• Confirmed single agent overall response rate of 43% and median duration of response of 17.8 months in MAPK-inhibitor naïve, V600+ population; 71% experienced clinical benefit of at least 24 weeks

• Responses observed in Primary CNS Tumors including both high grade and low grade gliomas

• FORE8394 is well-tolerated, with any adverse events being transient and manageable

• Company plans to initiate global Phase 2 study in 4Q 2022

Fore Biotherapeutics (Fore Bio), a precision oncology company dedicated to developing innovative treatments that provide a better outcome for cancer patients, announced the presentation of new data demonstrating that FORE8394, a next-generation BRAF inhibitor, provides evidence of durable anti-tumor activity and patient benefit in BRAF-mutated (V600+) cancers. Data from the ongoing Phase 1/2a study evaluating FORE8394 for the treatment of advanced solid and central nervous system (CNS) tumors with activating BRAF alterations were presented in a poster session at the European Society of Medical Oncology Congress (ESMO) taking place in Paris, France.

“I am extremely proud of the progress this team has made in advancing our next-generation, and potential best-in-class BRAF-inhibitor to address the limitations of the current standards of care and improve outcomes for patients with cancer,” said Matthew Ros, Chief Executive Officer of Fore Biotherapeutics. "These results are very encouraging and reinforce our conviction that FORE8394 has the potential to provide meaningful benefit to patients with BRAF-mutated cancers with high unmet need. We are embarking upon developing this novel treatment and are on track to initiate our global Phase 2 trial next quarter.”

As of the data cutoff date of July 31, 2022, 108 adults and children have received ≥1 dose of FORE8394 and are included in the safety population; 51 adults (≥18 years) met the criteria for the V600+ efficacy analysis; overall response rate (ORR) was 25.5% and median duration of response: 17.8 months. An additional analysis was conducted in the MAPK-inhibitor naïve subset, excluding patients with colorectal cancer (CRC) (N=21). Patients received 900-3600 mg/day of oral FORE8394 alone or with cobicistat (CYP3A4 inhibitor) to increase exposure, with the majority having been treated with total daily doses of 900-1800 mg.

Key Findings from the Ongoing Phase 1/2a Study

• In MAPK inhibitor-naïve adult V600+ patients (N=21, excluding CRC), confirmed responses and durable benefit was seen across multiple tumor types
  • Clinical activity observed in this population includes ORR= 42.9%, clinical benefit rate ≥ 24 weeks= 71.4%, median duration of response was 17.8 months and median progression free survival (PFS) was 28.6 months
    • In patients with primary CNS tumors, 4 of 4 patients with high grade glioma and 2 of 3 patients with low grade glioma experienced a partial response (PR) ; 1 had stable disease and remains on treatment after 15+ months
    • Of 6 patients with papillary thyroid cancer, median PFS was not reached (median follow-up 5.6 years)

• Additional responses were observed in patients with V600+ ovarian cancer where 3 of 3 patients had PR; 2 having received prior MAPK-targeted treatments

• FORE8394 demonstrated a favorable safety profile, with long-term tolerability, across the 108 patients
  • Adverse events were transient and manageable
  • Symptomatic adverse events (AEs) were low grade (Grade 1 or 2), mild and included fatigue, nausea, diarrhea & vomiting
  • Hepatic laboratory changes were manageable with dose interruption or modification
  • No secondary cutaneous skin malignancies or acanthomas occurred
  • Only 1 participant discontinued treatment due to treatment related adverse event

"In this heterogeneous and heavily pre-treated patient population, the overall response rate and meaningful durations of response demonstrates the potential of FORE8394 to uniquely target tumors with BRAF alterations," said Stacie Shepherd, MD, PhD, Chief Medical Officer of Fore Biotherapeutics. "We're excited that the majority of gliomas demonstrated response and the prolonged benefit and tolerability experienced by some patients receiving FORE8394. Based on the strength of these findings, our Phase 2 study will further evaluate FORE8394 in patients with both solid and CNS tumors with BRAF fusions and recurrent primary CNS tumors with BRAF V600E mutations.”

“There are several limitations with first-generation BRAF inhibitors, including treatment resistance leading to disease progression and the paradoxical activation of the MAPK pathway, leading to secondary cutaneous skin cancers. In addition, these agents are inactive against class II BRAF alteration,” said Eric Sherman, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center. “These results suggest FORE8394 may provide meaningful benefit to patients, and we look forward to further exploring its potential in the upcoming Phase 2 study.”

About FORE8394

FORE8394 is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAF^V600 monomers targeted by first-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class II mutants, fusions, splice variants and others. Unlike first-generation RAF inhibitors, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a “paradox breaker,” FORE8394 could therefore treat acquired resistance to current RAF inhibitors and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors.

About Fore Biotherapeutics

Fore Bio is a precision oncology company dedicated to developing innovative treatments that provide a better outcome for cancer patients. Its lead asset FORE8394 is a Class I/II BRAF inhibitor with demonstrated clinical safety and early efficacy signals in an ongoing Phase 1/2a clinical trial. Leveraging a proprietary functional genomics platform that can screen a wide range of known mutations for cancer-driving genes, the Fore R&D team is optimizing drug development by identifying existing compounds with known clinical profiles and a clear path through clinical development to advance new medicines for patients without treatment options. For more information, please visit www.fore.bio or follow us on Twitter and LinkedIn.

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