Therapeutic: olutasidenib for acute myeloid leukaemia

Published: 21-Jul-2023

Acute myeloid leukaemia (AML) is a blood cancer that progresses rapidly; it’s characterised by the fast build-up of abnormal cells in the bone marrow that adversely affects the production of blood cells

The prognosis is generally poor. Chemotherapy is the standard first line of treatment and the presence of genetic mutations often informs the choice of drug regimen.

One mutation that has potential as a target is isocitrate dehydrogenase 1 (IDH1), an enzyme that is part of the Krebs cycle. It has been found in AML patients as well as gliomas and other brain tumours.

Olutasidenib, originally discovered by chemists at Forma Therapeutics (acquired by Novo Nordisk in late 2022) and licensed to Rigel Pharmaceuticals, is a potent, orally available brain penetrant and selective inhibitor of IDH1.1

It has potential in various types of cancer, including AML. In a Phase I/II open label clinical study, 78 patients with AML or intermediate, high or higher risk myelodysplastic syndrome, all of whom had mutant IDH1, were given 150 mg doses of olutasidenib once or twice a day, or 300 mg once a day, either with or without doses of azacitidine.2

No dose-limiting toxicities were reported in the dose escalation cohorts and the 150 mg twice-daily dose was selected for the Phase II part of the study.

The most common treatment-emergent adverse events across all cohorts were thrombocytopenia, febrile neutropenia and anaemia.

An overall response was achieved by 41% of the AML patients given the monotherapy and 46% of those given the combination; for treatment-naïve AML patients, it was 25% with the monotherapy and 77% with the combination.

A trial has also been done in 153 patients with relapsed or refractory AML who were naïve to previous IDH1 therapy.3 Subjects with a median age of 71 were given 150 mg doses of olutasidenib as a twice-daily monotherapy.

The rate of complete remission and complete remission with partial haematologic recovery was 35% — with a median duration of 25.9 months — and the overall response rate was 48% with a median duration of 11.7 months.

The response rate was similar regardless of whether or not the patients had previously been treated with venetoclax. Grade 3 or 4 treatment-emergent adverse events included febrile neutropenia and anaemia, thrombocytopenia and neutropenia.  

It has also been investigated in a Phase Ib/II clinical trial in glioma patients with an IDH1 mutation.4 The 26 patients were given 150 mg oral doses twice a day. Of those evaluable for response, 48% achieved an objective response or stable disease.

Two patients had a partial response and eight had stable disease for at least 4 months.


  1. J.A. Caravella, et al., J. Med. Chem. 63, 1612 (2020).
  2. J.M. Watts, et al., Lancet Haematol. 10, e46 (2023).
  3. S. de Botton, et al., Blood Adv. (2023): doi: 10.1182/bloodadvances.2022009411.
  4. M.I. de la Fuente, et al., Neuro. Oncol. 25, 146 (2023).

You may also like