mIDH1 Inhibitor Research Articles

De novo design of mIDH1 inhibitors by integrating deep learning and molecular modeling

BackgroundMutations in the IDH1 gene have been shown to be an important driver in the development of acute myeloid leukemia, gliomas and certain solid tumors, which is a promising target for cancer therapy.MethodsBidirectional recurrent neural network (BRNN) and scaffold hopping methods were used to generate new compounds, which were evaluated by principal components analysis, quantitative estimate of drug-likeness, synthetic accessibility analysis and molecular docking. ADME prediction, molecular docking and molecular dynamics simulations were used to screen candidate compounds and assess their binding affinity and binding stability with mutant IDH1 (mIDH1).ResultsBRNN and scaffold hopping methods generated 3890 and 3680 new compounds, respectively. The molecules generated by the BRNN performed better in terms of molecular diversity, druggability, synthetic accessibility and docking score. From the 3890 compounds generated by the BRNN model, 10 structurally diverse drug candidates with great docking score were preserved. Molecular dynamics simulations showed that the RMSD of the four systems, M1, M2, M3 and M6, remained stable, with local flexibility and compactness similar to the positive drug. The binding free energy results indicated that compound M1 exhibited the best binding properties in all energy aspects and was the best candidate molecule among the 10 compounds.ConclusionIn present study, compounds M1, M2, M3 and M6 generated by BRNN exhibited optimal binding properties. This study is the first attempt to use deep learning to design mIDH1 inhibitors, which provides theoretical guidance for the design of mIDH1 inhibitors.

Symptom management in isocitrate dehydrogenase mutant glioma

Abstract According to the 2021 World Health Organization classification of CNS tumors, gliomas harboring a mutation in isocitrate dehydrogenase (mIDH) are considered a distinct disease entity, typically presenting in adult patients before the age of 50 years. Given their multiyear survival, patients with mIDH glioma are affected by tumor and treatment-related symptoms that can have a large impact on the daily life of both patients and their caregivers for an extended period of time. Selective oral inhibitors of mIDH enzymes have recently joined existing anticancer treatments, including resection, radiotherapy, and chemotherapy, as an additional targeted treatment modality. With new treatments that improve progression-free and possibly overall survival, preventing and addressing daily symptoms becomes even more clinically relevant. In this review we discuss the management of the most prevalent symptoms, including tumor-related epilepsy, cognitive dysfunction, mood disorders, and fatigue, in patients with mIDH glioma, and issues regarding patient’s health-related quality of life and caregiver needs in the era of mIDH inhibitors. We provide recommendations for practicing healthcare professionals caring for patients who are eligible for treatment with mIDH inhibitors.

Practical management of patients with IDH-mutant glioma in the coming era of mIDH inhibitors: New drugs, new evidence, new guidelines, and new considerations

Practical management of patients with IDH-mutant glioma in the coming era of mIDH inhibitors: New drugs, new evidence, new guidelines, and new considerations

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.

Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

A phase 1/2, safety lead-in and dose expansion, open-label, multicenter trial investigating the safety, tolerability, and preliminary activity of ivosidenib in combination with nivolumab and ipilimumab in previously treated subjects with IDH1-mutated nonresectable or metastatic cholangiocarcinoma.

TPS4197 Background: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options, though molecularly targeted therapies have demonstrated anti-tumor activity in certain subsets. Approximately 15% of patients with intrahepatic CCA harbor activating mutations in isocitrate dehydrogenase-1 (mIDH1), and treatment with the mIDH1 inhibitor, ivosidenib (IVO) improved progression-free survival in the phase 3 ClarIDHy trial. mIDH1 is associated with an immune-excluded tumor microenvironment, and anti-CTLA4 immune checkpoint inhibition (ICI) augments anti-tumor activity when combined with IVO in preclinical models. Preliminary anti-tumor activity of dual immune checkpoint inhibitors (IPI, NIVO) has been reported in biliary tract cancers. Methods: This is a phase 1/2, non-comparative, multicenter, open-label study of IVO, IPI, NIVO, in subjects with unresectable or metastatic CCA with mIDH1. Key eligibility criteria include: a histopathological diagnosis; tumor mIDH1 based on local testing; progression on and/or intolerance to 1-2 prior lines of systemic therapy, at least one of which contained either gemcitabine and/or 5-fluorouracil; prior anti-PD-(L)1 therapy is allowed in the safety lead in; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; at least 1 measurable lesion as defined by RECIST version 1.1. The study has a safety lead-in phase and an expansion phase with 2 different expansion cohorts: cohort 1, ICI-naive; cohort 2, prior ICI allowed. The primary objective is to evaluate the safety and tolerability of IVO in combination with IPI plus NIVO and determine the recommended combination dose (RCD). This phase will enroll ~6 to 12 dose-limiting toxicity (DLT)–evaluable patients. The first 6 patients enrolled will receive IVO 500 mg orally once daily in combination with IPI 1 mg/kg IV infusion and NIVO 3 mg/kg IV infusion concurrently once every 3 weeks for 4 doses followed by NIVO at 480 mg IV once every 4 weeks until progression or unacceptable toxicity (up to a maximum of 24 months of NIVO). DLTs will be evaluated during the first 2 cycles of treatment. An additional 6 patients may be enrolled to assess an alternative dose of ivosidenib 250 mg once daily. Upon determination of the RCD, the two expansion cohorts will be initiated to assess the clinical activity of the triplet combination in patients with and without prior ICI. First patient in occurred in November 2023. Clinical trial information: NCT05921760 .

Olutasidenib for mutated IDH1 acute myeloid leukemia: Final five-year results from the phase 2 pivotal cohort.

6528 Background: Olutasidenib is a potent, selective, oral inhibitor of mIDH1 and is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, Phase 2, open-label, multicenter trial (NCT02719574). We report final five-year results from the pivotal cohort. Methods: In the pivotal cohort of the Phase 2 trial, patients with mIDH1 AML received olutasidenib 150mg BID. Primary endpoint was complete remission (CR) + CR with partial hematologic recovery (CRh) by modified IWG Criteria 2003. Data cutoff: May 15, 2023. Results: Baseline characteristics of 153 enrolled patients are shown in Table. Of 147 efficacy evaluable patients, CR was achieved in 32% (95% CI: 24.5, 40.2) and CR/CRh in 35% (95% CI: 27, 43; P<0.0001). Median time to CR/CRh was 1.9 mo (range: 0.9, 5.6). The median duration of CR/CRh was 25.3 mo (95% CI: 13.5, not reached), with maximum duration 54.6 mo. Overall response rate was 48% (95% CI: 40, 56.7), with median duration 15.5 mo (95% CI: 7.4, 26.2) and maximum duration 54.6 mo. Median overall survival was 11.6 mo (95%CI: 8.9, 15.5). In the 12 patients R/R to prior venetoclax, 33% achieved a CR/CRh; median duration of CR/CRh is not reached (ongoing at 54.3 months), and median overall survival is 16.2 months (95%CI: 2.6, not reached). Transfusion independence from red blood cells and platelets was achieved in 34 of 87 (39%) patients and 28 of 69 (41%) patients, respectively, who were dependent at baseline. 16 (11%) patients proceeded to stem cell transplant. The 5-year safety profile was consistent with what was previously reported. The most common AEs (% reported over 3 years and over the full 5 years) were: febrile neutropenia (22% and 22%), constipation (26% and 27%), diarrhea (20% and 21%), nausea (38% and 39%), fatigue (23% and 23%), pyrexia (24% and 24%), hypokalaemia (20% and 22%), red blood cell count decreased (26% and 26%), white blood cell count increased (25% and 25%). Differentiation syndrome was reported in 14% by Year 3, with no new events by Year 5. The safety profile was stable with long-term follow up. Conclusions: This analysis provides an additional 2 years of data beyond the results that led to FDA approval of olutasidenib. This first report of the five-year data further demonstrates the rapid and durable responses observed with olutasidenib in heavily pretreated patients with mIDH1 AML, including those R/R to prior venetoclax. Clinical trial information: NCT02719574 . [Table: see text]

Identification of mIDH1 R132C/S280F Inhibitors from Natural Products by Integrated Molecular Docking, Pharmacophore Modeling and Molecular Dynamics Simulations.

Mutant isocitrate dehydrogenase 1 (mIDH1) is a common driving factor in acute myeloid leukemia (AML), with the R132 mutation accounting for a high proportion. The U.S. Food and Drug Administration (FDA) approved Ivosidenib, a molecular entity that targets IDH1 with R132 mutations, as a promising therapeutic option for AML with mIDH1 in 2018. It was of concern that the occurrence of disease resistance or recurrence, attributed to the IDH1 R132C/S280F second site mutation, was observed in certain patients treated with Ivosidenib within the same year. Furthermore, it should be noted that most mIDH1 inhibitors demonstrated limited efficacy against mutations at this specific site. Therefore, there is an urgent need to investigate novel inhibitors targeting mIDH1 for combating resistance caused by IDH1 R132C/S280F mutations in AML. This study aimed to identify novel mIDH1 R132C/S280F inhibitors through an integrated strategy of combining virtual screening and dynamics simulations. First, 2000 hits were obtained through structure-based virtual screening of the COCONUT database, and hits with better scores than -10.67 kcal/mol were obtained through molecular docking. A total of 12 potential small molecule inhibitors were identified through pharmacophore modeling screening and Prime MM-GBSA. Dynamics simulations were used to study the binding modes between the positive drug and the first three hits and IDH1 carrying the R132C/S280F mutation. RMSD showed that the four dynamics simulation systems remained stable, and RMSF and Rg showed that the screened molecules have similar local flexibility and tightness to the positive drug. Finally, the lowest energy conformation, hydrogen bond analysis, and free energy decomposition results indicate that in the entire system the key residues LEU120, TRP124, TRP267, and VAL281 mainly contribute van der Waals forces to the interaction, while the key residues VAL276 and CYS379 mainly contribute electrostatic forces.

Use, access, and initial outcomes of off-label ivosidenib in patients with IDH1 mutant glioma.

Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020. Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily. The cohort age range was 21-74 years. Tumor types included astrocytoma (n = 14) and oligodendroglioma (n = 16), with most being grade 2 (n = 21). The best radiographic response in nonenhancing disease (n = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, n = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, n = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%. Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.

P15.13.B DEVELOPMENT OF [18F]AG-120 AS AN IMAGING AGENT FOR THE DETECTION OF THE MUTANT ISOCITRATE DEHYDROGENASE 1 IN GLIOMA BY PET

Abstract BACKGROUND Gliomas are highly invasive and infiltrative solid tumors that present significant clinical challenges in terms of achieving complete surgical resection. These tumors often harbor mutated isocitrate dehydrogenase enzymes (mIDH), making them attractive theranostic targets. Therefore, accurately assessing mIDH status is essential for effective patient management. Currently, the presence of mIDH1 is determined either by invasive biopsy or indirectly by measuring the mIDH-derived oncometabolite 2-hydroxyglutarate (2-HG) using magnetic resonance spectroscopy (MRS). The availability of mIDH-targeted radioligands would allow for PET neuroimaging to detect the mIDH1 protein directly and non-invasively. MATERIAL AND METHODS The study involved obtaining 18F-labeled AG-120 (Ivosidenib), an FDA-approved small molecule inhibitor of mIDH, by Cu-mediated radiofluorination of a corresponding diastereomerically pure stannyl precursor. The researchers studied the internalization of [18F]AG-120 in vitro in U251 human glioblastoma cells stably transfected with IDH1 or IDH1R132H. Brain uptake and metabolism of [18F]AG-120 were investigated in healthy CD-1 mice by dynamic PET-MR imaging and radio-chromatographic analyses of plasma and brain tissue. Dynamic PET-CT imaging studies were performed in nude rats bearing U251-IDH1 or U251-IDH1R132H glioblastoma. RESULTS The (S,S)-enantiomer of [18F]AG-120 was successfully prepared, and the procedure was implemented into a remotely-controlled radiosynthesis module. A considerably higher uptake of activity was observed in U251-IDH1R132H cells compared to U251-IDH1 cells (0.422 vs. 0.014% applied activity/μg protein after 120 min incubation). The percentage of non-metabolized [18F]AG-120 in the mouse 30 min post i.v. injection was 85% in plasma and 91% in the brain, respectively. Dynamic PET studies showed limited blood-brain barrier permeation of [18F]AG-120 (SUV < 0.1 within the first 5 min post i.v. injection), which could be significantly increased by inhibiting the p-glycoprotein 1 with cyclosporine A. PET studies with glioblastoma rats indicated slightly higher tumor-to-blood ratios in IDH1R132H-tumors compared to IDH1-tumors (~1.7 vs. ~1.3 at 40-60 min p.i.). CONCLUSION For the first time, pure (S,S)-[18F]AG-120 has been synthesized. In addition, GMP-compliant production is facilitated by the established automated radiosynthesis. Despite limited BBB permeation, [18F]AG-120 shows target-specific internalization in vitro and high metabolic stability in vivo. Furthermore, the slightly higher accumulation of [18F]AG-120 in IDH1R132H-glioblastoma compared to IDH1-glioblastoma in vivo encourages further evaluation of mIDH inhibitors for the noninvasive detection of IDH1R132H in glioma by PET. SUPPORT European-Regional-Development-Fund ERDF and Sächsische-Aufbaubank SAB (#100364142).

Imidazole and Biphenyl Derivatives as Anti-cancer Agents for Glioma Therapeutics: Computational Drug Repurposing Strategy.

Targeting mutated isocitrate dehydrogenase 1 (mIDH1) is one of the key therapeutic strategies for the treatment of glioma. Few inhibitors, such as ivosidenib and vorasidenib, have been identified as selective inhibitors of mIDH1. However, dose-dependent toxicity and limited brain penetration of the blood-brain barrier remain the major limitations of the treatment procedures using these inhibitors. In the present study, computational drug repurposing strategies were employed to identify potent mIDH1- specific inhibitors from the 11,808 small molecules listed in the DrugBank repository. Tanimoto coefficient (Tc) calculations were initially used to retrieve compounds with structurally similar scaffolds to ivosidenib. The resultant compounds were then subjected to molecular docking to discriminate the binders from the non-binders. The binding affinities and pharmacokinetic properties of the screened compounds were examined using prime Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and QikProp algorithm, respectively. The conformational stability of these molecules was validated using 100 ns molecular dynamics simulation. Together, these processes led to the identification of three-hit molecules, namely DB12001, DB08026, and DB03346, as potential inhibitors of the mIDH1 protein. Of note, the binding free energy calculations and MD simulation studies emphasized the greater binding affinity and structural stability of the hit compounds towards the mIDH1 protein. The collective evidence from our study indicates the activity of DB12001 against recurrent glioblastoma, which, in turn, highlights the accuracy of our adapted strategy. Hence, we hypothesize that the identified lead molecules could be translated for the development of mIDH1 inhibitors in the near future.

Abstract 543: Preclinical characteristic of HMPL-306, a CNS-penetrable dual inhibitor of mutant IDH1 and IDH2

Abstract Background: Mutations in isocitrate dehydrogenase (IDH) 1/2 are frequently identified in various cancers, such as AML, cholangiocarcinoma, chondrosarcoma and glioma. Mutant IDHs (mIDHs) cause accumulated 2-HG, leading to blockage of cell differentiation, thereby inducing malignant transformation. Rare cases were identified carrying co-existing mutations in IDH1 and IDH2. mIDH isoform switching, from mutant IDH1 to mutant IDH2 and vice versa, have been reported as a mechanism of acquired resistance to IDH inhibition in AML and cholangiocarcinoma. Thus, simultaneous inhibition on both mIDH1 and mIDH2 may be a promising strategy to overcome resistance and improve clinical efficacy. HMPL-306, a dual inhibitor of mIDH1/mIDH2, developed by HUTCHMED, is being evaluated in clinical trials. Methods: The inhibition of HMPL-306 on IDH enzymes, including mutant and wild type, was determined by fluorescence-based assay. The selectivity of HMPL-306 was evaluated in 322 kinases (SelectScreenTM) and 88 proteins (Cerep). For cellular activities of HMPL-306, 2-HG production and differentiation were detected in cells harboring mIDH. Human tumor xenograft models carrying IDH1 or 2 mutations were established for evaluating mIDH inhibition by detecting 2-HG in plasma and tumor, and anti-tumor efficacies. Results: HMPL-306 inhibited mutant IDH enzyme activities including IDH1R132H, IDH2R140Q and IDH2R172K, while showed weaker inhibition on IDH1/2 wild type enzymes. HMPL-306 had a superior selectivity profile in a kinase panel and a safety panel, while enasidenib, an approved mIDH2 inhibitor, inhibited Adenosine-A3 with IC50 of 12 nM. In cellular assays, HMPL-306 displayed comparable activities to enasidenib and ivosidenib (approved mIDH1 inhibitor) and suppressed 2-HG through inhibition of mIDH1 or mIDH2 at similar level, indicating an equal potency against mIDH1 and 2. Moreover, in both mIDH1/2 cells, HMPL-306 reduced the levels of histone methylation, and promoted hemoglobin γ and Kruppel1 gene expression, which led to differentiation from immature malignant cells to mature normal cells. Oral administration of HMPL-306 remarkably decreased 2-HG level in plasma and tumor tissues in xenograft models carrying mIDH1 or mIDH2 and the inhibition is more potent and durable than either ivosidenib or enasidenib at the same dose. Pharmacokinetics (PK) study in rodents showed high exposures of HMPL-306 in brain and cerebrospinal fluid, a desirable feature for glioma therapy. Combination treatment of HMPL-306 and azacitidine synergized in releasing the differentiation block in mIDH AML cells. HMPL-306 also significantly improved in vivo anti-tumor efficacy of chemotherapy drugs in solid tumor models with mIDH1/2. Conclusion: HMPL-306 is a potent, dual inhibitor of IDH1/2 mutation. The strong activity and favorable PK profiles support further clinical evaluation. Citation Format: Na Yang, Jia Hu, Tingwen Li, Juntao Yu, Dongxia Shi, Min Cheng, Zeyu Zhong, Jian Wang, Yang Sai, Weiguo Qing, Guangxiu Dai, Yongxin Ren, Michael Shi, Weiguo Su. Preclinical characteristic of HMPL-306, a CNS-penetrable dual inhibitor of mutant IDH1 and IDH2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 543.

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas.

Gliomas are the most common primary brain tumors in adults. A diffuse infiltrative growth pattern and high resistance to therapy make them largely incurable, but there are significant differences in the prognosis of patients with different subtypes of glioma. Mutations in isocitrate dehydrogenase (IDH) have been recognized as an important biomarker for glioma classification and a potential therapeutic target. However, current clinical methods for detecting mutated IDH (mIDH) require invasive tissue sampling and cannot be used for follow-up examinations or longitudinal studies. PET imaging could be a promising approach for non-invasive assessment of the IDH status in gliomas, owing to the availability of various mIDH-selective inhibitors as potential leads for the development of PET tracers. In the present review, we summarize the rationale for the development of mIDH-selective PET probes, describe their potential applications beyond the assessment of the IDH status and highlight potential challenges that may complicate tracer development. In addition, we compile the major chemical classes of mIDH-selective inhibitors that have been described to date and briefly consider possible strategies for radiolabeling of the most promising candidates. Where available, we also summarize previous studies with radiolabeled analogs of mIDH inhibitors and assess their suitability for PET imaging in gliomas.

Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m ND-AML Treated with Ivo+AZA in the AGILE Study

Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in approximately 6-10% of patients (pts) with AML. Ivosidenib (IVO), a potent, oral, targeted inhibitor of mIDH1, is FDA approved as monotherapy for the treatment of relapsed/refractory AML and newly-diagnosed AML (ND-AML) in adults >75 years of age or with comorbidities that preclude the use of intensive chemotherapy. In addition, the combination of IVO with azacitidine (AZA) was recently FDA approved in older or unfit AML pts with mIDH1 as a result of the global Phase 3 AGILE trial (NCT03173248). Compared to placebo (PBO) + AZA, the combination of IVO + AZA extended event-free survival (EFS; hazard ratio 0.33, 95% CI [0.16 - 0.69]; P = 0.002), overall survival (OS; median 24.0 months vs. 7.9 months; hazard ratio 0.44; 95% CI [0.27 - 0.73]; P = 0.001), and increased the rates of complete remission or complete remission with partial hematologic recovery (CR/CRh; 52.8% vs. 17.6%). To date, biomarker analysis has shown that IVO+AZA is associated with deep and durable clearance of IDH1m clones with improved clinical responses and EFS/OS in several pt subgroups, including those with mutations in receptor tyrosine kinase (RTK) pathway genes, a subgroup refractory to IVO monotherapy. Aim: To characterize clonal evolution and relapse mechanisms in pts with mIDH1 ND-AML treated with IVO+AZA. Methods: Patients received oral IVO + AZA per study protocol. Next-generation DNA sequencing (DNA-seq) on baseline and longitudinal samples was performed on bone marrow aspirates (BMA), bone marrow mononuclear cells (BMMCs), or peripheral blood mononuclear cells (PBMCs) depending on sample availability using the ACE Extended Cancer Panel (Personalis, Inc); limit of detection (LOD) 2% variant allele frequency (VAF). This analysis was focused on variants in 95 AML-associated genes with known or likely oncogenic potential. Results: Among 72 pts enrolled on the IVO+AZA arm, 46 had both baseline and longitudinal DNA-seq data available, with a median follow-up of 366 days on study (range 16 - 1210). The median number of baseline mutations was 3 (range 1 - 10). Suppression of all baseline non-DTA (DNMT3A / TET2 / ASXL1) mutations to below the LOD ("mutation clearance") was observed in 28 patients, including 22/34 (65%) pts who achieved CR/CRh [Table 1]. To identify potential mechanisms of acquired resistance, on-treatment samples were analyzed for the emergence of mutations not detected at baseline. Overall, emerging mutations were identified in 22/46 (48%) pts (median 2 emerging mutations; range 1-6). 2/46 (4%) pts had emerging mutations in IDH2, but discontinued treatment due to adverse events and stable disease, respectively. No second-site IDH1 mutations were observed across any response category. Longitudinal samples were available for 8/10 (80%) pts who discontinued treatment due to relapse (RL) following an objective response (4 CR, 2 CRh, 1 CRi, 1 MLFS). Emerging mutations were detected in 6/8 (75%) of RL pts [Table 2]. Genes with emerging mutations recurrently associated with RL included ASXL1, FLT3, RUNX1, and TET2 (2 pts each). The IDH1 mutation was not detected at RL in 6/8 (75%) pts. Among the two RLs that occurred in the absence of emerging mutations, one was associated with expansion of a baseline FLT3-ITD subclone, and one was not associated with any new emerging or expanding mutations. To further evaluate clonal evolution and disease progression of these pts, scDNA-seq is being performed and will be presented. Conclusion: IVO+AZA combination therapy leads to deep and durable remissions associated with clearance of mIDH1 and baseline co-mutations. To date, no second-site IDH1 mutations have been observed, but mutations in other genes, including IDH2, can emerge and may provide an opportunity for relapse. Relapses were observed in a subset of responders and were generally associated with expansion or emergence of high-risk mutations occurring independently of mIDH1. Further study is needed to better characterize mechanisms of RL to IVO+AZA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-Effectiveness of Azacitidine and Ivosidenib in Newly Diagnosed Older, Intensive Chemotherapy-Ineligible Patients with IDH1-Mutant Acute Myeloid Leukemia

Introduction Ivosidenib (IVO) is an oral inhibitor of mIDH1 that is approved in the USA as monotherapy for pts with mIDH1AML, either relapsed/refractory or newly diagnosed, but older/unfit for intensive therapy. The recent AGILE trial (Montesinos et al. NEJM 2022) randomized newly diagnosed, older/intensive chemotherapy-ineligible mIDH1 AML pts to IVO + AZA vs placebo + AZA and showed improved event-free survival (EFS) and overall survival (OS) in the intervention arm. We sought to understand the health economic implications by conducting a cost-effectiveness analysis. Methods Pts with newly diagnosed mIDH1 AML entered our partitioned survival model at age 75 years and received either IVO/AZA or AZA monotherapy. We used recreated pt-level data derived from the Kaplan-Meier curves and at-risk tables for EFS and OS from the AGILE trial for the IVO/AZA arm to fit loglogistic parametric survival distributions. Hazard ratios (HRs) for EFS and OS were used to derive the EFS and OS curves for the AZA arm, respectively. Medication costs were derived from the average sales price (ASP) for AZA and cytarabine listed by the Centers for Medicare and Medicaid Services or the average wholesale price (AWP) for IVO and venetoclax (Ven), respectively. As ASP ranges between 26-30% below the AWP, we used a 28% discount off the AWP for the base-case scenario and varied this discount during sensitivity analyses between 18% and 38%. Costs and practice patterns of treatment discontinuation or treatment interruption due to adverse events, subsequent treatments, supportive and terminal care, and incidence of complications were derived from the original trial or published literature (Table 1). Costs were adjusted for inflation to 2021 US dollars using the personal consumption expenditure health index. Utilities were derived from the literature and were assumed to be equal between treatment arms for the base case scenario as the quality-of-life assessment were not statistically significantly different for IVO/AZA vs AZA in the AGILE trial at most timepoints. Costs and utilities were modeled over a 30-year time horizon and discounted by 3% annually. Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) for IVO/AZA, which represents the cost in 2021 US dollars (USD) of each additional quality adjusted life-year (QALY) gained compared to AZA. One-way sensitivity analyses were performed to evaluate the impact of individual parameters on the overall model. Utility values were varied with a 10% range and all other variables were varied across a 50% range. We also performed probabilistic sensitivity analyses, in which we described each parameter using a distribution and performed 10,000 Monte Carlo simulations, each time randomly sampling from the distributions of model inputs. Results In the base case scenario, IVO/AZA and AZA resulted in life-time costs of $652,088 and $242,828, respectively, for an incremental cost of $409,260 with IVO/AZA. With an incremental gain of 2.21 QALYs with IVO/AZA (IVO/AZA: 3.10 QALYs; AZA: 0.89 QALYs), the ICER of IVO/AZA compared to AZA was $185,024/QALY. In one-way sensitivity analyses, only a reduction in the AWP of IVO by 32.4% (from $33,693 to $22,788 per 28-day cycle) would yield a reduction in the ICER to below the conventional willingness-to-pay (WTP) threshold of $150,000/QALY. Figure 1 shows the ten variables with the greatest influence on the ICER demonstrating that variations in any of the variables would not achieve an ICER of less than $150,000/QALY. Probabilistic sensitivity analysis yielded a median ICER of $205,124/QALY (95% CI: $129,344 - $346,479) with AZA favored in 91.2% of 10,000 iterations at a WTP threshold of $150,000/QALY. Conclusion Even in the best-case scenario in favor of the IVO arm following AGILE trial assumptions, we calculated an ICER of $185,024/QALY, which makes IVO/AZA unlikely to be cost-effective compared to AZA alone when applying the traditional WTP threshold of $150,000/QALY in patients with newly diagnosed mIDH1 AML. Only a reduction in the price of IVO by 32.4% lowered the ICER to below $150,000/QALY. The influence of more frequent use of 2nd line IVO in the control arm, comparison against an AZA-Ven control arm, differences in utilities, and extended duration of follow up in the prematurely terminated trial on the ICER warrant additional analyses but are likely to further worsen the cost effectiveness of IVO. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Discovery of Novel and Potent Inhibitors Against Mutational Variants of IDH1 Protein for Glioma Therapy: A Fragment-Based Approach

Somatic mutations in the isoenzymes of isocitrate dehydrogenases (IDHs) account for the pathogenesis of various malignancies including gliomas. To date, ivosidenib is the only FDA-approved drug candidate widely used to target mutated isocitrate dehydrogenase 1 (mIDH1). However, the impotence of the existing drug to evade the blood barrier remains an obstacle to harness ivosidenib as therapeutics against glioma. Thus, in this study, we elucidate a fragment-based drug discovery strategy to design novel lead molecules against the mIDH1 protein. Initially, a fragment library was constructed using 27 known mIDH1 inhibitors from the literature. The vast chemical classes of constructed library consisting of 1109 fragments were then used for breeding. A total of 18,000 breed compounds were generated and the resultant compounds were scrutinized based on the breed score ([Formula: see text]) and Tanimoto coefficient ([Formula: see text]). The binding affinity and the energetics of the resultant molecules (2069) were investigated using molecular docking and MM-GBSA calculations. Eventually, the compounds with higher affinity were included in the mutational analysis incorporating the second site mutations namely IDH1S280F and IDH1R119P. The bioavailability analysis and toxicity profiling were carried out for screened hybrid molecules. The pipeline of the integrated in-silico approach identified hybrid 209, hybrid 237 and hybrid 504 as the drug-like candidates against the mutational variants of mIDH1 protein. Interestingly, all three compounds exhibited greater binding affinity and better brain penetrating capability. The machine learning-based anti-cancerous sensitivity prediction tool affirmed the inhibitory effect of the resultant hits against various glioma cell lines. In the end, the structural stability of the screened molecules was examined using the molecular dynamic simulation study for a stipulated time of 100[Formula: see text]ns. Indeed, this evidence speculates that the identified hybrid molecules could serve as important leads for the management of glioma in the near future.

AML-295 AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 Mutation

Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic drivers in acute myeloid leukemia (AML), with 6-10% of AML patients harboring mutant IDH1 (mIDH1). Ivosidenib (IVO) is a small molecule mIDH1 inhibitor that silences the oncogenic pathways activated by this mutation. Assess efficacy/safety of IVO+azacitidine (AZA) as frontline therapy for AML patients ineligible for intensive chemotherapy (IC). Randomized, placebo (PBO)-controlled, global phase 3 study. Patients with untreated AML, centrally confirmed mIDH1 status, ineligible for IC. Once daily IVO 500 mg (or PBO) plus AZA 75 mg/m2 for 7 days in 28-day cycles. Event-free survival (EFS), overall survival (OS), response rates, blood counts, transfusion dependence, health-related quality of life (HRQoL), and adverse events (AEs). 146 patients were randomized to IVO+AZA (n=72) and PBO+AZA (n=74). Median age was 76.0 and 75.5 years, respectively. EFS was significantly in favor of IVO+AZA (HR=0.33; 1-sided P=0.0011). Median OS was 24.0 vs 7.9 months for IVO+AZA vs PBO+AZA, respectively (HR=0.44; 1-sided P=0.0005). Complete response rates were 47.2% and 14.9% for IVO+AZA vs PBO+AZA, respectively (P<0.0001). During 2 weeks after treatment initiation, only the IVO+AZA treatment group showed an increase in absolute neutrophil count (from 0.99×109/L at baseline to 2.05×109/L at week 2). Significantly more patients in the IVO+AZA group became RBC and platelet transfusion independent (2-sided P=0.006). IVO+AZA preserved or improved HRQoL from treatment cycles 5 to 19, with few clinically meaningful improvements with PBO+AZA. Grade ≥3 AEs occurring in >20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), pneumonia (22.5% vs 28.8%), and infections (21.1% vs 30.1%). In patients with IC-ineligible, newly diagnosed mIDH1 AML, IVO+AZA significantly improved EFS, OS, and clinical response compared with PBO+AZA. Blood counts rapidly recovered in patients given IVO+AZA, patients were less dependent on RBC/platelet transfusion than those given PBO+AZA, with HRQoL improvements in the IVO+AZA group. The safety profile of IVO+AZA was favorable, with fewer febrile neutropenia and infection events with IVO+AZA vs PBO+AZA.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Neomorphic transformations in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors showed modest brain penetrating potential and dose-limiting toxicity. Herein, we elucidate virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, a structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified Abemaciclib as the hit against mIDH1. Notably, abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamics simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100[Formula: see text]ns. It is worth noting that benzimidazole moiety of abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that abemaciclib has the potential as a lead molecule against glioma. Indeed, the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.

SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors.

Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na+-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na+/Ca2+ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.