Sep. 27 at 2:43 PM
What we are seeing here is an overpromised platform not living up to the hype. Not just
$ARVN but all protein degraders. The idea that targeting the protein would make the drug useful across all mutations is flawed.
$ARVN PROTACS are “too selective” since the design makes it dependent on specific mutation-driven conformation, leading to activity only in a narrow subset of patients, it reduces usefulness for broader indications where multiple variants or wild-type proteins drive disease.
A degrader tied to one mutation is essentially a niche therapy.
Unless the mutation is highly prevalent (EGFR KRAS), the patient pool is too small compared with a broadly active therapy. The market prefers pan-mutant or wild-type–plus-mutant activity to maximize market size.
$ARVN "PROTACS" use E3 ligase for ubiquitination and degradation. If the degrader recognizes a neo-epitope, its activity might only occur in patients with that exact mutation.
This is the realization
$PFE made, after spending BIGG$$$
