Table 3. Drugs currently in clinical development for treatment of mIDH AML and MDS.
| Drug | Mechanism of action | Clinical phase | Patient type | Clinical activity | Registrationa |
|---|---|---|---|---|---|
| AG-221 | Small-molecule allosteric inhibitor of mIDH2 protein; reduces the oncometabolite, 2-HG | 2 and 3 | Patients with R/R AML (phase 2); older patients (⩾60 years) with mIDH2 R/R AML after second- or third-line therapy (phase 3) | 41% ORR in phase 1 dose-escalation and expansion study70 | NCT01915498 https://www.clinicaltrials.gov/ct2/show/NCT01915498?term=NCT01915498&rank=1NCT02577406 https://clinicaltrials.gov/ct2/show/NCT02577406 |
| AG-120 | Small-molecule allosteric inhibitor of mIDH1 protein; reduces the oncometabolite, 2-HG | 2 | mIDH1 advanced hematological malignancies | 35% ORR in phase 1 dose-escalation and expansion study71 | NCT02074839 https://clinicaltrials.gov/ct2/show/NCT02074839?term=NCT02074839&rank=1 |
| AG-881 | Small-molecule mIDH1 and mIDH2 protein inhibitor; reduces the oncometabolite, 2-HG | 1 | mIDH1 and mIDH2 relapsed or refractory advanced hematological malignancies—after prior mIDH inhibitor failure | Unknown | NCT02492737 https://clinicaltrials.gov/ct2/show/NCT02492737?term=NCT02492737&rank=1 |
| IDH305 | Small-molecule mIDH1 inhibitor | 1 | mIDH1 advanced malignancies | Unknown | NCT02381886 https://clinicaltrials.gov/ct2/show/NCT02381886?term=NCT02381886&rank=1 |
| FT-2102 | No description available | 1/1b | AML or high-risk MDS with mIDH1; under evaluation as monotherapy and in combination with azacitidine | Unknown | NCT02719574 https://clinicaltrials.gov/ct2/show/NCT02719574 |
| ABT-199 | Small-molecule BCL-2 inhibitor; works via synthetic lethality; that is, mIDH cells require BCL-2 to survive | 2 | R/R AML and patients unfit for chemotherapy | 15.5% ORR (5/32); antileukemic activity (reduction of BM blasts >50%) was shown in 6/11 (54%) patients with mIDH AML89 | NCT02203773 https://clinicaltrials.gov/ct2/show/NCT02203773?term=NCT02203773&rank=1 NCT02287233 https://clinicaltrials.gov/ct2/show/NCT02287233?term=NCT02287233&rank=1 |
| CB-839 | Glutaminase inhibitor | 1 | R/R AML and older patients (⩾60 years) unfit for IC (also includes patients with ALL) | Preliminary data showed 2/16 evaluable patients attained CRi92 (prespecified end point to evaluate response in mIDH patients) | NCT02071927 https://clinicaltrials.gov/ct2/show/NCT02071927?term=NCT02071927&rank=1 |
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; BM, bone marrow; Comb, combination; CRi, complete remission with incomplete hematological recovery; MDS, myelodysplastic syndromes; mIDH, mutant isocitrate dehydrogenase; ORR, overall response rate; R/R, relapsed or refractory; 2-HG, 2-hydroxyglutarate.
a
ClinicalTrials.gov registration number.