Vorasidenib

Vorasidenib: Pioneering Therapy for Grade 2 Gliomas with IDH Mutations

Voranigo is a targeted cancer therapy that inhibits mutated isocitrate dehydrogenase enzymes—specifically IDH1 and IDH2. It was developed for the treatment of brain cancers, particularly Grade 2 astrocytoma and oligodendroglioma, both of which are slow-growing gliomas that commonly affect younger adults and are associated with IDH mutations. This mutation is found in approximately 80% of low-grade gliomas, making it a significant target for therapeutic intervention.

Drug Overview

• Drug Name: Voranigo
• Drug Class: Isocitrate Dehydrogenase (IDH) Inhibitor
• Indication: Grade 2 astrocytoma and oligodendroglioma with susceptible IDH1 or IDH2 mutations
• Mechanism of Action: Voranigo targets and inhibits the activity of mutated IDH1 and IDH2 enzymes. These mutations can lead to the production of abnormal metabolites, which contribute to cancer growth. By inhibiting these enzymes, voranigo helps to slow the progression of the cancer by preventing the production of these harmful metabolites.
• Administration: Oral, 40 mg once daily for adults and pediatric patients aged 12 and older (with weight-based dosing for pediatric patients under 40 kg).

FDA Approval and Regulatory Milestones

The FDA approved voranigo on August 6, 2024, marking a significant breakthrough in the treatment of IDH-mutant gliomas. The approval is specifically for adult and pediatric patients aged 12 years and older with Grade 2 astrocytoma or oligodendroglioma, who have undergone surgery, including biopsy, sub-total resection, or gross total resection. This is the first FDA-approved systemic therapy for these types of brain tumors.

The approval was based on the results from the INDIGO trial (NCT04164901), a phase 3, randomized, multicenter, double-blind, placebo-controlled study. The trial evaluated the efficacy of voranigo in 331 patients with IDH-mutant Grade 2 gliomas following surgery. The patients were split into two groups: one received voranigo, and the other received a placebo.

Efficacy Results

• Progression-Free Survival (PFS): The primary efficacy outcome was progression-free survival (PFS), which was significantly improved in patients receiving voranigo compared to the placebo group. The hazard ratio for PFS was 0.39, with a 61% reduction in the risk of progression or death (95% CI: 0.27–0.56; p < 0.0001).
• Time to Next Intervention: An additional efficacy outcome was time to the next intervention, defined as the time from randomization to the start of chemotherapy or radiation therapy. The median time to the next intervention was not reached in the vorasidenib group, while it was 17.8 months in the placebo group, further showing the drug’s effectiveness in delaying the need for additional treatments (HR=0.26; 95% CI: [0.15, 0.43]; p < 0.0001).

Safety and Side Effects

The safety profile of voranigo was generally manageable, with the most common side effects being:

• Fatigue
• Headache
• Musculoskeletal pain
• Diarrhea
• Nausea
• Seizure

Serious laboratory abnormalities were relatively rare but included:

• Increased alanine aminotransferase (ALT)
• Increased aspartate aminotransferase (AST)
• Increased gamma-glutamyl transferase (GGT)
• Decreased neutrophil counts

These side effects were more frequently seen at higher dosages but were typically mild to moderate in severity.

Approval Under FDA Expedited Programs

Vorasidenib’s development benefited from multiple expedited FDA programs due to its potential to address a significant unmet medical need:

1. Priority Review: Vorasidenib was reviewed more quickly than usual because it represented a significant improvement in the treatment of IDH-mutant gliomas.
2. Fast Track Designation: This designation facilitated more frequent communication between the drug developers and the FDA, expediting the review of clinical trial data.
3. Breakthrough Therapy Designation: Vorasidenib received this designation due to early evidence indicating substantial improvement over existing therapies for these cancers.
4. Orphan Drug Designation: This was given because IDH-mutant gliomas are a rare disease, and the drug’s approval helps to ensure that patients with these rare conditions have access to innovative therapies.

The approval was also part of Project Orbis, a collaborative initiative between the FDA and international regulatory agencies, including Australia’s TGA, Brazil’s ANVISA, Health Canada, Switzerland’s Swissmedic, and Israel’s Ministry of Health. This program allows for concurrent submission and review of oncology drugs across multiple countries.

Clinical Significance and Impact

Vorasidenib’s approval is a major step forward in the treatment of IDH-mutant low-grade gliomas. These tumors are often slow-growing but can significantly impact quality of life due to their location in the brain and their potential for malignant transformation. Vorasidenib offers a targeted approach that allows patients to delay more aggressive treatments like radiation and chemotherapy, which are associated with significant long-term side effects.

By inhibiting the IDH mutations, vorasidenib addresses the root cause of the abnormal cancer cell growth in these patients, making it one of the first examples of precision medicine in neuro-oncology. It is expected to become a new standard of care for patients with these types of gliomas.

The drug’s impact extends beyond this specific cancer type. The research that led to the development of vorasidenib has helped usher in the era of precision cancer medicine, where treatments are tailored to the specific genetic mutations driving a patient’s cancer.

This approval also highlights the importance of genomic sequencing in cancer treatment, as the discovery of the IDH mutation has led to better outcomes for patients with these types of brain tumors.

Conclusion

The FDA’s approval of vorasidenib represents a significant advancement in the treatment of Grade 2 IDH-mutant gliomas. By offering a targeted therapy option that delays disease progression and reduces the need for more invasive treatments, vorasidenib improves patient outcomes and quality of life.

This approval also underscores the importance of precision medicine and genomic research in developing new cancer treatments.