Vorasidenib 40mg tablets

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

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BACKGROUND: Proton radiation therapy (PRT) and mutant isocitrate dehydrogenase inhibitors (mIDH-inhibitors) are emerging therapies for mIDH lower grade gliomas (LGGs). Despite their substantial theoretical benefits, comparisons with current standards - particularly pertaining to patient-centred outcomes - are limited. METHODS: Through PubMed and Scopus, a search strategy based on keywords focusing on PRT and mIDH-inhibitors was applied on December 3, 2024. Studies in English on at least 20 adult patients (≥ 18 years) with mIDH-LGG grade 2 or 3 and published between January 1, 2011 and August 31, 2024 were included. Review articles were excluded. RESULTS: Of 6383 identified articles, seven per treatment strategy were included. Overall survival was not reported for mIDH-inhibitors. The lack of high-quality studies comparing PRT to photon radiation therapy precludes conclusions regarding efficacy, effectiveness or even post-PRT radiological manifestations. For the mIDH-inhibitor Vorasidenib (AG-881), the radiological objective response rate was 10.0-42.9%, although lower for contrast-enhancing tumors. Vorasidenib significantly delayed tumor progression (27.7 versus 11.1 months, p < 0.001) and time to next intervention (not reached versus 17.8 months, p < 0.001) when compared to placebo. Adverse events were mostly mild, including elevated liver enzymes (15.6-44.2%) and headache (26.9-46.2%). Only 1/14 studies included assessments related to quality of life (QoL)-domains with inconclusive research on cognitive outcomes. CONCLUSION: Studies reporting on patient-centred data including survival, cognition and QoL remain scarce. Larger, comparative prospective studies, preferably randomized controlled trials, with such outcomes are needed to inform clinicians whether the theoretical and radiological benefits can be translated to improved outcomes that matter to patients, i.e. living better and/or longer.

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INTRODUCTION: Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field. MECHANISM OF ACTION: Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion. Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option. CLINICAL EVIDENCE: Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable. Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy. CONCLUSION: orasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

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Vorasidenib, a dual inhibitor of isocitrate dehydrogenase 1 and 2 (IDH1/2), has shown promise as a therapeutic agent following its recent FDA approval for the treatment of grade 2 astrocytomas and oligodendrogliomas harboring IDH mutations in patients 12 years of age and older following surgery. While Vorasidenib offers significant potential in targeting altered metabolic pathways in low-grade gliomas, its comprehensive toxicologic and safety profile has not been adequately explored. This research letter addresses this critical gap by presenting an in silico analysis of the potential toxicologic effects of Vorasidenib. Using computational tools - ADMETlab 3.0, FAF-Drugs 4.1, DeepPK, vNN-ADMET, Pred-hERG 5.0, ADVERPred, PreADMET, and ADMET-AI - and databases such as ChEMBL, PubChem, and ChemSpider, we evaluated the key physicochemical properties and predicted ADMET profiles of Vorasidenib, along with a comparative analysis of two other drugs, namely Ivosidenib and Enasidenib. Our results suggest potential risks associated with drug-induced liver injury (DILI) and hepatotoxicity, with structural properties indicative of hepatocellular damage during and after treatment. The low clearance rates associated with the low maximum recommended dose suggest that Vorasidenib may accumulate in the bloodstream over time, increasing the likelihood of toxic reactions. In addition, the predictive models indicate concerns for neurotoxicity, nephrotoxicity and cardiotoxicity, including potential blockade of hERG channels leading to QT interval prolongation and cardiac arrhythmias. Importantly, the analysis also indicates risks of genotoxicity and carcinogenicity, raising concerns about promoting additional tumor formation in patients already prone to malignancies. These results emphasize the need for further preclinical and clinical studies to validate the safety of Vorasidenib. A comprehensive understanding of the toxicologic profile is critical to ensure that the therapeutic benefit for patients with IDH1/2-mutated low-grade gliomas is not compromised by potential adverse effects. Careful monitoring of patients and tailored therapeutic strategies are essential to optimize clinical outcomes and guide physicians in the safe use of Vorasidenib in clinical practice.

Abstract licence: CC BY-SA

Vorasidenib, a brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), represents a significant advancement in the management of IDH-mutant gliomas. This review explores the clinical implications of its recent FDA approval for grade 2 IDH-mutant astrocytomas and oligodendrogliomas. We delve into the pivotal INDIGO trial, which demonstrated substantial improvements in progression-free survival, and discuss vorasidenib's pharmacokinetics, safety profile, and dosing guidelines. Additionally, we analyze its role within evolving treatment paradigms, including watchful waiting, IDH-targeted therapy, and integration with radiotherapy and chemotherapy. Comparative insights into traditional and novel approaches highlight the potential of vorasidenib to delay invasive therapies while preserving quality of life. Challenges such as adverse effects, long-term safety, and its application to higher-grade gliomas are also addressed. This comprehensive review underscores the transformative impact of vorasidenib and emphasizes the necessity of multidisciplinary care and patient-centered decision-making in glioma management.

Abstract licence: CC BY