Novartis will team up with a subsidiary of IFM Therapeutics to develop immunotherapies designed to fight inflammatory and autoimmune diseases by inhibiting the cGAS/STING pathway. Mutations activating that pathway (shown in red) can cause serious autoinflammatory and autoimmune diseases in humans, including STING-associated vasculopathy with onset in infancy (SAVI; pictured) [Zuoming Deng, and Michael DiMattia, National Institute of Arthritis and Musculoskeletal and Skin Disease]

Novartis will team up with a subsidiary of IFM Therapeutics to develop immunotherapies designed to fight inflammatory and autoimmune diseases by inhibiting the cGAS/STING pathway, through a collaboration that IFM said today grants the pharma giant an option to acquire the subsidiary for up to $840 million.

In return for the exclusive option to acquire IFM Due, Novartis agreed to fully finance the IFM subsidiary’s R&D development costs for the program to develop inhibitors of cGAS/STING, which stands for cyclic GMP-AMP Synthase, Stimulator of Interferon Genes.

The cGAS/STING pathway functions within the innate immune system to sense cytosolic DNA, a signal of cellular danger, then trigger a STING-dependent inflammatory response. According to IFM, mutations that activate the cGAS/STING pathway can cause serious autoinflammatory and autoimmune diseases in humans that are characterized by excessive interferon/cytokine signaling—including rare diseases such as Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI) and a subset of systemic lupus erythematosus (SLE).

When cGAS/STING activation departs from the norm, such as in mitochondrial dysfunction, more common diseases can result such as nonalcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease (COPD), age-related macular degeneration (AMD), and Parkinson’s disease.

“In the broad set of diseases where excessive production of interferon and other pro-inflammatory cytokines via the cGAS/STING pathway is an underlying driver, precisely targeting this pathway is the most attractive therapeutic approach,” H. Martin Seidel, PhD, EVP of research and development at IFM, said in a statement.

Success with STING

Novartis has been interested for years in STING-based treatments, having inked an up-to-$750 million collaboration with Aduro Biotech in March 2015 to develop cancer immunotherapies designed to target and activate the STING receptor.

On June 2 at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Funda Meric-Bernstam, MD, department chair, investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, presented positive data from an ongoing Phase Ib clinical trial (NCT03172936) in patients with advanced solid tumors or lymphomas. The combination of Aduro’s STING pathway activator ADU-S100 (MIW815) and Novartis’ spartalizumab (PDR001), an investigational anti-PD-1 monoclonal antibody showed antitumor activity in anti-PD-1-naïve triple-negative breast cancer (TNBC) and previously immunotherapy-treated melanoma.

As of the April 5, 2019 data cut-off, Aduro said, five patients treated in the weekly dosing schedule group achieved confirmed responses, one of which was a complete response. Of eight evaluable TNBC patients, one anti-PD-1 naïve TNBC patient achieved a complete response, while two achieved partial response (Abstract #2507).

Novartis isn’t the only biopharma targeting cGAS/STING to treat autoimmune and other inflammatory diseases—or doing so with Aduro, for that matter. Eli Lilly and Aduro launched their cGAS/STING collaboration in December 2018, agreeing to develop an undisclosed number of treatments in return for Lilly paying Aduro up to approximately $620 million per treatment developed.

Two preclinical programs

IFM Due was launched in February with an undisclosed amount of capital. IFM Due’s pipeline includes two preclinical programs. One is aimed at developing oral small-molecule antagonists of STING that can block its ability to stimulate excessive production of interferons and other pro-inflammatory cytokines. Clinical trials of the first STING antagonist are expected to begin in 2021, IFM Due said.

The second program is designed to develop small-molecule inhibitors of cGAS, which will block the pathway further upstream.

Upon its launch, IFM Due also announced the appointment of immunologist Andrea Ablasser, MD, of the École Polytechnique Fédérale de Lausanne in Switzerland, as founding scientist for IFM Due and a member of its Scientific Advisory Board.

The up-to-$840 million buyout price includes an undisclosed upfront payment to IFM Due’s shareholders, plus unspecified milestone payments.

The deal with IFM Due is Novartis’ second involving a subsidiary of Boston-based IFM Therapeutics LLC. On May 8, Novartis completed an up-to-$1.575 billion acquisition of IFM Tre, a deal intended to expand the pharma giant’s pipeline with one clinical and two preclinical programs designed to treat chronic inflammation by inhibiting targets in the innate immune system. IFM Tre specializes in developing small-molecule antagonists targeting abnormal or chronic inflammatory responses of the innate immune system through the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) pathway.

IFM Therapeutics LLC was established by management members of the original IFM Therapeutics Inc., following its acquisition by Bristol-Myers Squibb (BMS) in 2017 for $300 million upfront and up to $1.01 billion in milestones. That deal gave BMS full rights to the original IFM’s preclinical STING and NLRP3 agonist programs focused on enhancing the innate immune response for treating cancer.

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