FDA issues partial hold affecting Gilead’s Magrolimab, an investigational monoclonal antibody

USA – The FDA has temporarily halted trials of Gilead Sciences’ anti-CD47 antibody magrolimab in combination with azacitidine, citing an “apparent imbalance” in investigator-reported suspected unexpected serious adverse reactions (SUSARs) between study arms.

In 2020, the company acquired the investigational treatment as part of its US$4.9 billion acquisition of Forty Seven.

Gilead said “no clear trend in the adverse reactions or new safety signal” has so far been identified, but the partial clinical hold is being implemented across all ongoing magrolimab and azacitidine combination studies worldwide “as additional data is gathered and analyzed to address the concerns raised by the FDA.”

The partial hold affects three Phase III studies: ENHANCE in myelodysplastic syndrome (MDS), ENHANCE-2 in TP53-mutated patients with acute myeloid leukemia (AML), and ENHANCE-3 in unfit AML.

 The regulatory action also affects the azacitidine combination cohorts of a Phase II study in myeloid malignancies as well as a Phase Ib study in MDS.

Promising early results

At the American Society of Hematology (ASH) conference in 2019, Forty-Seven presented findings from the Phase Ib trial showing that among 24 higher-risk MDS patients who received a priming dose of magrolimab, followed by full doses of azacitidine plus a magrolimab maintenance dose once weekly, the overall response rate was 92 percent.

Forty Seven said at the time that the combination was well-tolerated and that there was no evidence of increased toxicity when compared to azacitidine alone.

During the partial hold, new study participant screening and enrollment will be halted, while patients already enrolled in the affected studies will continue to receive magrolimab and azacitidine, or placebo, while being closely monitored.

The FDA’s action has no bearing on other magrolimab studies or cohorts that are not investigating the combination.

CD47 is an immunoglobulin that is found on the surface of many cancer cells. CD47 forms a signaling complex with signal-regulatory protein (SIRP), allowing cancer cells to escape macrophage-mediated phagocytosis.

Magrolimab, formerly known as Hu5F9-G4, is a potentially first-in-class monoclonal antibody that inhibits the recognition of CD47 on tumor cells and its binding partner, Signal-regulatory protein alpha (SIRP), on macrophages, according to Gilead.

The drug is being researched for use in a variety of hematologic cancers as well as solid tumor malignancies.

Meanwhile, Pfizer paid nearly US$2.3 billion for Trillium Therapeutics last year, bolstering its oncology pipeline with the addition of the latter’s two lead molecules, TTI-622 and TTI-621, both of which block the SIRP-CD47 axis.

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