FDA Grants FORE8394 Orphan Drug Designation for Primary Brain/CNS Malignancies

The first orphan drug designation from the FDA has been received by FORE Biotherapeutics and for the FORE8394 program for patients with primary brain and central nervous system malignancies.

The FDA has granted an orphan drug designation to FORE8394 for the treatment of patients with primary brain and central nervous system (CNS) malignancies, according to Fore Biotherapeutics.1

FORE8394 is an investigational, novel, small-molecule, next-generation, oral, selective BRAF inhibitor. The agent was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF.

This marks the first orphan drug designation received by FORE Bio and for the FORE8394 program.

“The receipt of orphan drug designation is another important regulatory achievement that reinforces the FDA’s recognition of the potential of FORE8394 to improve clinical outcomes in patients with BRAF-altered brain tumors,” Stacie Shepherd, MD, PhD, chief medical officer of Fore Biotherapeutics, stated in a news release. “This designation will help us continue to expedite the development of our novel BRAF inhibitor, and we look forward to working closely with the global investigator community supporting FORTE [NCT05503797] and to advancing the development of FORE8394 for patients in need.”

Previously, preclinical studies and clinical trials have demonstrated the unique mechanism of action of FORE8394 as it effectively inhibits BRAF V600 monomers targeted by first-generation RAF inhibitors. FORE8394 also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants, and others. Additionally, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway.

The phase 2 FORTE trial is currently underway and evaluating the agent in patients with locally advanced or metastatic solid tumors, or recurrent or progressive primary CNS tumors that harbor BRAF fusions (group A), as well as in patients with recurrent BRAF V600E–mutated high-grade glioma (group B).2

In group A, patients must be at least 10 years of age and weigh at least 30 kg. Patients are required to have a histologic diagnosis of a solid tumor or primary CNS tumor with a BRAF mutation, have received at least available standard therapy, be intolerant to available therapies, or have an investigator determine that treatment with standard therapy is not appropriate.

Patients in group B must also be at least 10 years of age and weigh at least 30 kg. These patients are required to have a histological diagnosis of a grade 3 or 4 glioma or glioneuronal tumor harboring a BRAF V600E mutation and have received at least 1 line of prior therapy including radiation. However, patients for whom radiotherapy is not considered standard of care can still be eligible for enrollment in the trial.

Both groups will administer patients FORE8394 orally at 900 mg with 150 mg of cobicistat once per day in continuous 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.

Investigators are assessing the primary end point of objective response rate (ORR) per blinded independent central review, as well as the secondary end points of duration of response (DOR), investigator-assessed ORR, CNS DOR in group A, time to response, progression-free survival, overall survival, disease control rate, CNS ORR in group A, safety, and pharmacokinetics.

“Available treatments are limited for patients with primary recurrent CNS tumors or those patients living with solid tumors with a BRAF fusion,” said Matthew Ros, chief executive officer of Fore Biotherapeutics, in a press release.1 “With its unique mechanism of action as a paradox breaker, we believe we have a significant opportunity to deliver a novel and best in class potential therapeutic option with FORE8394. We look forward to accelerating enrollment in the phase 2 Forte master protocol throughout 2023.”

  1. FORE Biotherapeutics receives FDA orphan drug designation for FORE8394 for the treatment of primary brain and CNS malignancies. News release. FORE Biotherapeutics. March 20, 2023. Accessed March 21, 2023. https://bit.ly/3JVq9ND
  2. A study to assess the efficacy and safety of FORE8394 in participants with cancer harboring BRAF alterations. ClinicalTrials.gov. Updated March 15, 2023. Accessed March 22, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05503797
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