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A patient’s immune system is one of the most powerful weapons in the fight against cancer. Now, a rapidly growing class of new drugs, protein degraders, are emulating the immune system’s strategy of hijacking our cells’ garbage disposal systems to remove disease-causing proteins — an approach that could ultimately address thousands of diseases.
John Huston, CEO of Albinus
Used with permission from Albinus
If all goes according to plan, Albinus Therapeutics Phase 3 trial of metastatic breast cancer drugBepdegestrant could be the first of the drugs approved as early as 2025, opening the door to a wave of new therapies to treat cancer, neurological disorders and more.
“This will be an incredibly exciting transition not only for the company but for the entire protein degradation space,” said Albinus CEO John Huston.
The origins of this technology Two biochemists — Yale University professor Craig Crews and Amgen research executive Raymond Deshaies — pioneers of protein degradation drugs. Proteasome Ubiquitin system.
“When a protein reaches the end of its life, it gets plucked away by the proteasome, a waste-processing device that breaks it down into peptides and puts them back into the cell for the cycle of protein synthesis,” Houston says.
Crews’ original work showed that slamming the lid on a garbage can would cause proteins to build up inside cells, causing them to burst and destroy the cells. This discovery became the basis for Amgen’s proteasome inhibitors for multiple myeloma. CyprolisIt was approved in 2012.
Crews then pivoted to a different approach, tagging these proteins and letting the body do the dirty work of hauling disease-causing proteins to a waste dump inside cells. He founded Albinus in 2013, a company that Pipeline Houston said they have been successful in discovering chimeric protein degraders that target protein degradation.
“All of the big pharmaceutical companies have some connection or involvement in protein degradation, either through their own research or through partnerships.”
John Huston
CEO of Alvinus Therapeutics
The most advanced candidate, bepdegestrant, is Albinus A partnership with Pfizer worth $2.4 billionIt has been tested both as a monotherapy and in combination with other therapies. The challenging type It is effective in patients with ER+/HER2 metastatic breast cancer. In preclinical studies, the drug Better performance Fulvestrant alone and in combination with a CDK4/6 inhibitor was found to be more effective than the standard treatment, fulvestrant, and was given fast track designation by the FDA.
The company’s other candidates include prostate cancer drug ARV-766, which it has licensed out. NovartisThe company is also developing a BCL6 protein degrader targeted at blood cancers that could be introduced into the clinic this year. The company’s promising early-stage candidates also include drugs to treat neurological disorders such as Parkinson’s and Huntington’s diseases.
Increasing competition
Protein degraders have advantages over traditional drugs because they remove problematic proteins rather than inhibit them, Houston says, and they could enable scientists to target tricky proteins that evade small-molecule drugs, helping to overcome treatment-resistant diseases. Blood-brain barrier It’s especially promising for treating brain disorders. Houston says early studies have shown that bepdegestrant doesn’t cause any side effects related to the technology; its only effect comes from eliminating the target.
“When you take away androgens, you see androgen-related effects. When you take away estrogen, you see estrogen-reducing effects. But that’s also what you want to see in the context of this disease,” Houston said.
This may be of benefit to patients.
“This is really important for patients who are battling breast cancer,” Houston says. “They don’t want a drug that’s going to make them really sick.”
The early success of these drugs has attracted attention.
“When we first started, we were the only company in the space,” Houston said, noting that things changed around 2015. “If you look now, every big pharma company is somehow connected or involved in protein degradation, either through their own research or partnerships. There are probably 50 to 60 companies that claim to be working on protein degradation in some way. That tells us the technology is mature enough that both big and small companies want to invest in it.”
Other candidates in this field include: C4 Therapeutics, Rannoch Therapeutics and Chimera TherapeuticsOne of the most common differentiators between companies is how they deploy technology and who they target.
Companies are addressing a growing number of diseases
“If you want to carve out a unique space, it’s more important than ever to be selective about which targets you address and which diseases you address, so we’re seeing a range of companies putting resources into cardiovascular, oncology and other areas,” Houston said.
Ultimately, protein degraders may be able to treat thousands of diseases by targeting them inside cells.
“This technology has the potential to provide an important therapeutic alternative for patients, particularly in areas where there is high treatment resistance and new mechanisms to approach targets are needed,” Houston said. “That’s why people are so excited about this technology. We’re just scratching the surface.”
