STING antagonists(Merck)

For more than four years, Novartis has foot the bill for a partner’s preclinical development of molecules with the potential to target a pathway implicated in inflammatory disorders. Now the pharmaceutical giant has seen enough progress to plunk down $90 million to buy the company, IFM Due, and continue its inflammation drug research. The acquisition announced Wednesday is the culmination of a 2019 agreement that Novartis reached with IFM Due’s parent company, IFM Therapeutics. In exchange for fully funding IFM Due’s R&D, Novartis gained an option to acquire all of that biotech’s stock. IFM Due’s research focuses on cGAS, a protein that regulates STING, a pathway in the innate immune system that senses signals of cellular danger. Picking up these signals triggers an inflammatory response. Inappropriate activation of the STING pathway leads to excessive signaling that drives inflammation. IFM Therapeutics says dysregulation of this pathway could be the basis for several inflammatory disorders. Specific diseases covered by IFM Due’s research remain undisclosed. But Novartis now has full rights to IFM Due’s portfolio of small molecules that could potentially treat conditions driven by excessive STING pathway activity. The Novartis acquisition marks the third exit event for IFM Therapeutics. The Boston company houses its research in subsidiaries, a corporate structure that enables each business unit to strike up partnerships with big pharmaceutical companies that can finance the research and potentially acquire it. The first such deal was Bristol Myers Squibb’s 2017 acquisition of IFM Therapeutics’ cancer immunotherapy research for $300 million up front. In 2019, Novartis paid $310 million up front to acquire IFM Tre, a clinical-stage IFM Therapeutics subsidiary whose lead program was a treatment for the fatty liver disease now known as MASH. Like the prior two IFM Therapeutics deals, the latest acquisition could pay out more depending on the progress of the research. IFM Due milestones could add another $745 million to Novartis’s tab. “The acquisition of IFM Due represents the culmination of a highly productive, four-year preclinical collaboration between Novartis and IFM to develop novel small-molecule STING inhibitors with the potential to treat a spectrum of inflammatory diseases,” Richard Siegal, global head of immunology research at Novartis, said in a prepared statement. “We are excited to advance IFM Due’s STING program and leverage our deep expertise in inflammation science to bring forward transformative medicines that address major unmet patient needs.” Novartis’s IFM Due acquisition comes as a potential rival makes progress with its own research drugging the cGAS-STING pathway. At the start of this year, Ventus Therapeutics began a Phase 1 trial for VENT-03, a molecule the company claims is the first cGAS inhibitor to enter clinical development. In an interview during the J.P. Morgan Health Care Conference in San Francisco in January, Ventus CEO Marcelo Bigal said previous efforts to drug cGAS have fallen short because even though drug hunters could hit the target, their molecules failed to show sufficient potency to make them viable medicines. Bigal said the cell is a dynamic environment in which protein shapes change with the movement of fluid. Ventus’s ReSOLVE technology analyzes proteins in this watery environment to find the pockets where a molecule can bind to its target. “If the proof is in the pudding, I think what ReSOLVE has is the pudding,” Bigal said. Ventus’s Phase 1 trial of VENT-03 is testing various doses of the drug candidate in healthy volunteers. Preliminary data are expected in the second half of this year.

Novartis has gained full rights to a portfolio of STING antagonists. Novartis is stepping on the cGAS. Three years after securing an option on an IFM Therapeutics subsidiary, the Swiss drugmaker has accelerated into the deal and paid $90 million upfront for small molecules that inhibit the cGAS-STING pathway. Researchers have uncovered the role the cGAS-STING pathway plays in the mediation of inflammation in response to infection, cellular stress and tissue damage over the past decade or so, spurring interest in targeting the axis to treat autoimmune and degenerative diseases. Novartis threw its weight behind the push by agreeing to fund research at an IFM subsidiary, IFM Due, in 2019. Having bankrolled the preclinical research, Novartis has seen enough promise to warrant pumping more money into the program. The drugmaker has paid $90 million upfront and committed up to $745 million in milestone payments to acquire IFM Due. In return, Novartis has gained full rights to a portfolio of STING antagonists with potential applications in the treatment of a range of diseases characterized by excessive interferon and other pro-inflammatory cytokine signaling. This morning's release lacks details of the status of the molecules, but the original plan was for Novartis to fund IFM Due through late-stage preclinical development of the lead program. Drug developers are attacking the cGAS-STING pathway from multiple angles. One approach is to inhibit cGAS, an enzyme that activates STING. Ventus Therapeutics recently began a phase 1 clinical trial of a cGAS inhibitor, while Nimbus Therapeutics has a discovery-stage cGAS program in its pipeline. Other groups, including Bayer and Novartis, have inked deals for antagonists of STING. Novartis’ decision to take up its option on IFM Due comes four years after it paid $310 million to buy another of the biotech’s subsidiaries. The earlier deal gave Novartis control of the clinical and preclinical NLRP3 antagonists in development at IFM Tre. IFM sold preclinical STING and NLRP3 agonist programs to Bristol Myers Squibb in 2017.