A hefty price tag for NLRP3

Novartis snaps up subsidiary IFM Tre and trio of NLRP3 antagonist molecules

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BOSTON—Novartis and IFM Therapeutics, a privately held biopharmaceutical company, opened the second quarter of the year with the announcement of an acquisition. And while the deal may have been announced on April 1, it’s no joke—especially not with a potential total of nearly $1.6 billion.
Under the terms of the definitive agreement, Novartis will acquire all outstanding capital stock for IFM Tre, a subsidiary company of IFM. Once the agreement closes, Novartis will pay IFM $310 million up front, with the potential for up to $1.265 billion in milestone payments, for a total deal value of $1.575 billion. Both Novartis’ and IFM’s boards of directors have approved the transaction, as have IFM’s shareholders. The companies expect the transaction will close in Q2 2019, subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Act.
IFM’s specialization is the development of therapies that can modulate the innate immune system. Its subsidiary, IFM Tre, launched last July to develop a pipeline of NLRP3 antagonists to treat inflammatory diseases. At present, the pipeline that Novartis will gain with its acquisition consists of three NLRP3 inhibitors, including two preclinical molecules—one for inflammatory bowel disease and one described as “central nervous system-penetrant”—and IFM-2427, a Phase 1 clinical-stage systemic antagonist against chronic inflammatory conditions.
According to the Genetics Home Reference website, part of the NIH’s U.S. National Library of Medicine, the NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing receptor pyrin domain containing 3) gene generates cellular instructions for the protein cryopyrin. “NLR proteins are involved in the immune system, helping to start and regulate the immune system’s response to injury, toxins or invasion by microorganisms. These proteins recognize specific molecules, become activated and respond by helping to engage components of the immune system. Cryopyrin recognizes bacterial particles; chemicals such as asbestos, silica and uric acid crystals; and compounds released by injured cells. Once activated, groups of cryopyrin molecules assemble themselves along with other proteins into structures called inflammasomes, which are involved in the process of inflammation. Inflammation occurs when the immune system sends signaling molecules as well as white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair.”
As IFM explains on its website, “By blocking inflammasome activity, our small-molecule inhibitors may help reduce overactive cytokine production and stop inflammatory signaling. IFM is investigating several members of the NLR family including NLRP1, NLRP3, NLRP6, NLRP10 and NLRC4. By targeting components of the inflammasome, the potential exists for our NLR antagonists to be used for multiple indications and to serve as first-in-class innate immune modulators for the treatment of liver fibrosis/non-alcoholic steatohepatitis (NASH), neurodegeneration/Alzheimer’s disease, cardio-metabolic diseases such as atherosclerosis and type 2 diabetes, gout, age-related macular degeneration and autoimmune diseases that include systemic sclerosis, inflammatory bowel disease (IBD), vitiligo, type 1 diabetes, celiac disease, systemic lupus erythematosus and rheumatoid arthritis.”
Despite being less than four years old as a company, Forbes’ Bruce Booth notes that “[T]his is the second transformative deal struck by IFM around its innate immune portfolio in less than two years. Back in August 2017, BMS acquired IFM’s preclinical STING and NLRP3 agonist programs aimed at enhancing the innate immune response in cancer, for $300M upfront and up to $2B in milestones.” The STING antagonists, along with cGAS antagonists, are being developed by another IFM subsidiary, IFM Due.
“The NLRP3 inflammasome has been a hard-to-drug but well-validated target for years: human genetics links it to a number of conditions (e.g., NLRP3 mutations are implicated in Muckle-Wells Syndrome and other rare fevers); pharmacological pathway validation exists with broad range of IL-1-related approaches; and lastly, the CRID3/MCC950 tool compound has been out in academic and industry hands for almost a decade helping elucidate more about the approach in preclinical settings,” according to Booth. “That said, CRID3’s drawbacks as a drug were challenging, and limited success was made in getting new chemical matter beyond those tool compounds. That’s where Gary [Glick, CEO and co-founder of IFM] and his team stepped up, armed with conviction around the biology and a commitment to cracking it.”

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