Agios Pharmaceuticals’ AG-120, a first-in-class inhibitor of the IDH1 mutant protein has shown remarkable efficacy in an early-stage trial in patients with acute myeloid leukaemia.

“We’re very excited to report these clinical responses,” said lead investigator Daniel Pollyea of University of Colorado. “We’ve had a complete remission in every single dose cohort.” Dr Pollyea reported his results at the recent EORTC meeting in Barcelona, Spain.

Granted the work is very early (a Phase I, dose-ranging study) and the enrollment is small (N=17), but the responses observed were striking. “Isocitrate dehydrogenase (IDH) is one of the most promising targets in AML,” Dr Pollyea said.  

The target, IDH, comes in two flavours - IDH1, found in the cell’s cytoplasm, and IDH2, found in the mitochondria. AG-120, an oral agent, is a potent, selective inhibitor of the IDH1 oncogenic mutation found in a significant minority of AML (6-10%) and myelodysplastic syndromes (3-6%) patients,” explained Dr Pollyea.

The Phase I study enrolled AML or MDS patients with the IDH1 mutation and in terms of efficacy, without even looking at tumour response, Dr Pollyea knew that the drug was at least working mechanistically. Patients were observed to have upwards of a 98% reduction in 2-hydroxyglutarate (2HG) plasma levels as compared to baseline.

Responses were also early and durable, with the earliest noted at two weeks. Dr Pollyea added that “for a relapse and refractory AML population, taking a single agent and having responses of 3-5 months is quite impressive.”

Ruth Plummer, from Freeman Hospital in Newcastle-upon-Tyne, UK, was also bullish about the early results, noting that IDH enzymes “are among the most frequently mutated metabolic genes in cancer. Not only is this drug mechanistically useful in reducing the production of tumour cells, it’s also an extremely useful biomarker for the mutation”.