Ivosidenib is
indicated for people with acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma.[4][14][15]
Adverse effects
In ivosidenib-treated patients, reported adverse effects have been febrile neutropenia, alanine aminotransferase increased, aspartate aminotransferase increased, colitis, hypertension, maculopapular rash. However, Ivosidenib was taken in conjunction with standard AML induction treatment, and side effects can not be directly related to the drug.[16]
On 23 February 2023, the
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tibsovo, intended for the treatment of adults with newly diagnosed acute myeloid leukemia and for the treatment of adults with locally advanced or metastatic cholangiocarcinoma.[21] The applicant for this medicinal product is Les Laboratoires Servier.[21] Tibsovo was approved for medical use in the European Union in May 2023.[6]
Research
In tumors from people diagnosed with
glioma, acute myeloid leukemia (AML), cholangiocarcinoma, and
chondrosarcoma, somatic mutations in the conserved active site of isocitrate dehydrogenase (IDH) 1 and 2 are observed. With these new mutations, these enzymes exhibit new, neomorphic behavior, which results in the reduction of α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate. The new molecule competitively inhibits α-ketoglutarate–dependent enzymes, ultimately leading to epigenetic alterations and impaired hematopoietic differentiation. Mutations in the IDH1 enzyme mutations occur in approximately 6 to 10% of the patients with AML, and IDH2 mutations occur in approximately 9 to 13% of those with AML, with unknown statistics on other conditions listed.[22]
The drug is also believed to be a slow-binding inhibitor of the IDH1-WT homodimer. Ivosidenib showed
uncompetitive inhibition to the
NADP cofactor, showing a hyperbolic curve for the rate constant of inhibition relative to concentration. Ivosidenib also showed no time-dependence in
IC50 between 1 and 16 hours of incubation for either
homodimer.[23]
References
^
ab"Tibsovo". Therapeutic Goods Administration (TGA). 19 April 2023.
Archived from the original on 19 April 2023. Retrieved 29 April 2023.
^
ab"Tibsovo: Pending EC decision". European Medicines Agency. 24 February 2023.
Archived from the original on 24 February 2023. Retrieved 24 February 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
Clinical trial number NCT02074839 for "Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation" at
ClinicalTrials.gov
Clinical trial number NCT02989857 for "Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy) (ClarIDHy)" at
ClinicalTrials.gov