A first-of-its-kind protein degrader just won FDA approval, marking a milestone for an accelerating drug class. But the landmark “PROTAC” drug for breast cancer may make a quiet entry into the market.
Vepdegestrant, which will be marketed as Veppanu, only modestly slowed disease progression in a phase 3 trial, with the clearest benefit in patients with ESR1 mutations, narrowing its market potential. The results from last March have reshaped strategy at Arvinas, which announced last May that it would lay off about a third of its workforce. Rather than commercializing the drug itself, the company and its partner Pfizer are seeking a third-party to take the treatment forward as it refocuses on earlier-stage programs.
“We need to shift over time to where [we’re] best positioned to win, where we can best invest our resources, which may not be in as broad a set of areas as we are now," said Randy Teel, president and CEO of Arvinas.
Despite what may be a muted launch, the protein degrader field is gaining momentum.
Companies like Novartis and Bristol Myers Squibb have inked deals in this space, and the bustle includes not only stand-alone degraders, but variations such as degrader-based ADCs, which is being pursued by several large pharma companies. Roche struck a deal with C4 Therapeutics worth up to $1 billion to partner on so-called degrader-antibodies for two oncology targets.
Rising drug classes merge together
PROTAC protein degraders exploit the ubiquitin-proteasome system, a natural disposal system inside cells that can eliminate disease-causing proteins. The approach traces back to two biochemists: Craig Crews, a Yale University professor, and Raymond Deshaies, a research executive at Amgen who helped develop the concept of targeted protein degradation. Crews went on to found Arvinas, building its PROTAC model on his later work that tags problematic proteins for destruction using the cell’s own machinery. The approach may have broad potential across many disease areas.
Protein degraders are also gaining clinical traction. Kymera Therapeutics recently saw favorable results in phase 1 with KT-621, its pill targeting a severe form of eczema. The oral STAT6 degrader also received FDA fast track designation for moderate to severe eosinophilic asthma.
Arvinas, meanwhile, is shifting from a primary focus on vepdegestrant to emerging options, Teel said.
The company is nurturing programs in neurodegeneration and oncology, including its most advanced LRRK2 protein degrader being tested in Parkinson’s disease and a rare brain disorder called progressive supranuclear palsy. Arvinas engineered the drug to cross the blood-brain barrier, Teel said. In phase 1 the drug was able to reduce the amount of LRRK2, a protein implicated in several neurodegenerative diseases, in the spinal fluid of patients with Parkinson’s disease by 50% or more.
The company is also jumping into the RAS field with its KRAS G12D degrader, ARV-806. RAS mutations, including KRAS, are a top target in oncology, and companies like Revolution Medicines have seen recent successes in the space, but there are still problems to overcome, including drug resistance.
“Everyone's already talking about what would come after that,” Teel said. “What could you combine with that? What are the other therapies that are going to build around this new momentum?”
Protein degraders could factor into those conversations for their potential to overcome the common resistance mechanism of overexpression or amplification, Teel said.
Despite the bumps it’s encountered, vepdegestrant represents an early test for the field.
“Today’s FDA approval is a transformative moment for Arvinas as we achieve our first approved medicine and the first-ever approved PROTAC therapy based on the technology we’ve pioneered since 2013,” said Teel in a written statement. “This milestone demonstrates that targeted protein degradation can translate into meaningful clinical impact. It also strengthens our confidence in the breadth and versatility of our exciting clinical pipeline across oncology, neurodegenerative, and neuromuscular diseases.”
But more work needs to be done to help the technology find its footing.
“Protein degradation, probably faster than any other modality, has cemented itself as one of the tools in the toolbox that pharma and biotech companies have to focus on specific problems,” Teel said, adding that the trick will be applying it strategically. “A protein degrader is going to be the best tool that we have in a number of situations, and it won't be in others.”
