Sierra Signs Exclusive Deal with AstraZeneca for Potent BRD4 BET Inhibitor

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Sierra Signs Exclusive Deal with AstraZeneca for Potent BRD4 BET Inhibitor


Sierra Oncology, the late-stage biopharmaceutical firm specializing in treatments for rare cancers, has signed an exclusive deal to use AstraZeneca’s product to develop a potential new drug for myelofibrosis.

Under the terms of the agreement, Sierra Oncology will have exclusive access to AZD5153, a potent and selective BRD4 BET inhibitor with a novel bivalent binding mode. Sierra plans to initiate a study combining the component with its JAK inhibitor, momelotinib, for the treatment of patients with myelofibrosis.

AZD5153 works by inhibiting protein bromodomains from improving drug potency. At present, the treatments for the disease involve JAK inhibitors, which are myelosuppressive. 

According to Sierra’s statement, combining AZD5153 with momelotinib, which is not myelosuppressive, may provide an efficacy and safety advantage over other JAK inhibitor plus BET inhibitor combinations. It could also allow for prolonged treatment duration and dose intensity. BET inhibition — particularly for Bromodomain and Extra-terminal domain in this case — can lead to reduced inflammatory cytokine release, reduced mutant cell proliferation, and anti-fibrotic activity, which all point to disease-modifying effects. 

The trial, which is expected to start in the first half of 2022, is endeavoring to provide preliminary proof of concept for a future confirmatory study. It may also be used to support even more research on the effectiveness of momelotinib when combined with other agents in development with the hope of treating myelofibrosis. 

Momelotinib is an orally bioavailable JAK1, JAK2, and ACVR1/ALK2 inhibitor for the possible treatment of the said disease. Myelofibrosis is a product of dysregulated JAK-STAT signaling and is manifested through symptoms such as progressive anemia and an enlarged spleen (splenomegaly). 

At present, momelotinib is being evaluated in the MOMENTUM clinical trial for symptomatic and anemic myelofibrosis patients. It has also received a Fast Track designation from the U.S. Food and Drug Administration

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“The combination of JAK inhibition and BET inhibition has been identified as a promising emergent approach for the treatment of myelofibrosis. However, currently available JAK inhibitors are myelosuppressive, leaving a critical unmet need for patients with anemia or those at risk of developing treatment-emergent anemia. Given momelotinib’s unique mechanism as an inhibitor of ACVR1 / ALK2 in addition to JAK1 and JAK2, we are excited by the potential for improved outcomes for myelofibrosis patients with this promising combination,” commented Mark Kowalski, M.D., Ph.D., the chief of research and early development at Sierra.

In the same press release, Sierra Oncology president and chief executive officer Stephen Dilly said that the global in-licensing agreement with AstraZeneca is of two-fold importance to the company’s growth plans. For one, the partnership brings in a new compound to its pipeline, effectively expanding its discovery and development opportunities. Second, it would allow Sierra to enhance its ability and resources to find a treatment for patients diagnosed with myelofibrosis by building on the strengths of momelotinib.

Sierra will pay AstraZeneca an undisclosed amount upfront and later pay more as pre-determined development, regulatory, and commercial milestones are achieved. Sierra will also give tiered royalties based on future sales and will be responsible for the initial Phase II trial execution, as well as all future development and commercialization activities.  


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