Rezlidhia (olutasidenib)

Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

P2, N=60, Not yet recruiting, Rigel Pharmaceuticals | Initiation date: Jun 2024 --> Nov 2024

P1/2, N=31, Not yet recruiting, M.D. Anderson Cancer Center

The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML...Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax...Single arm studies show post-transplant maintenance is safe, however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.

In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor)...To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.

P2, N=45, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=78, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Nov 2024 --> Aug 2024

Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.

P2, N=15, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=15, Recruiting, City of Hope Medical Center

Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's comorbidities and AML genomic profile.

Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

P1/2, N=78, Not yet recruiting, M.D. Anderson Cancer Center

Olutasidenib provided clinical benefit with a manageable safety profile. Additional analyses to further characterize the safety and efficacy of olutasidenib in frontline and R/R settings as monotherapy and as combination therapy are ongoing.

Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

P1/2, N=336, Completed, Forma Therapeutics, Inc. | Active, not recruiting --> Completed

P1/2, N=336, Active, not recruiting, Forma Therapeutics, Inc.

P2, N=65, Not yet recruiting, Nationwide Children's Hospital

Baseline bone blast count was strongly predictive of response to treatment. Further evaluation of these observations is needed.

P1/2, N=93, Completed, Forma Therapeutics, Inc. | Phase classification: P1b/2 --> P1/2

The phase 1/2 study included 10 cohorts for a total of 335 patients, and there were patient subsets that were R/R to previous hematopoietic stem cell transplant (HSCT), ivosidenib (IVO) or venetoclax (VEN)...This descriptive analysis suggests that olutasidenib alone or in combination with azacitidine may induce complete remissions in patients with mIDH1 AML or MDS that is R/R to VEN, IVO or even HSCT. Further investigation of these difficult-to-treat subpopulations is needed. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.

This treatment had a tolerable and manageable safety profile. These encouraging results, which warrant further investigation with a larger number of patients, show that olutasidenib has clinically meaningful activity in patients with mIDH1 MDS.

Context: IDH1/2 inhibitors (IDHi) ivosidenib, olutasidenib and enasidenib are US Food and Drug Administration-approved salvage therapies for IDH-mutated (IDHm) R/R AML...6 FLT3-mutated patients were treated with additional gilteritinib and 1 NRAS-mutated patient with trametinib... ACTIVE regimen demonstrated high antileukemic efficacy in R/R IDHm AML. Most common AEs were infectious complications with incidence of tumor lysis syndrome.

Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets FLT3 and IDH1/2 mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting TP53-mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.

Single agent olutasidenib, a potent and selective IDH1mut inhibitor, demonstrated highly durable remission rates along with meaningful outcomes such as transfusion independence in patients with R/R IDH1mut AML. This review will examine the preclinical and clinical development, and the positioning of olutasidenib in the IDH1mut AML treatment landscape.

P1/2, N=336, Active, not recruiting, Novo Nordisk A/S | Trial completion date: Jul 2023 --> Feb 2024 | Trial primary completion date: Jun 2023 --> Dec 2023

While lower intensity, hypomethylating agent (HMA)-based therapies such as azacitidine+venetoclax have improved patient outcomes significantly, responses are not durable, and most patients die from disease-related complications. The approvals of oral HMAs such as cedazuridine-decitabine (C-DEC) and oral azacitidine (CC-486) have kindled the hope that myeloid malignancies may soon be treated with total oral therapy...Oral HMAs have the potential to be a convenient and efficacy-equivalent treatment option for patients with HR-MDS or AML and improve their quality of life by reducing clinic visits for medication administration. Total-oral therapy combinations, largely including an oral HMA 'backbone,' are in the early phases of clinical development, and it is our hope that well-designed trials employing these agents may soon allow the identification of optimal regimens that deliver effective disease-directed therapy with good tolerability.

This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. relapsed/refractory, Acute myeloid leukemia, Phase II

Olutasidenib was recently approved in the USA for the treatment of adults with R/R AML with a susceptible IDH1 mutation as detected by a US Food and Drug Administration-approved test. This article summarizes the milestones in the development of olutasidenib leading to this first approval for R/R AML.

Response rates were similar in patients who had and who had not received prior venetoclax. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognosis patient population with mIDH1 R/R AML. This trial is registered at www.clinicaltrials.gov as NCT02719574.

In two clinical trials (N=192) on ND mIDH-2 AML patients, ORR was 74%-89%, CR was 54%-55%, and MLFS was 4%-11% with enasidenib + chemotherapy/azacytidine as compared to ORR of 36%, CR of 12%, and MLFS of 0% with azacytidine alone...In two clinical trials, ORR with BAY1436032 (N=27) and olutasidenib (N=123) were 15% and 46% respectively...Olutasidenib was also effective in patients with R/R mIDH-1 AML. More randomized double-blind multicenter clinical trials are needed to confirm these results.

Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.

Most cases of DS resolved with treatment interruption, dexamethasone and/or supportive care; 1 fatal case was reported. The observed activity is clinically meaningful and represents a therapeutic advance in the treatment of this molecularly defined, poor-prognosis patient population with R/R AML, including those with prior venetoclax failure. Investigation of olutasidenib as monotherapy and in combination with azacytidine is ongoing in other mIDH1 hematologic malignancies.

FDA approved IDH2 inhibitor enasidenib in 2017 and IDH1 inhibitor ivosidenib in 2018 for adults with relapsed/refractory (R/R) IDH2 and IDH1MT AML. In May 2022, FDA approved ivosidenib combined with azacitidine for adults aged 75 years or older with newly diagnosed AML who cannot undergo intensive induction chemotherapy...IDHi-induced differentiation syndrome (DS) was reported in 6 patients (32%); 4 (21%) who developed DS received Olutasidenib, and 2 (11%) received Enasidenib...All patients with DS were treated with medication discontinuation and intravenous dexamethasone... Only a minority of patients with IDHMT AML had received IDHi-based therapy, which is attributed to patients diagnosed and treated before the FDA approval. Surprisingly, the median survival for patients who didn't receive IDHi therapy seemed not different, underscoring the other therapies' effects, including the influence of the venetoclax-based regimen. More extensive randomized studies are needed to compare the efficacy of IDHi to other therapies in treating IDHMT AML.

P1b/2, N=93, Completed, Forma Therapeutics, Inc. | Active, not recruiting --> Completed

Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1  R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population.

P1b/2, N=93, Active, not recruiting, Forma Therapeutics, Inc. | N=200 --> 93

P1/2, N=336, Active, not recruiting, Forma Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=500 --> 336

P1b/2, N=200, Active, not recruiting, Forma Therapeutics, Inc. | Trial primary completion date: Sep 2021 --> May 2021