AZD-5153

Nathan Stirk/Getty Images 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. "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.

Almost a decade ago, Gilead shelled out $510 million in cash for YM BioSciences and its only drug, a JAK inhibitor for a rare type of bone marrow cancer called myelofibrosis. But when the candidate didn’t show any benefit over its rival, Incyte’s Jakafi, the molecule ended up in the hands of Sierra Oncology. Now, confident it’s got a diamond in the rough, Sierra $SRRA is putting that drug, momelotinib, through another Phase III trial in myelofibrosis. And on Thursday, the biotech unveiled a $216 million deal for the rights to AstraZeneca’s BRD4 BET inhibitor AZD5153, which it plans on putting through a Phase II trial in combination with momelotinib. “Sierra, from a company perspective, has been very highly focused on single asset development in myelofibrosis, that being momelotinib,” CMO Barbara Klencke told Endpoints News . “So I think it’s very exciting for us to start to have a pipeline.” Recent research has shown the promise of BET and JAK inhibitors in myelofibrosis, Klencke said, including data released in December showing that patients who took Constellation’s BET inhibitor with Jakafi saw a 67% spleen volume response rate. “The JAK/STAT pathway that is so active in myelofibrosis causes cytokines, inflammatory proteins, to be abnormally high. That causes fibrosis,” Klencke said. “Whereas the BET inhibitor can actually reduce some of the inflammation and can potentially reduce that fibrosis as well, so I think they’re very complementary biologic systems.” But unlike other currently available JAK inhibitors, momelotinib doesn’t cause a reduction in platelet count, meaning it could potentially be given in higher doses. Plus, AZD5153 binds at two active binding sites within BRD4, as opposed to one at a time, which the company believes contributes to its potency. Sierra’s putting down $8 million upfront for AZD5153, plus another $208 million in biobucks and tiered royalties on global sales from the “high single-digits to low double-digits.” The team plans on launching the Phase II combination trial in the first half of next year. They’re also on track to read out results from the Phase III monotherapy study in the first quarter. Jakafi was approved back in 2011 to treat myelofibrosis and raked in over $1.9 billion last year. While it was in Gilead’s pipeline, momelotinib proved statistically non-inferior to Jakafi on a key measure of efficacy, but didn’t look any better and didn’t hit its mark on a key secondary for the total symptom score. The studies were also hit with a high washout rate for patients due to side effects. What makes Sierra think this time around will be different? “We have used our prior data from Gilead and from earlier Phase IIs to design the right trial. MOMENTUM is designed knowing the patient type and the expected level of activity,” Klencke said. “So we have a very high level of confidence around MOMENTUM being a trial that should be able to confirm the efficacy of momelotinib.”