What Is Vorasidenib?
Vorasidenib is an investigational medication being studied for its potential to treat certain types of brain tumors. It is an oral, first-in-class, dual inhibitor of mutant isocitrate dehydrogenase (mIDH 1 and 2). These mutations are found in some cancers, including glioma, and can drive tumor growth.
By blocking the activity of mIDH1 and mIDH2, Vorasidenib aims to disrupt the metabolic pathways that support cancer cell proliferation. This drug is currently under investigation in clinical trials for conditions such as glioma, diffuse glioma, and specific types of astrocytoma and oligodendroglioma that carry IDH1 or IDH2 mutations.
Uses and Conditions Under Study
Vorasidenib is primarily being studied in clinical trials for various forms of glioma, which are tumors that originate in the brain or spinal cord. These include general Glioma, Low Grade Glioma of Brain, and Diffuse Glioma. A total of 9 trials focus on these broad categories of brain tumors. The drug is specifically designed to target gliomas that have mutations in the IDH1 or IDH2 genes, which are common in certain types of these tumors and contribute to their development.
More specific conditions under investigation include Grade 2 Astrocytoma or Oligodendroglioma With an IDH1 or IDH2 Mutation, and Grade 2 Glioma, each studied in 1 trial. For these conditions, Vorasidenib's mechanism as a dual inhibitor of mIDH1 and mIDH2 is believed to interfere with the metabolic processes that drive the growth of these specific brain tumors.
Additionally, Vorasidenib is being studied in trials involving Healthy Adult Participants and Healthy Adult Female Participants. These studies are typically conducted to understand how the drug is absorbed, distributed, metabolized, and eliminated by the body, as well as to assess its safety profile in individuals without the target condition. One trial also examines Disease Attributes, which may involve understanding specific characteristics of a disease or patient population relevant to drug response.
Dosing
Vorasidenib is an oral medication, meaning it is taken by mouth. Clinical trials have investigated different dosing regimens and strengths. The most commonly studied strengths are 20 mg and 40 mg.
Dosing instructions have varied across studies, often involving daily administration. For example, some trials specify taking 40 mg orally daily in continuous 28-day cycles. Another regimen involved 40 mg taken orally daily from Day 6 through Day 24 of a cycle. For participants weighing less, a lower dose has been explored: 20 mg orally daily for those weighing between 25 kg and less than 40 kg, compared to 40 mg daily for participants weighing 40 kg or more.
Studies have also examined Vorasidenib in various contexts, including with positron emission tomography (PET) imaging, in participants with severe hepatic impairment, and in combination with other medications like temozolomide or pembrolizumab. Investigations have also looked at how the drug is affected by fasting conditions versus a low-fat meal, and its interactions with other drugs like ciprofloxacin or drospirenone/ethinyl estradiol.
Side Effects
In a clinical trial involving Vorasidenib for residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation, the most common side effect was an increase in alanine aminotransferase, a liver enzyme. This occurred in 38.3% of patients taking Vorasidenib, compared to 14.7% of those on placebo.
Other frequently reported side effects included:
- Fatigue, experienced by 32.3% of patients on Vorasidenib and 31.9% on placebo.
- Increased aspartate aminotransferase, another liver enzyme, seen in 28.7% of patients on Vorasidenib versus 8.0% on placebo.
- Headache, reported by 26.9% of patients on Vorasidenib and 27.0% on placebo.
- Diarrhea, affecting 24.6% of patients on Vorasidenib compared to 16.6% on placebo.
- Nausea, occurring in 21.6% of patients on Vorasidenib and 22.7% on placebo.
- Increased gamma-glutamyltransferase, another liver enzyme, observed in 15.6% of patients on Vorasidenib versus 4.9% on placebo.
- Hyperglycemia (high blood sugar), reported by 9.6% of patients on Vorasidenib compared to 4.3% on placebo.
These side effect rates are based on data from one clinical trial where 167 patients received Vorasidenib.
Clinical Trial Results
Vorasidenib has been studied in patients with residual or recurrent Grade 2 glioma that has an IDH1 or IDH2 mutation. The INDIGO study (NCT04164901) was a clinical trial that evaluated Vorasidenib against placebo in 331 participants (168 on Vorasidenib, 163 on placebo).
Key findings from the INDIGO study include:
- Progression-Free Survival (PFS): Patients treated with Vorasidenib had a median PFS of 27.7 months, meaning half of the patients lived without their disease worsening for at least this long. This was significantly longer than the 11.1 months observed in patients who received placebo. This represents an increase of 16.6 months in the time patients lived without disease progression.
- Objective Response (OR): An objective response, indicating tumor shrinkage or disappearance, was observed in 10.7% of patients (18 out of 168) taking Vorasidenib. In comparison, 2.5% of patients (4 out of 163) on placebo showed an objective response.
- Tumor Growth Rate (TGR): On average, patients receiving Vorasidenib experienced a -2.5% change in tumor growth rate, indicating tumor shrinkage. In contrast, patients on placebo had an average tumor growth rate increase of 13.9%.
- Duration of Response (DoR): For those patients who experienced an objective response, the median duration of response for Vorasidenib was 16.6 months. Data for duration of response was not available for the placebo group.
Complete Response (CR) and Partial Response (PR) by BIRC: 2 participants on Vorasidenib (1.2%) achieved a complete or partial response, while no participants on placebo did. The median time to achieve CR or PR with Vorasidenib was 9.6 months, and the median duration of these responses was 13.8 months.
Overall Survival (OS) data was not yet mature at the time of this analysis, meaning it was too early to determine the median overall survival for either group.
Currently Recruiting Trials
Several clinical trials are actively recruiting participants to further investigate vorasidenib. These studies aim to understand how vorasidenib can help patients with specific types of brain tumors, improve treatment outcomes, or enhance quality of life.
- The European Organisation for Research and Treatment of Cancer (EORTC) is sponsoring a Phase 3 study, NCT06809322, known as VIGOR. This trial aims to enroll 468 participants to evaluate vorasidenib as a maintenance therapy. It seeks to determine if vorasidenib can improve progression-free survival in patients with IDH-mutant, CNS5 WHO Grade 2 or 3 astrocytoma after they complete first-line chemoradiotherapy.
- iOMEDICO AG is conducting an observational study, NCT07240662, called VIOLETA. This study plans to include 150 adults with IDH1- or IDH2-mutant WHO grade 2 glioma. The primary goal is to collect real-world data on vorasidenib treatment in a broad patient population.
- A Phase 1 study, NCT05609994, named ViCToRy, is led by Katy Peters, MD, PhD. This trial is recruiting 48 participants to assess the safety and efficacy of a PEPIDH1M vaccine when combined with vorasidenib. It focuses on adult patients diagnosed with recurrent IDH1 mutant lower grade gliomas.
- Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta is conducting a study, NCT07547163, focusing on the patient voice. This study aims to enroll 90 individuals with IDH-mutant, grade 2 gliomas. It will assess patient-reported perceptions of quality of life, treatment-related symptoms, and anxiety levels for those undergoing radiotherapy or pharmacological treatment with vorasidenib.
Where to Participate
Currently, participation in vorasidenib clinical trials is focused in a specific region. A key site for these studies is located in Durham, North Carolina. To be eligible for these trials, participants must be between 18 and 18 years of age. All genders are welcome to participate, but the studies do not enroll healthy volunteers or children.
Development Timeline
The journey for Vorasidenib began on November 15, 2019, with the initiation of its first clinical trial. Since then, the development program has grown significantly, encompassing a total of 18 trials and enrolling 1,899 participants. Initially, studies explored conditions such as IBS-C and hyperphosphatemia.
Over time, the focus shifted and expanded considerably, particularly towards various forms of glioma. This includes conditions like Diffuse Glioma, Glioma of Brain, and specifically IDH-mutant Grade 2 or 3 Astrocytoma, as well as IDH1-mutant and IDH2-mutant gliomas. The pipeline also explored its use in recurrent and residual gliomas.
The trials have progressed through various phases, with a notable presence in Phase 1 studies (7 trials) and Phase 3 studies (4 trials), indicating a move towards advanced stages of clinical investigation. Major sponsors like Institut de Recherches Internationales Servier have been instrumental in driving this extensive research, with the latest trial projected to conclude by April 23, 2026.