Foghorn downgraded to full clinical hold, with more patient deaths clouding AML, MDS trial

Three months after the FDA sent a warning to Foghorn Therapeutics via a partial clinical hold on its phase 1 trial, regulators have become even more dismayed, downgrading the company's study to a full hold in light of additional patient deaths. 

The company disclosed Tuesday that further analysis of the data turned up additional suspected cases of fatal differentiation syndrome tied to the company’s med, FHD-286, in its phase 1 advanced acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) trial.

Foghorn would not disclose additional details about the cases at this time, including how many arose, Ben Strain, a company spokesperson, said in an email response. Wall Street reacted harshly to the news, with the company's shares down more than 23%, from $14.69 to $11.28 as of 10:47 A.M. ET.

In differentiation syndrome, the body is flooded with cytokines released by leukemia cells that anti-cancer drugs target. Foghorn says it’s an effect “that has been seen with, and is believed to be on-target for, the proposed mechanism of action for FHD-286.” The med is an enzyme inhibitor targeting BRG1 and BRM, two similar proteins that can help cancer grow. 

The FDA's decision stifles the AML and MDS development program, which has been underway for more than 15 months. As recently as Aug. 9, the company said it was continuing to work with the FDA to get the partial hold lifted. The partial hold was initiated in May after one death was identified.

All is not lost with FHD-286, however, with another phase 1 study testing the med in metastatic uveal melanoma continuing to enroll

It’s not the first time the FDA has had to pump the breaks over differentiation syndrome. Kura Oncology’s KO-539 and Agios’ enasidenib and ivosidenib all received partial holds. The latter two meds were able to reach the market, while KO-539 had its partial hold lifted after two months.

The severity of the adverse events seen in Foghorn's trial won’t be totally understood until the company releases more details. An FDA analysis of enasidenib and ivosidenib found that grade 3 side effects or worse appeared in 66% and 68% of patients, respectively, with 5% and 6% fatal. 

At the very least, Foghorn has the cash to stave off clinical hurdles, at least for the time being. The company had $394.7 million as of June 30, with R&D expenses in the second quarter reaching $26 million.