Novartis, Biogen, Takeda and Novo Nordisk are all betting on advances in the molecular glue degraders space, collectively investing billions in hopes of treating cancer, Alzheimer’s disease, cardiometabolic disease and more.
When the mechanism of action behind a decades-old drug was serendipitously discovered, a new field of drug discovery was ripped open and molecular glue degraders were born. Now, nearly 15 years later, Big Pharma is taking notice. In 2024, Biogen, Novartis, Takeda and Novo Nordisk each struck deals to add molecular glue degraders to their pipelines—collaborations that could collectively be worth over $6 billion.
“This year in particular seems to be a big year for deals,” Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research, told BioSpace. “This is a kind of next stage maturity in this space.”
The investments have not only been in dollars and cents but on the research front as well, Schoenfeld said. “The whole field of chemical biology has spent a lot of effort in this area the last 10 years, so it’s nice that this inflection point seems to be here.”
A big part of the appeal for molecular glue degraders lays in their potential to go where no small molecule has gone before.
Many small molecule drugs work by binding to specific target proteins to inhibit function. However, over 90% of disease-causing proteins lack binding pockets where a small molecule can grab hold. A molecular glue degrader (MGD) is a small molecule that enhances the interaction between a disease-causing protein and a ligase that will help initiate its destruction—the ultimate goal of all protein degrader drugs, which have earned a reputation for being able to reach targets once thought “undruggable.”
“For years companies have had to work according to the conventional rules governing druggability with a limited druggable genome,” Phil Chamberlain, CEO of Neomorph, told BioSpace. “Glues give companies the opportunity to go after the most impactful targets with a completely different set of rules. It’s an incredible opportunity.”
The therapeutic potential for MGDs is far reaching, with initial indications ranging from oncology to neurodegeneration to autoimmune and cardiometabolic diseases. Vienna-based Proxygen’s lead program is in oncology, but CEO Bernd Boidol told BioSpace that MGDs are disease agnostic. “Any disease driven by a misfunctioning protein, glue degraders can be an answer to that,” he said.
A Serendipitous Discovery
The majority of the players in the MGD space are focused on one of two E3 ubuiquitin ligases—cereblon and the von Hippel-Lindau (VHL) protein. The discovery of cereblon was the “launch pad” for glue research efforts, Georg Winter, a principal investigator at the Research Center for Molecular Medicine and Proxygen co-founder, told BioSpace.
It all started with an infamous drug discovered in the 1950s. Thalidomide was commonly used, especially in Europe, to treat morning sickness until it was discovered to be the cause of severe limb abnormalities in babies when given to pregnant women. The drug was then withdrawn from the market, until it was later approved for a complication of leprosy in 1998 and then for myeloma in 2006.
Still, its mechanism of action remained a bit of a mystery. Then in 2010, a group of Japanese researchers discovered the cellular target to be cereblon. Further research revealed the drug was not inhibiting cereblon but reprogramming the ligase to act as a molecular glue degrader. Their discoveries opened the door to the potential targets whose degradation can be initiated by cereblon, according to Winter.
Catching the Craze
Today, several pharmaceutical companies are cashing in on the headway made by researchers and biotech companies in the MGD space, striking deals to add promising molecules to their pipelines through collaborations and acquisitions.
In 2019, BMS bought thalidomide’s U.S. manufacturer Celgene for $74 billion, bringing in a handful of MGDs. Three molecules are in multiple Phase III trials for lupus and various blood cancers.
This year has seen a number of deals in the space. In November, Novartis handed over $150 million upfront to Boston–based Monte Rosa Therapeutics, with another $2.1 billion on the line in potential milestones. The deal has Novartis queuing to take the reins on development of Monte Rosa’s MGDs targeting the VAV1 protein for immune-mediated diseases.
VAV1 is a key signaling protein involved in T and B cell cascades. According to Monte Rosa, destroying it could have potential for multiple systemic and neurological autoimmune indications such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and dermatological disorders.
Meanwhile, Neomorph garnered two big name collaborations with Biogen and Novo Nordisk. While the out-of-pocket payments on both deals remain under wraps, they include potential payouts of $1.45 billion and $1.46 billion, respectively. Each of the larger companies is targeting indications near and dear to their core pipelines. Biogen’s partnership will focus on developing an MGD for Alzheimer’s, rare and immunological diseases, while Novo’s will prioritize cardiometabolic and rare diseases. Neomorph also has its own pipeline of glue degraders targeting solid tumors. Elsewhere, Takeda signed an up to $1.2 billion deal in May with China-based Degron Therapeutics to develop MGDs for various oncology, neuroscience and inflammatory disease targets.
This all follows the considerable investment in 2023, when Roche’s Genentech tied up with Orionis Biosciences to target cancer and neurodegeneration in a deal that could exceed $2 billion and Proxygen and Merck drew up a deal worth up to $2.55 billion.
The Molecular Glue Degrader Advantage
Molecular glue degraders aren’t the only protein degradation option in the works. Another, called PROTACs (proteolysis-targeting chimeras), are bifunctional molecules with two distinct binding sites—one for a target protein and one for an E3 ubiquitin ligase—that also act as a molecular glue to target a protein for destruction.
One advantage of MGDs over other varieties of protein degraders is their small size. They are typically around the size of your average small molecule and half the size of PROTACs, Winter explained. He noted that pharma has a lot of interest in using MGDs in neurological diseases, where size particularly matters.
Schoenfeld noted that one company, Arvinas, has optimized its PROTAC to be able to cross the BBB. “But I think you’re always going to be better off starting with a smaller molecule,” he said.
Perhaps the tallest challenge in the space has been finding a rational way to design MGDs, Schoenfeld said, adding that he believes the field has finally cracked the code for rational design. Based on the big dollar deals, “There’s presumably some breakthroughs.”
Neomorph’s ambition is to have broader activity across the proteome, Chamberlain said. Research he conducted with collaborators while working at Celgene resulted in the discovery of a structural component of cereblon’s mechanism of action that opened up the potential field even further.
Neomorph has now identified additional structures within proteins that can be targeted, as well as novel ligases beyond cereblon and VHL, Chamberlain said, offering access to thousands of proteins that may be tractable for the MGD approach.
“It’s exciting to see this happen for this field,” Schoenfeld said. “There’s been so much hope and so much investment. It’s been a long time coming to reach this point, and I don’t see any signs that [interest] is slowing.”
