Voranigo (vorasidenib)

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: Aug 2025 --> Aug 2027

"Thermo Fisher Scientific...has received approval from the U.S. Food and Drug Administration (FDA) for its Ion Torrent Oncomine Dx Target Test as a companion diagnostic (CDx) to identify patients eligible for treatment with Servier Pharmaceuticals, LLC’s VORANIGO (vorasidenib) tablets. VORANIGO is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery including biopsy, sub-total resection or gross total resection...Today’s approval expands clinical indications for the Oncomine Dx Target Test, which is currently approved and reimbursed by government and commercial insurers in 19 countries, including the U.S., Japan, South Korea and countries across Europe and the Middle East, covering more than 550 million lives globally."

No abstract available

In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma.

Notably, the patient experienced diffuse hair regrowth on the scalp, including in areas affected by severe androgenetic alopecia. This report holds significance as it highlights a previously unreported side effect, thereby enhancing our understanding of emerging therapies for brain tumors and their associated adverse reactions.

P1, N=95, Completed, Institut de Recherches Internationales Servier | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Jun 2024

Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy.

A phase III clinical trial of an IDH1 and IDH2 inhibitor vorasidenib yielded promising results among patients with low-grade IDH-mutant gliomas who had undergone initial surgery and no radiation or chemotherapy...In this review, we discuss the importance of IDH mutations in oncogenesis of adult-type diffuse gliomas and current evidence supporting the use of IDH inhibitors as therapeutic agents for glioma treatment. We also examine unresolved questions and propose potential directions for future research.

P1/2, N=45, Not yet recruiting, Institut de Recherches Internationales Servier

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib...Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively...Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.

Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.

P1, N=72, Recruiting, Institut de Recherches Internationales Servier | Trial primary completion date: Mar 2024 --> Feb 2025

Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

P1, N=95, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Dec 2023 --> Mar 2024

With advancements in molecular diagnostics and precision therapy, IDH inhibitors such as ivosidenib, vorasidenib and enasidenib are now mainstay in management of patients with a susceptible mutation. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit (RUO) is a fully automated qPCR assay for the qualitative detection of 15 common mutations in IDH1 (R132C/H/G/S/L) and IDH2 (R140Q/L/G/W, R172K/M/G/W/S) at codon level. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit demonstrates a high concordance with established reference methods across a range of different specimen types.

P1, N=49, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: May 2024 --> May 2025

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.

P1, N=16, Completed, Institut de Recherches Internationales Servier | Recruiting --> Completed

No abstract available

P3, N=331, Active, not recruiting, Institut de Recherches Internationales Servier

No abstract available

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

INDIGO is the first randomized Phase 3 study of targeted therapy in grade 2 mIDH1/2 diffuse glioma. HRQoL, as measured by FACT-Br, was maintained during treatment with vorasidenib. These data support the clinical benefit of vorasidenib in this patient population for whom chemotherapy and radiotherapy are being delayed.

Introduction: Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain...The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ...Clinically, the patient has no symptoms from tumor. Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.

Introduction: Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ)...Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown...Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment.

These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.

In this phase, ~60 patients will be randomized 1:1:1 to the RCD, VOR 40 mg QD alone, or no treatment prior to surgery. All patients can receive the RCD post-surgery.

Nonetheless, advances have been made with the IDH1/2 inhibitor vorasidenib for IDH-mutant grade 2 gliomas, the combination of dabrafenib and trametinib for BRAFV600E mutated gliomas, and the therapies for subsets of patients with fusions and H3K27M-altered diffuse midline gliomas. While there has been progress in the use of molecular profiling for the classification and treatment of gliomas, much work remains for targeted therapies to realize their potential.

VOR significantly improved PFS by BIRC, compared with PBO, with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD | Initiation date: Jul 2023 --> Nov 2023

In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

P1, N=95, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

According to the phase III INDIGO trial, vorasidenib, an IDH1/2 inhibitor, significantly benefited adults with IDH1/2-mutant low-grade gliomas, reducing progression risk and delaying the need for chemoradiotherapy. Meanwhile, in a pediatric low-grade glioma cohort of FIREFLY-1, a phase II trial, robust responses to the type II pan-RAF inhibitor tovorafenib were seen.

Findings show the clinical benefit of VOR in pts for whom chemotherapy and radiotherapy are being delayed. (NCT04164901 funded by Servier Pharmaceuticals LLC).

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD | Initiation date: Apr 2023 --> Jul 2023

This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.

Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD | Initiation date: Jan 2023 --> Apr 2023

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.

We investigated that ZINC9449923 of isocitrate dehydrogenase enzyme 1 and ZINC 93978407 of isocitrate dehydrogenase enzyme 2 could serve as promising candidates for the treatment of lower-grade glioma as they cross the blood-brain barrier, and present with lower toxicity levels relative to AG-881.

P1, N=72, Recruiting, Institut de Recherches Internationales Servier | Not yet recruiting --> Recruiting | Initiation date: Aug 2022 --> Nov 2022

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD