The FDA has placed a partial clinical hold on five clinical trials—of which three are Phase III pivotal studies—by Gilead Sciences assessing its combination of magrolimab plus Vidaza® (zacitidine) in various blood cancers, the company has acknowledged.

Gilead said the FDA acted after the agency raised concerns over “an apparent imbalance in investigator-reported suspected unexpected serious adverse reactions (SUSARs) between study arms.”

The company did not specify that it had more SUSARs in the trials’ treatment arms compared with control arms.

“While no clear trend in the adverse reactions or new safety signal has been identified by Gilead at this time, the partial clinical hold is being implemented by Gilead across all ongoing magrolimab and azacitidine combination studies worldwide in the best interests of patients as additional data is gathered and analyzed to address the concerns raised by FDA,” Gilead stated on Tuesday.

The five trials halted for now are nearly half of the 11 clinical studies (including all of the Phase III studies) now assessing magrolimab, including:

  • Phase III ENHANCE study in myelodysplastic syndrome (MDS; NCT04313881)
  • Phase III ENHANCE-2 study in acute myeloid leukemia (AML; TP53 mutated patients; NCT04778397)
  • Phase III ENHANCE-3 study in unfit AML (NCT05079230)
  • Phase Ib study in MDS (NCT03248479)
  • The azacitidine combination cohorts of a Phase II study in myeloid malignancies (NCT04778410)

Not affected by the halt are five Phase II trials assessing magrolimab in two additional blood cancers and three solid tumor cancers, including:

A sixth Phase II trial assessing magrolimab in colorectal cancer has been in planning stages and had not begun recruiting patients, Gilead added.

Investors responded to the partial clinical halt with a slight selloff that sent Gilead shares down 2% to $67.34 at the close of trading Wednesday, from Tuesday’s close of $68.84.

No near-term BLA Filing

Michael Yee, an analyst with Jefferies, wrote in a research note Tuesday night, said the partial halt ends hope, for now, that Gilead can file a Biologics License Application for magrolimab this year

“It certainly means no near-term magro BLA filing some were hoping for and mgmt previously guided was possible too,” Yee wrote.

Gilead raised that possibility for magrolimab during its presentation at the recent virtual J.P. Morgan 40th Healthcare Conference, when the company included the Phase III magrolimab trials in its category of “Phase III, Filed or Approved” within a graphic displaying its pipeline. That pipeline, Gilead said, consisted of 55 clinical stage programs, of which 18 were advanced enough to be at BLA, FDA New Drug Application (NDA) or European Medicines Agency Marketing Authorization Application stages.

The partial halt on magrolimab trials raises the stakes, Yee added, for an upcoming Phase III trial evaluating Gilead’s marketed cancer drug, Trodelvy® (sacituzumab govitecan-hziy) in hormone receptor-positive (HR+) breast cancer.

“The stakes are high since GILD acquired Trodelvy for $20B and this HR+ breast cancer study represents the largest portion of the $2-3B+ peak [sales] consensus,” Yee observed. “If the data are marginal or fail, sentiment will get hit hard, reflecting weak conviction in the BD [business development] strategy at GILD on what was their largest acquisition. If data are good, [Wall] Street will be relieved, and we can move on.”

“Our call is the data is likely positive, but with modest PFS [progression-free survival] benefit, and hopefully will have some OS [overall survival] trend to file to FDA—and remove the fear the study will be very disappointing,” Yee predicted.

Third disappointment

The partial halts, he added, mark the third disappointment for magrolimab under Gilead. The company moved its next planned data update to the first quarter of this year following a disappointing Takeda Pharma Phase III readout in MDS, as well as what Gilead said was its need to confer with the FDA. Also, the continuing response (CR) rate in the Phase IB study had declined as data matured, from 55% down to 42%, with the data update to offer additional CR figures.

Gilead added magrolimab to its pipeline in 2020 when it acquired the drug candidate and others as part of its $4.9 billion cash purchase of Forty Seven. Through that deal, Gilead intended to bolster its immuno-oncology R&D pipeline, starting with magrolimab, which was Forty Seven’s lead pipeline candidate and which generated positive Phase Ib results trumpeted by that company in December 2019.

Magrolimab is, according to Gilead, a potential first-in-class monoclonal antibody designed to target CD47, a protein that allows cancer cells to avoid destruction, thus allowing a patient’s own innate immune system to engulf and eradicate those cancer cells—an effect nicknamed “don’t eat me” by Forty Seven as well as Stanford University School of Medicine researchers that discovered the immunotherapy and successfully tested it in Phase I in 2018.

Magrolimab is also a macrophage checkpoint inhibitor that is designed to interfere with recognition of CD47 by the signal regulatory protein alpha (SIRPα) receptor on macrophages, with the goal of blocking the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages.

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