Rezlidhia (olutasidenib)

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.

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.

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.

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

Responses were observed across IDH1 R132 mutation subtypes, with a relatively lower CR/CRh response rate for pts with a R132H mutation as compared to other subtypes. Pts with a best response of CR/CRh had fewer co-mutations than pts who did not achieve CR/CRh. While the ORR was not significantly reduced for pts with RTK mutations, these pts had a lower CR/CRh response rate compared to pts without any RTK mutations.

Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 6 (8%) pts; most cases resolved with treatment interruption, dexamethasone, and/or supportive treatment; 2 pts had concomitant leukocytosis. Olutasidenib in combination with AZA was well tolerated and induced durable CR/CRh in a subset of high-risk pts with mIDH1 AML. Transfusion independence was achieved in a subset of pts in all cohorts. Additional analyses of safety and efficacy will be presented.

P1/2, N=500, Recruiting, Forma Therapeutics, Inc. | Trial completion date: Jul 2021 --> Jul 2023 | Trial primary completion date: Jun 2021 --> Jun 2023

Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 21 pts (14%); most cases resolved with treatment interruption, dexamethasone, and/or supportive treatment; one case was fatal; 19 pts had concomitant leukocytosis. Clinical benefit, as evidenced by DOR and OS, extended to pts who responded but didn’t achieve CR/CRh. A favorable tolerability profile was observed; additional analyses of safety and efficacy will be presented.

P1/2, N=500, Recruiting, Forma Therapeutics, Inc. | Trial completion date: Sep 2020 --> Jul 2021 | Trial primary completion date: Apr 2020 --> Jun 2021

Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102, inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 and Tamezostat. To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.

P1/2, N=0, Withdrawn, Vanderbilt-Ingram Cancer Center | N=80 --> 0 | Suspended --> Withdrawn

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

P1/2, N=80, Suspended, Vanderbilt-Ingram Cancer Center | Recruiting --> Suspended

Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Research Funding: FORMA Therapeutics, Inc.

Median number of prior treatments was 2 (1-5); 86% had received prior temozolomide. SA olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in glioma pts. Evaluation of CO is ongoing. Updated safety and clinical activity, as well as evaluations of serum/CSF PK/PD will be provided.

The ongoing Phase 1/2 study (NCT02719574) has evaluated the safety, PK/PD, and clinical activity of olutasidenib alone or in combination with azacitidine (AZA) or cytarabine in IDH1m AML/MDS pts. Olutasidenib has shown favorable safety profile and clinical activity in IDH1m MDS, with an overall response rate (ORR) rate of 59% (95% CI: 33-82%) and durable disease control. Phase 2 is ongoing at 150 mg BID single agent and in combination with AZA.

Ten (13%) pts had differentiation syndrome (4 SA; 6 COMBO), which resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care... SA and COMBO olutasidenib has shown favorable safety and clinical activity in IDH1m R/R AML with a SA ORR of 41% (95% CI: 21, 64) and a COMBO ORR of 46% (27, 67), and durable disease control. Olutasidenib induces deep responses with IDH1 mutation clearance in a subset of treated pts. Phase 2 investigations of SA and COMBO olutasidenib at the RP2D are ongoing in multiple IDH1m AML populations.

Median number of prior treatments was 2 (range 1-5) and 78% had received prior temozolomide. FT-2102 at 150 mg BID demonstrates acceptable safety and tolerability with potential clinical activity in with gliomas. The Phase 2 study is ongoing, evaluating both single agent, FT-2102 and in combination with azacitidine.