Protein degraders destroy disease proteins as drugmakers invest billions

Lisa Moore entered remission after 10 months on Bristol Myers mezigdomide

After Lisa Moore’s cancer treatments stopped working, the 64-year-old Whately, Mass., small-business owner enrolled in a late-stage trial of a new type of drug. Ten months later, she went into remission.

“It was pretty amazing, considering I’d been over three years at that point on the other protocol and had never gotten there,” Moore said.

Moore is just one case. The kind of drug she tested has yet to be proven widely effective across large patient populations, but companies such as Bristol Myers Squibb, Pfizer and Roche are pouring billions of dollars into protein degraders, hoping to find a new tool to attack diseases from cancer to Parkinson’s.

Most medicines on the market today work by latching onto the rough surface of a protein and blocking it from causing disease. Protein degraders go after a different kind of target. Some disease-driving proteins are so flat that they are hard to latch on to; these elusive, smooth proteins are involved in 85% of disease drivers that researchers have so far been unable to attack.

The two most advanced types of protein degraders are known as Protacs, or proteolysis targeting chimeras, and molecular glue. Both commandeer a cell’s recycling system to destroy proteins that normally drive the course of a disease. The E3 ligase enzyme cleans up the cell, tagging proteins that are damaged or misfolded for destruction, but it doesn’t recognize the disease-causing protein. One end of a Protac drug binds to the disease-causing protein, and the other end binds to the E3 ligase. The drug brings the disease-causing protein and the E3 ligase closer together, causing the E3 ligase to tag the protein for destruction, and the cell destroys the disease-causing protein by cleaving it into short peptides.

In 1998, Yale scientist Craig Crews and California Institute of Technology professor Raymond Deshaies discovered the underlying technology for Protacs. They proved a problematic protein could be destroyed by bringing it closer to an enzyme that helps dispose of cell waste — without needing to latch on to the protein like traditional drugs do.

The Food and Drug Administration has already approved a handful of protein degraders for cancers with small patient populations or with other treatment options. The first degrader to hit the market was Veppanu, a breast-cancer drug developed by Pfizer and Arvinas. The therapy, approved in May, works in patients with a specific genetic mutation called ESR1 who have failed hormone therapy, which represents around 1% of all newly diagnosed breast-cancer patients globally.

Veppanu didn’t prove as effective in a wider population of breast-cancer patients whose tumors weren’t explicitly driven by the ESR1 mutation, a failure that led to a 53% stock selloff for Arvinas. Arvinas and Pfizer ended up unloading the drug to Rigel Pharmaceuticals for $70 million. The approval has nevertheless given companies more confidence as they go after more ambitious targets in cancer, autoimmune and neurodegenerative spaces.

Yale scientist Craig Crews, founder of Arvinas, said the FDA approval “will change how the industry views what is potentially druggable.”

In August, Bristol Myers Squibb received approval for Zenbexus, a next-generation multiple myeloma treatment that works as a form of molecular glue. In clinical trials, severe multiple myeloma patients who took Zenbexus on top of two existing treatments lived 42 months before their cancer got worse, compared with 20 months for those without Bristol’s drug.

Bristol Myers is seeking approval of another degrader, called mezigdomide, targeting the disease. In May, the company announced that mezigdomide in combination with other treatments led to patients living 18 months without progression, versus eight months in those on existing treatments. This is the drug Moore was taking.

A few other protein degraders have reached late-stage trials. California biotech Nurix Therapeutics, along with pharma partner Roche, and Switzerland-based BeOne Medicines are each developing degraders to eliminate the BTK protein, which drives common blood cancers. They are testing those drugs against the normal medical regimen for patients with leukemia and lymphoma. BeOne’s results are expected in 2028, Nurix’s in 2029. These trials should help establish the drugs’ advantages when compared with existing therapies.

Some companies are testing whether degraders can better target diseases that have mutated or become resistant to first-line treatments. Others are testing whether degraders are more effective at tackling disease on the first go-round.

Companies are exploring the potential for degraders outside cancer as well. Arvinas is pursuing two candidates for Parkinson’s disease and for spinal and bulbar muscular atrophy, a rare disorder that leads to progressive muscle weakness and wasting. Kymera Therapeutics is studying degraders in autoimmune disorders such as asthma and atopic dermatitis.

Virtually all major pharmaceutical companies are developing protein degraders, through their own research or licensing deals. Around 200 protein degraders are being studied worldwide, with more than $5 billion in deals for these drugs from 2021 to 2026, according to biopharma-intelligence service Sleuth.

Scientists are still figuring out where protein degraders can provide the most benefit and making sure these new drugs don’t accidentally kill healthy proteins. The drugs interfere with the cell’s recycling machinery, which is important in all healthy cells.

“We’re interfering with the cell’s recycling machinery that’s important in all of our healthy cells,” said Dr. Julie Gralow, chief medical officer of the American Society of Clinical Oncology. “There could be off-target effects that accidentally recruit and destroy healthy proteins. We just have to watch out for that.”

The molecular glue form of degraders was discovered serendipitously. The drug thalidomide was developed in the 1950s for morning sickness and used in several countries outside of the U.S., but it caused thousands of birth defects before being taken off the market. Decades later, scientists repurposed the drug and its derivatives to safely treat cancer and leprosy. In studying it further, researchers discovered it was a protein degrader — the drug was able to destroy a problem protein by binding it with the right enzyme to attack a disease.