Delving into the Latest Updates on IDH-305 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

IDH1

Mechanism

IDH1 inhibitors(Isocitrate dehydrogenase [NADP] cytoplasmic inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication

IDH1 Mutation Acute Myeloid LeukemiaIDH1-mutant Glioma

Originator Organization

Novartis Pharma AG

Active Organization

Novartis Pharmaceuticals Corp.

Inactive Organization

Novartis AG

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H22F4N6O2

InChIKeyDCGDPJCUIKLTDU-SUNYJGFJSA-N

CAS Registry1628805-46-8

Cohort A - neoadjuvant administration of IDH305 at 550 mg BID for 6 weeks followed by surgical resection at 6 weeks. If there is no evidence of progressive disease at 6 weeks (clinical, radiographic or histopathologic exam), the patient will continue on IDH305 at 550 mg BID post-operatively for a maximum of 11 additional 28 day cycles. Subsequent assessment of disease will occur every 2 months starting in Cycle 2.
Cohort B - patients who have inoperable tumors but measurable 2HG pre-treatment will be treated with IDH305 at 550 mg BID x 6 weeks. If there is adequate sustained knockdown of 2HG on MRS and disease is stable or improved, then the patient will continue on treatment for a maximum of 11 additional 28 day cycles.

Start Date01 Jan 2017

Sponsor / Collaborator

The University of Texas Southwestern Medical Center

NCT02826642 / WithdrawnPhase 1

A Phase I, Open Label, Multicenter, Dose Finding Study of IDH305 With Standard of Care in IDH1 Mutant Acute Myeloid Leukemia

The purpose of this study is to evaluate the safety, tolerability and potential efficacy of IDH305 with standard treatments for newly diagnosed IDH1R132 mutant acute myeloid leukemia (AML).

Start Date26 Aug 2016

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with IDH-305

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100 Translational Medicine associated with IDH-305

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100 Patents (Medical) associated with IDH-305

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3

Literatures (Medical) associated with IDH-305

01 Mar 2023·Journal of Cancer Research and Clinical OncologyQ3 · MEDICINE

A phase 1 study of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia or myelodysplastic syndrome

Q3 · MEDICINE

Article

Author: DiNardo, Courtney D ; Parikh, Nehal S ; Zander, Thomas ; Ji, Yan ; Krämer, Alwin ; Chen, Xueying ; Choi, Joanne ; Hochhaus, Andreas ; Yee, Karen ; Frattini, Mark G ; Wei, Andrew H

PURPOSEIsocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1^R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).METHODSIDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1^R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity.RESULTSIDH305 exhibited rapid absorption with mean T_1/2 approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification.CONCLUSIONDue to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared.TRIAL REGISTRATIONClinicaltrials.gov identifier: NCT02381886.

06 May 2022·Open Medicine

Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis

Article

Author: Huang, Yi ; Zheng, Lei ; Li, Ping ; Wu, Yue ; Su, Li ; Zhu, Zhifa

AbstractThe present study intends to clarify the hypothesis that isocitrate dehydrogenase 1 (IDH1) mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis through the in vitro and in vivo experiments. Cholangiocarcinoma RBE cell line was transfected with IDH1 R132C mutation plasmids and treated with erastin to induce ferroptosis, which were then microscopically photographed. Cell viability rate was calculated by trypan blue staining. The lipid ROS level was determined by using flow cytometer. The BALB/c nude mice were injected subcutaneously with IDH1 knockout (KO), WT, or R132C mutation cell line, followed by injecting erastin intraperitoneally. The tumor tissue was surgically separated for the measurement of tumor volume and weight. The results showed that IDH1 mutant RBE cell line are sensitive to erastin-induced ferroptosis, evidenced by the increased number of propidium iodide-positive cells, the decreased cell viability, and increased lipid ROS level. 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.

12 Oct 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

Q3 · MEDICINE

Article

Author: Dooley, Julia ; Shultz, Michael ; Farsidjani, Ali ; Chen, Jinyun ; Caferro, Thomas ; Gould, Ty ; Xie, Xiaoling ; Cho, Young Shin ; Liu, Gang ; Costales, Abran ; Sendzik, Martin ; Shafer, Cynthia M. ; Firestone, Brant ; Heimbach, Tycho ; Pagliarini, Raymond ; Dodd, Stephanie ; Villalba, Brian ; Sutton, James ; Liang, Guiqing ; Growney, Joseph D. ; Chenail, Gregg ; Pu, Minying ; Levell, Julian R. ; Zhao, Qian ; Kulathila, Raviraj ; Manning, James R. ; Slocum, Kelly

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg¹³². Having identified an allosteric, induced pocket of IDH1^R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

100 Deals associated with IDH-305

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
IDH1 Mutation Acute Myeloid Leukemia	Phase 2	-	Novartis Pharmaceuticals Corp.	26 Aug 2016
Neoplasms	Phase 1	BE	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	AU	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	DE	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	ES	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	US	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	NL	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	CA	Novartis Pharmaceuticals Corp.	06 Mar 2015
Neoplasms	Phase 1	SG	Novartis Pharmaceuticals Corp.	06 Mar 2015
IDH1-mutant Glioma	Preclinical	US	Novartis AG	01 Apr 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02381886 (Pubmed \| J Cancer Res Clin Oncol)	Phase 1	Myelodysplastic Syndromes	41	IDH305	(ezflaitgmh) = 12.2% uqlllrynwh (uyyzsmsfvi ) View more	Positive	30 Mar 2022
NCT02381886 (IDH305X2101, ASH2016) Manual	Phase 1	Neoplasms IDH1 R132 Mutation	81	IDH-305	(hkyctsrula) = grade 3 elevated bilirubin were observed in 2 pts with solid tumors (2 at 550 mg BID), grade 3 elevated lipase in 1 pt with glioma (900 mg BID)， grade 3 rash in 1 pt with a solid tumor (750 mg BID) itqvlhmetr (rhltyxupaj ) View more	Positive	02 Dec 2016