By Robert Langreth | Bloomberg
One of the biggest advances in pancreatic cancer in decades came out of a crazy idea born in a Harvard University lab.
Chemical biologist Gregory Verdine believed you could fight disease-causing proteins hidden inside cells by chemically gluing them to something else in the body and smothering them.
“Everybody told us this is crazy, that it would never work,” he recalls.
Revolution Medicines Inc., which bought one of Verdine’s companies in 2018, recently announced that one of its drugs doubled the typical survival time for patients with aggressive forms of the disease, from 6.7 months to 13.2 months. The full results from the company’s final-stage trial are expected to be the star of the show at the annual confab of cancer doctors in Chicago this weekend.
Spurred by the success of RevMed, numerous companies are now racing to develop similar drugs, dubbed “molecular glues,” which can be used to treat a variety of ailments. And investors and pharmaceutical companies with deep pockets are chasing after them, creating one of the hottest corners of dealmaking in the industry.
It’s not unusual for exciting new drugs to spark surges in stock prices and dealmaking frenzy. But molecular glue is a particularly complicated science, and the startups pursuing technologies similar to RevMed are mostly in early stages of testing. Their medicines won’t be ready for years, if ever.
That hasn’t stopped big drugmakers such as Novartis AG, Roche Holding AG and Eli Lilly & Co. from inking research pacts with glue developers that could pay out billions of dollars in milestones.
The boom has been especially lucrative for Monte Rosa Therapeutics Inc. Over the past three years, the Boston-based biotech firm has signed three agreements that could be worth over $10 billion to develop molecular glue drugs with both Novartis and Roche.
The company, which trades under the stock ticker GLUE, has seen its shares surge nearly 400% over the past year. It’s preparing to start mid-stage trials for multiple drugs by the end of this year.
“The run-up in the share price is justified based on what we’ve seen so far,” says Robert Driscoll, an analyst at Wedbush who covers Monte Rosa and RevMed, whose stock has quadrupled over the past 12 months. The gains are “due to the success of their drugs rather than kind of exuberance around the glue technology as a whole,” he says.
The science of glue
Molecular glues work in a fundamentally different way from other oral medicines.
Most pills — like Prozac for depression or Lipitor for cholesterol — are tiny chemicals that squeeze into a pocket inside a much larger protein to gum up its functioning. But many proteins have few obvious pockets, including key cancer-causing proteins.
In fact, about 80% of all proteins in the body are what scientists refer to as “undruggable,” meaning they can’t be targeted with traditional drug technologies.
RevMed’s daraxonrasib cleverly circumvents this problem by acting as a molecular stickum. Once inside the body, it binds to a healthy protein on one side, and then draws in the bad protein to stick to the other side. The healthy protein helps block the bad protein and turn off its signaling.
Some glue-style drugs target bad proteins for destruction after sticking to them. These are known as degraders. It’s a promising concept, though destroying a bad protein isn’t necessarily more effective than just blocking it.
Harvard chemist Stuart Schreiber is credited with coining the term “molecular glue” in the early 1990s to describe how certain organ transplant drugs worked. Schreiber later cofounded a company called Magnet Biomedicine, which has a pact with Lilly to develop glue drugs for cancer.
Each new glue or degrader has to be designed from scratch, “like a unique work of art,” says Jacob Van Naarden, head of the cancer unit and business development at Lilly. It can take years of chemical tinkering to craft one potent enough to fit in a small pill that can also survive the trip down the digestive tract intact.
Competitors line up
Multiple companies are chasing RevMed’s lead in pancreatic cancer despite the long odds. San Diego-based Erasca Inc. is in early stages of testing a drug it says is more potent than daraxonrasib. Japanese drugmaker Astellas Pharma Inc. has begun final-stage trials of a degrader that may help a subset of pancreatic and lung cancer patients.
“The interest level is high,” says Craig Crews, a Yale University chemistry professor and scientific founder of Halda Therapeutics, which pioneered a related “hold and kill” technology.
Johnson & Johnson spent $3.05 billion to acquire Halda last year in one of the biggest bets in the space so far. The company’s lead drug is a once-daily pill for advanced prostate cancer that cements the male hormone receptor present in prostate cancer to another protein essential for cell survival, gumming up its function and causing the cancer cells to die.
In an interview, two J&J executives said they had been following Halda’s technology for years and were impressed by lab data suggesting it could work broadly against tumors with difficult-to-treat mutations.
“Every day our list keeps growing longer and longer, what we can do with it,” says Yusri Elsayed, J&J’s global oncology therapeutic area head. “There is an opportunity to use this in almost all tumor types.”
Molecular glues and degraders are also being developed as alternatives to injectable drugs used to treat autoimmune and skin disorders. Shares of Kymera Therapeutics Inc. have soared more than 180% in the past year thanks to promising early trial results. The Watertown, Massachusetts-based company is developing a once-daily pill it hopes will one day compete with Sanofi and Regeneron Pharmaceuticals Inc.’s Dupixent, one of the world’s bestselling drugs.
“The technology allows you to go after things that would have been almost impossible” to do previously with pills, says Nello Mainolfi, Kymera’s founder and chief executive officer.
Not all of these new drugs wind up being a massive advance over existing treatments. Pfizer Inc. agreed to develop a breast cancer degrader with a company called Arvinas Inc., located just down the street from Halda’s headquarters in New Haven, Connecticut. But the final study results disappointed investors, and the drug has been limited to a subset of patients. The companies recently sold their commercial rights to a third company.
Future blockbuster
With few effective options for pancreatic cancer, analysts expect RevMed’s daraxonrasib to become an enormous bestseller for the Redwood City-based company.
There’s already been extensive media attention, including interviews with former US Senator Ben Sasse, who called it a “miracle drug” after he participated in a clinical trial. So many people are clamoring for the medicine that the US Food and Drug Administration agreed to a special expanded access program for dying patients who don’t qualify for trials.
Prospects for daraxonrasib and speculation about a potential takeout deal have inflated RevMed’s market cap to nearly $33 billion. That’s a lofty figure for a drugmaker with no approved medicines.
But if you ask RevMed, the payoff is warranted after years of wrangling chemistry to make Verdine’s vision a reality. When RevMed acquired Verdine’s company, it had a prototype glue that blocked a cancer-causing protein in mice. But it wasn’t potent enough to be a drug, so RevMed set out on improving it.
“We put every employee we had working on it because we felt we had to make it work,” says Mark Goldsmith, RevMed’s CEO.
Eventually one of RevMed’s chemistry teams came up with a way to use the glue concept to block all forms of the bad protein. Many researchers thought this would be impossible to do without producing too many side effects, but so far they have turned out to be manageable.
The company is preparing to file for US approval soon, and the FDA has promised to give the drug an ultrafast review. It’s projected to reach $7 billion in sales a year by 2032, according to the average of estimates compiled by Bloomberg.
Angel Adegbesan at Bloomberg contributed to this report.