FDA Action Alert: GSK and Alnylam

FDA Action Alert: GSK and Alnylam

This week, GSK is expecting a verdict for its myelofibrosis candidate momelotinib and Alnylam will make the case for patisiran in cardiomyopathy of ATTR amyloidosis.

Alnylam Looks to Make Patisiran’s Case in Second Indication

On September 13, the FDA will convene its Cardiovascular and Renal Drugs Advisory Committee to discuss Alnylam’s supplemental New Drug Application (sNDA) for Onpattro (patisiran) in adults with cardiomyopathy of wild-type or hereditary transthyretin-mediated (ATTR) amyloidosis. The FDA’s verdict is due on October 8.

ATTR amyloidosis is a rare and progressive disease that arises when misfolded transthyretin proteins accumulate as amyloid fibrils in various organs throughout the body—including the nerves, gastrointestinal tract and heart—leading to dysfunction. In the heart, these amyloid clumps make the walls stiff and compromise its pumping function.

In its current application, which the FDA accepted in February 2023, Alnylam is proposing patisiran as a treatment for cardiomyopathy arising from transthyretin accumulation in the heart. The sNDA includes data from the Phase III APOLLO-B trial, a randomized, placebo-controlled and double-blinded study that demonstrated improvements in quality of life and functional capacity in patients following treatment with patisiran.

Patisiran was found to be safe in ATTR-cardiomyopathy patients in APOLLO-B, with most side effects being mild or moderate in severity. The overall adverse event profile was consistent with that established in prior clinical studies.

Patisiran—marketed in the U.S. as Onpattro in polyneuropathy of hereditary ATTR amyloidosis—is an injectable double-stranded siRNA therapeutic that works by binding to messenger RNA encoding transthyretin and tagging it for destruction, which results in an overall lower level of the protein in the body.

This mechanism of action won Onpattro the FDA’s approval in August 2018 for hereditary ATTR amyloidosis polyneuropathy, making it the first-ever RNA interference therapeutic to secure the regulator’s authorization.

GSK Awaits Momelotinib Verdict in Myelofibrosis After Delay

Following a three-month delay to review new information, the FDA is expected to release its decision on GSK’s NDA for momelotinib as a treatment for myelofibrosis patients with anemia by September 16.

Momelotinib is an investigational medication that has a “novel mechanism of action,” inhibiting three signaling pathways: the JAK1 and JAK2 pathways and the activin receptor type I (ACVR1) cascade, according to a GSK press release announcing the delay. The molecule was most recently developed by California biotech Sierra Oncology, which was acquired by GSK for $1.9 billion in April 2022.

By silencing the JAK1 and JAK2 pathways, momelotinib eases symptoms of splenomegaly and elicits improvements in the patients’ constitution. This is complemented by its activity along the ACVR1 cascade, potentially lowering levels of the hepcidin protein, which is elevated in myelofibrosis and contributes to anemia.

The FDA first accepted GSK’s NDA in August 2022 and set an initial target action date of June 16, 2023. On the day of the deadline, the regulator announced it would need three more months to evaluate new data.

GSK supported momelotinib’s regulatory bid with data from the Phase III MOMENTUM trial, which showed that the candidate met its primary efficacy endpoint, reducing Total Symptom Score after 24 weeks of treatment by at least 50%. Momelotinib likewise aced its secondary efficacy metrics, including transfusion independence and splenic response rate.

The company presented these 48-week data in December 2022 at the 64th American Society of Hematology (ASH) Annual Meeting.

Source: BioSpace