Aspiring to become the leader in inflammasome-targeted therapeutics, Novartis will acquire IFM Tre, a subsidiary of Boston-based IFM Therapeutics, in a deal worth up to $1.6 billion. The purchase gives Novartis a portfolio of antagonists of NLRP3, a drug target that is being hotly pursued by big and small companies alike.
Novartis will pay $310 million upfront and up to roughly $1.3 billion in milestones to access three early-stage NLRP3 antagonists: IFM-2427, a systemically acting compound that began its first human studies last week, and two preclinical compounds: one gut-penetrating, and the other directed at the central nervous system.
The NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing receptor pyrin domain containing 3) inflammasome is a multiprotein complex that is part of the innate immune system, the body’s first line of defense against pathogens. NLRP3 is on constant alert for signs of danger, responding to errant microbes or sensing molecules associated with tissue damage or disease. But overactivation of the inflammasome is implicated in a host of diseases.
Although drug hunters have been trying to develop NLRP3 inhibitors for years, many have failed. The complex poses several problems, IFM CEO Gary Glick says. For one, scientists still don’t have a crystal structure of the monomeric or full-assembled form of the protein—a hefty oligomer that forms when the complex kicks into gear. And the inflammasome is hard to make and work with.
Moreover, Glick adds, there are no natural ligands known to the complex, meaning researchers don’t have good starting points for finding even tool compounds. “Lots of compounds in the literature are reported to be NLRP3 inhibitors, but many, in fact, don’t work on NLRP3 itself, but on the pathway,” he says.
Although Glick won’t elaborate on IFM’s drug-discovery strategy, the biotech firm managed to overcome those hurdles and last week said it has begun a clinical trial of IFM-2427.
For its part, Novartis has spent the better part of seven years working on the inflammasome and is exploring a range of approaches to targeting the complex or the partners it activates. The company already has an approved drug, Ilaris, that binds one of those partners, IL-1, and is working other inflammasome-targeted small molecules, antibodies, and bispecific molecules.
The effort is a response to the potentially vast therapeutic opportunity of the inflammasome. “We want to own this space,” says Christian Bruns, head of Novartis’ autoimmunity, transplantation, and inflammation research team, which spans more than 400 scientists. “It’s an all-in approach.”
Bruns notes that preclinical studies have provided clear evidence for the importance of the pathway for a swath of diseases—gout, irritable bowel syndrome, nonalcoholic steatohepatitis, cardiovascular disease, Parkinson’s disease, and Alzheimer’s disease, to name a few. “We cannot address these different diseases with one single compound,” he adds. For example, neurological disorders require a molecule that can slip past the blood-brain barrier, while inflammatory bowel disease patients are better treated with a gut-targeted compound like the one IFM Tre designed.
Early on, Novartis identified IFM as a potential partner, and both companies say the acquisition was the result of a competitive process. It’s the latest in a blistering run for IFM Therapeutics, which Glick founded in late 2015. In 2017, Bristol-Myers Squibb paid $300 million for IFM’s portfolio of STING agonists for cancer.
After that deal, the IFM team stuck around to keep doing science together. IFM Tre formally launched last year with $30 million in funding from a series of investors, and in February, IFM launched IFM Due, a subsidiary devoted to developing STING antagonists.