Merck's acquisition of Peloton Therapeutics gives it access to a novel inhibitor of a protein that enables cancer cells to survive hypoxia. The drug blocks the HIF2α transcription factor and is being tested in a phase I/II trial for clear cell renal cell carcinoma. A phase II trial is testing a related Peloton compound in glioblastoma.
With Merck's acquisition of Dallas, TX–based Peloton Therapeutics for $1.05 billion and milestone payments, announced in May, the pharmaceutical giant will obtain Peloton's lead compound, PT2977. The HIF2α inhibitor could become a treatment for clear cell renal cell carcinoma (ccRCC) and other cancers.
“It's a drug with a lot of potential,” says Rodrigo Toledo, PhD, of Vall d'Hebron Institute of Oncology in Barcelona, Spain.
HIF2α and the related protein HIF1α help tumors endure hypoxia. The proteins each dimerize with another protein (HIF1β/ARNT) to activate genes affecting metabolism, genome stability, angiogenesis, and other functions. Because of the proteins' involvement in cancer and other diseases, “people have thought about targeting the HIFs for a long time,” says M. Celeste Simon, PhD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.
Although skeptics had argued that HIF2α is not a viable target, researchers identified a pocket in a domain of the protein that allows dimerization with HIF1β, and Peloton subsequently developed small molecules to exploit this vulnerability; PT2977 is the latest. “Peloton's remarkable development of HIF2-specific inhibitors is a milestone in the field,” says Gregg Semenza, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, MD. Seeing responses to PT2977 should counter skepticism in the field about the ability to target transcription factors, he adds.
The rationale for testing HIF2α inhibitors in ccRCC is clear: In more than 90% of patients with the cancer, VHL is missing or defective, often because of mutations in its gene, VHL. VHL promotes degradation of HIF2α by the proteasome, but when VHL is absent, HIF2α remains active and drives tumor growth.
The company is testing PT2977 in several patient populations, including people with advanced ccRCC. Earlier this year, researchers presented the latest data from a phase I/II study that included 55 patients. The drug led to confirmed partial responses in 22% of patients, and median progression-free survival (PFS) had not been reached.
HIF2α inhibitors may also be effective against glioblastomas, but for a different reason. Although the tumors rarely have mutations in VHL, they rely on this pathway and other pathways for cellular adaptations to their hypoxic microenvironment, notes Roy Strowd, MD, of the Wake Forest School of Medicine in Winston-Salem, NC. “If we are able to target that pathway, it could prevent recurrence,” he says.
Strowd is leading a phase II study of Peloton's first-generation HIF2α inhibitor, PT2385, in patients with recurrent glioblastoma. (Peloton is no longer developing PT2385, but it was the only HIF2α inhibitor available when researchers planned the trial, says Strowd.) At the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, researchers with his team presented data for 24 patients who received one of three doses of the drug. Although there were no objective radiographic responses, patients who achieved the highest circulating levels of the drug had a median PFS of 6.7 months, versus 1.8 months for those with lower circulating levels.
Toledo says that two other promising targets for HIF2α inhibitors are pheochromocytomas and paragangliomas, which often carry HIF2α-stabilizing mutations in several genes, including EPAS1, which codes for HIF2α. The acquisition of Peloton should boost development of PT2977 because Merck's resources will allow testing of the drug in combination with other treatments and possibly in other tumor types, he adds.
Yet, researchers raise some caveats about HIF2α inhibition. “We still don't have a phase III study establishing the effectiveness of these compounds,” says Strowd. And as Simon notes, in some cancers, such as sarcoma, HIF2α serves as a tumor suppressor, suggesting that researchers will have to carefully select which cancers to target. “Every disease has to be evaluated on a case-by-case basis,” she says. –Mitch Leslie