A little over five years ago, the biotech world became intrigued with the promise of Antibody–Drug Conjugates (ADCs). Investors poured resources into CDMOs and production capabilities expanded. With the apparent success of ADCs, we now see the next ‘hot area’ for conjugates as part of the rapidly emerging modality targeting “undruggable” proteins for degradation. PROteolysis-TArgeting Chimaeras (PROTACs) are today to innovators and CDMOs what ADCs were a few years ago, as the next big modality innovation.
Most significantly, it’s the science that has advanced. The realisation of key milestones in discovery and development has inspired investors to reconsider their commercial assessments
and we are currently entering a new chapter for targeted protein degradation.
For example, the significant technical hurdle of achieving PROTAC pharmacodynamic activity in the central nervous system through oral administration has now been reported. Beyond additional orally bioavailable PROTACs entering the clinic, we note the first positive pivotal Phase III trial and the first new drug applications being filed. What was once speculative is consolidating into an expanding area of opportunity and potentially sometime next year, we will see the first PROTAC FDA approval. In fact, there are now around 90 PROTACs in various
phases of clinical trials, with Arvinas alone having six advanced programmes spanning oncology, neurology and beyond, and the field is rapidly expanding in therapeutic indications.
Just this September, Arvinas out-licensed its commercialisation rights for Vepdegestrant immediately post submission of its NDA to the FDA. This has the potential to prime the wider
industry for far more late-stage assets and potential dealmaking.
We are further encouraged by reports of scientific innovations in linker chemistry/composition, ligase discovery/ applications, computational models forecasting ternary complex stability and proteomics-based selectivity profiling, all leading to enhanced PROTAC characteristics such as the aforementioned oral bioavailability and CNS penetration.
These combine with refined clinical and regulatory strategies to augment commercial viability.
