degrader development remains. Nonetheless, design should become more rational & systemic discovery approaches should be successfully developed, enabling degraders to become the next iteration of small-molecule drugs.

UNDERSTANDING THE TARGETED PROTEIN DEGREDATION FIELD

Targeted protein degradation is a new, fast-growing field that is attracting much excitement and investment. TPD aims to harness existing cellular machinery to specifically tag and destroy proteins linked to diseases. Its unique way of targeting problematic proteins potentially opens up the ~85% of disease-associated proteins that are currently inaccessible to small molecule inhibitors, presenting a very large market opportunity.

However, as with any new modality, there is much to be resolved. This includes how best to identify targets and prospectively design candidates (particularly for molecular glues), as well as how to define the pharmacological “rules” that govern TPD agents.

TPD OVERVIEW

In our full report, we:

• dive into the science behind TPD
• examine existing data on first-generation programs (heterobifunctional degraders/PROTACs)
• discuss platforms for second-generation molecular glue approaches
• identify the challenges academics and companies are addressing to unlock the full potential of TPD

Ultimately, we believe there is significant opportunity and differentiation among TPD candidates in the clinic, as well as novel approaches by molecular glue companies to identify new targets and advance rationally designed candidates into the clinic.

TARGETED PROTEIN DEGRADERS VS. SMALL MOLECULE INHIBITORS

Degraders are exceedingly potent, and dose optimization/selection will require a different approach than conventional small molecule inhibitor development. Over the near to mid-term, we expect to see an increasing focus on dose selection and optimization as initial Phase I and Phase II datasets for the first wave of clinical-stage degraders mature.

Degrader pharmacology differs from that of inhibitors. This is because degraders are far more potent. One degrader can degrade thousands of proteins and, therefore, exert a more durable effect on the target. Indeed, the clinical data to date indicates that they can achieve sufficient target exposure at doses well below what is needed for a conventional small molecule. However, this potency can come at a cost, as it could risk uncovering new and/or more severe on-target toxicity. This liability is likely to be target-specific, and the more essential a protein is for a particular cell lineage, the more vulnerable it will be to a degrader.

WHAT TO WATCH

Given how early the space is in development, accurately forecasting the future TPD market is impossible. However, we note that the cumulative total addressable market for programs from the more visible public TPD companies in the clinic equates to tens of billions alone. We are watching multiple catalysts for clinical-stage or near-clinical degraders.