Agios Exits Oncology

The company behind the only two IDH-targeted drugs on the market has exited the cancer field. Late last year, Agios Pharmaceuticals, maker of the IDH1 inhibitor ivosidenib (Tibsovo) and originator of the IDH2 inhibitor enasidenib (Idhifa; Bristol Myers Squibb), announced plans to sell its oncology business to Servier for $1.8 billion plus royalties and a potential $200 million milestone payment.

Ivosidenib and enasidenib are approved to treat acute myeloid leukemia (AML). The drugs target oncogenic forms of isocitrate dehydrogenase, a key enzyme in cellular energy metabolism that, when mutated, produces a metabolite implicated in tumor progression.

The deal also includes a third IDH inhibitor, the dual IDH1/2 blocker vorasidenib (AG-881) now in phase III testing for low-grade glioma, along with two early clinical-stage assets—a MAT2A inhibitor (AG-270) and a DHODH inhibitor (AG-636)—and several preclinical discovery programs.

“We're happy that Servier wanted all of that, and was willing to pay a good price, and that they're going to invest behind them,” says Agios CEO Jacqualyn Fouse, PhD. “This was a pretty tough decision for us to take,” she adds, but it made sense given Servier's greater marketing might and pipeline of other cancer drugs ready for testing with Agios's agents.

Since the FDA approvals of ivosidenib and enasidenib in 2018 and 2017, respectively, sales of both drugs have been somewhat sluggish. The infrequency of IDH1 and IDH2 mutations, each found in roughly 10% of AML cases, partially explains the low uptake, as does direct competition with the recently approved combination of azacitidine plus the BCL2 inhibitor venetoclax (Venclexta; AbbVie/Genentech), which seems to work well in patients with IDH mutations.

Neither approval was supported by randomized, controlled trial data—and European regulators declined to approve ivosidenib based on single-arm phase I results, as the FDA had done. Plus, each IDH inhibitor carries a boxed warning about differentiation syndrome, a potentially fatal side effect.

But there are bright spots. Ivosidenib is under evaluation in two phase III studies for patients with newly diagnosed IDH1-mutant AML: In one, older patients receive the drug with azacitidine; in the other, younger patients receive a combination of ivosidenib and intensive chemotherapy. As Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, points out, smaller trials that he and others have run indicate that combination regimens can induce deep, durable remissions. “Down the road,” he says, “I do think we are going to be giving a backbone of azacitidine–venetoclax with [an IDH inhibitor] as a triplet.”

Potentially boosting sales further, ivosidenib could soon earn approval for previously treated IDH1-mutant cholangiocarcinoma, a biliary tract cancer. In phase III testing, patients with refractory disease who received the drug had significantly longer progression-free survival, with a trend toward longer overall survival, compared with those given placebo.

Financial models from Andrew Berens, MD, senior research analyst at SVB Leerink, put the risk-adjusted value of Agios's entire oncology portfolio at approximately $2.9 billion.

The accuracy of that forecast will ultimately depend on the fate of vorasidenib, which has shown early signs of efficacy in low-grade gliomas, around 70% to 80% of which harbor IDH mutations. A phase III, placebo-controlled trial is ongoing for patients with IDH-mutant grade 2 glioma who have been treated only with surgery.

“We are hoping that inhibition of mutant IDH will stop the otherwise relentless growth of these tumors and delay the need for radiation and chemotherapy,” says trial investigator Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center.

With oncology now in the rearview mirror, Agios will focus on developing drugs that modulate cellular metabolic pathways implicated in rare genetic diseases, including thalassemia and sickle cell anemia. –Elie Dolgin