IDH305 / Novartis - LARVOL DELTA

Translational PBPK modeling and model-informed drug development of IDH305, a complex CYP3A4 modulator. (PubMed, J Pharm Sci) - "Both the predicted food effect and accumulation ratio were consistent with the observed data in the FIH study. This integrative translational approach informed clinical development of IDH305 and can be used to support MIDD of molecules with complex metabolic properties in oncology drug development."

First-in-human • Journal • Oncology • CYP3A4

Comprehensive genomic profiling to identify molecular determinants of efficacy of IDH1 inhibition in intrahepatic cholangiocarcinoma. (ASCO 2026) - "Background: Ivosidenib (IVO) in IDH1-mutant iCCA yields modest mPFS (2.7 m) with heterogenous responses... We analyzed 93 IDH1-mutant iCCA cases (MD Anderson n=59, Moffitt n=23, Yonsei n=11) treated with IVO (n=78), IDH305 (n=15)... Co-occurring genomic alterations may serve as prognostic markers in IDH1-mutant iCCA, suggesting distinct trajectories of response and resistance to IDH1 inhibition. This molecular classification could guide clinical decision-making by identifying pts likely to benefit from monotherapy vs pts requiring combination strategies to overcome intrinsic resistance."

Clinical • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Oncology • Solid Tumor • ARID1A • BAP1 • CDKN2A • CDKN2B • FGFR • IDH1 • NTRK1 • PBRM1 • TP53

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1 | N=166 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2027 ➔ Oct 2030

Trial completion date • Oncology

The metabolite α-ketoglutarate induces AIM2-dependent PANoptosis through demethylase TET2. (PubMed, Cell Commun Signal) - "Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection...These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses."

Journal • Infectious Disease • Melanoma • Oncology • Septic Shock • Solid Tumor • AIM2 • IDH1 • TET1 • TET2

Characterizing Secondary-Site Mutations in Isocitrate-Dehydrogenase-1 (IDH1) (ASH 2024) - "The inhibitors investigated include ivosidenib (AG120), IDH889, IDH305, DS-1001b, GSK864, BAY1436032, olutasidenib (FT-2102), and vorasidenib (AG881), some of which either are in clinical trials or are FDA-approved. Conclusion Second-site mutants of mIDH1 exhibit different leukemogenic properties and differentiation potential in vivo, and show distinct patterns of resistance and sensitivity to ivosidenib, olutasidenib and other mIDH1 inhibitors. Our study provides a rationale to choose an IDH1 inhibitor in patients with secondary site IDH1 mutations."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HOXA9 • IDH1 • ITGAM

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1 | N=166 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2026 ➔ Feb 2027

Trial completion date • Oncology

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1 | N=166 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Feb 2026

Trial completion date • Oncology

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1 | N=166 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2024 ➔ Oct 2025

Metastases • Trial completion date • Oncology

Discovery of IDH305, a brain penetrant mutant IDH1 inhibitor for the treatment of cancer (ACS-Fall 2023) - "Inhibition of mutant IDH1 (hotspot mutation at Arg132) is both being evaluated clinically as a treatment option for various cancers and has led to the approval of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML.Here we will describe the hit finding, design, preclinical characterization, and medicinal chemistry optimization of a series of 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors. IDH305 has progressed into human clinical trials for the treatment of cancers with IDH1 mutation. we will also describe chemistry optimization for the synthesis of IDH305."

Acute Myelogenous Leukemia • Angiosarcoma • Brain Cancer • CNS Tumor • Glioma • Hematological Malignancies • Leukemia • Melanoma • Oncology • Sarcoma • Solid Tumor • ARG1 • IDH1 • IDH2

Evolution of the AML Genome and Epigenome during IDH Inhibitor Therapy and their Association with Clinical Response and Resistance (SOHO 2019) - P1, P1/2; "However, most responders eventually relapse.Objective We aimed to understand the molecular underpinnings of clinical response and resistance of IDH inhibitors.Design We performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from IDH1/IDH2-mutant advanced myeloid malignancies patients treated with IDH inhibitors.Setting The study was performed in a research facility.Patients We studied patients with relapsed and refractory AML (R/R AML) and MDS/CMML who received IDH inhibitor therapy in one of the 4 clinical trials conducted in our institution: NCT01915498 (enasidenib for IDH2 mutated patients), NCT02074839 (ivosidenib for IDH1 mutated patients), NCT02381886 (IDH305 for IDH1 mutated patients), and NCT02481154 (AG-881 for IDH1 or IDH2 mutated patients). In addition, acquired mutations in the RAS-RTK pathway, BCOR, reciprocal IDH gene, and TET2 were also implicated at..."

Clinical

Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis. (PubMed, Open Med (Wars)) - "However, current targeted inhibitors of IDH1 mutation (AG120 and IDH305) reversed these effects caused by IDH1 mutation. The in vivo experiment showed that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis. This study indicated that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

A phase 1 study of IDH305 in patients with IDH1-mutant acute myeloid leukemia or myelodysplastic syndrome. (PubMed, J Cancer Res Clin Oncol) - P1 | "Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Leukemia • Myelodysplastic Syndrome • Oncology • IDH1

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1; N=166; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Jun 2022 ➔ Oct 2024

Clinical • Trial completion date • Oncology

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1; N=166; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Jun 2020 ➔ Jun 2022; Trial primary completion date: Jun 2020 ➔ Jun 2022

Clinical • Trial completion date • Trial primary completion date • Oncology

IDH1-mutated relapsed or refractory AML: current challenges and future prospects. (PubMed, Blood Lymphat Cancer) - "...Ivosidenib in monotherapy achieved complete remission (CR) of 24%, overall response of 42%, and median overall survival of 9 months in R/R AML, and promising outcomes were reported with IDH305 and FT-2102...Also, venetoclax, CB-839, PARP inhibitors, and IDH1 peptide vaccine are being studied in IDH1 AML...The results of the ongoing and upcoming clinical trials will bring new evidence to establish the role of IDH1 inhibitors in therapeutic strategies of AML."

Journal • PARP Biomarker • Review

A Study of IDH305 in Patients With Advanced Malignancies That Harbor IDH1R132 Mutations (clinicaltrials.gov) - P1; N=166; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Apr 2019 ➔ Jun 2020; Trial primary completion date: Apr 2019 ➔ Jun 2020

Trial completion date • Trial primary completion date