Arvinas and Pfizer, co-developers of vepdegestrant – the most advanced of the new bifunctional protein degrader drug class – are jointly seeking a new partner to bring it to market. The firms are looking to out-license the selective oestrogen receptor degrader (SERD) after clinical trial results published in March showed vepdgestrant works, but didn’t outperform existing treatments.
They have applied for US Food and Drug Administration (FDA) approval, with a decision due by June 2026. Yet Arvinas will now cut 15% of its workforce, largely commercial roles relating to vepdegestrant, after already announcing in May it would reduce headcount by 30% and scrap two further phase 3 trials in May.
Rather than blocking a protein’s function like traditional small-molecule inhibitors, degrader drugs harness the cell’s protein recycling machinery. Bifunctional degraders like vepdegestrant bring together disease-related proteins – in this case mutated oestrogen receptors – with E3 ubiquitin ligase enzymes that label proteins for shredding by the proteasome.
Vepdegestrant will compete against established SERD drugs, including AstraZeneca’ Faslodex (fulvestrant), which was first approved in 2002 and is now available generically. When fulvestrant and related SERD drugs bind to oestrogen receptors, they change the protein’s conformation, which initiates a process by which enzymes including E3 ligases label it for degradation. Most existing SERD drugs are only effective in patients with certain mutations in oestrogen receptor genes.
Pfizer and Arvinas had viewed vepdegestrant as a potential blockbuster therapy, says Glenda Walker, senior healthcare research and data analyst, oncology, at Clarivate in London, UK, aiming to show the drug could be more broadly effective. But the companies’ phase 3 trial was disappointing, showing that vepdegestrant was only more effective than fulvestrant in patients with mutations in one specific gene, ESR1. Walker expects the FDA to approve the therapy in people with ESR1 mutations who’ve previously received hormone-targeting therapies.
Walker believes vepdegestrant’s biggest opportunity is as the first treatment breast cancer patients receive, in combination with other drugs. Reaching that market ‘would likely require large phase 3 combination trials, which may necessitate collaboration with partners capable of supporting further development’, she tells Chemistry World. Meanwhile, competition is growing further, as the FDA has approved Inluriyo (imlunestrant), another orally available SERD drug from Eli Lilly.
Nevertheless, Zoran Rankovic, director of the Centre for Protein Degradation at the Institute of Cancer Research in London, UK, hails Arvinas’ drug reaching this stage. ‘To see vepdegestrant – one of the earliest pioneers in targeted protein degradation – reach this stage within just a decade is truly remarkable,’ he says. It has ‘opened the door to a new generation of therapies with the potential to transform how we treat disease,’ Rankovic says. ‘In my view, the future of targeted protein degradation is brighter than ever.’