Fore Biotherapeutics Secures $75M Series D Financing to Advance Plixorafenib, an Orphan Drug-Designated Therapy for BRAF-Mutant CNS Malignancies

Fore Biotherapeutics (hereinafter referred to as “Fore Bio”) recently announced the completion of a $75 million Series D financing round. The round was led by SR One, with participation from Medicxi and existing investors. Its investor consortium now includes new investor Medicxi, as well as existing investors OrbiMed, HBM Healthcare Investments, Novartis Venture Fund, 3B Future Health Fund, Cormorant Asset Management, Wellington Management, and Samsung Securities.

The proceeds from this financing round will be used to accelerate the clinical development of the company’s core asset, Plixorafenib (formerly known as PLX-8394). Plixorafenib is a candidate product launched by Fore Biotherapeutics through its high-throughput functional genomics platform, Foresight, designed to treat both V600 and non-V600 BRAF mutations. It is an investigational next-generation novel small-molecule oral inhibitor intended for cancer patients harboring V600 and non-V600 BRAF mutations, including those with primary central nervous system (CNS) tumors. In March this year, Plixorafenib received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of primary brain and central nervous system malignancies.

BRAF mutations are highly prevalent in tumors such as colorectal cancer (with an incidence of approximately 8%–10%). These mutations include both V600 and non-V600 BRAF variants. BRAF mutations also represent a key therapeutic target in multiple solid tumors, including melanoma, thyroid cancer, colorectal cancer, and non-small cell lung cancer (NSCLC). Although targeted therapies are currently available for patients with BRAF-mutated cancers across different tumor types, first-generation BRAF inhibitors (BRAFi) primarily suppress V600 BRAF mutations, leaving significant unmet medical needs for patients with non-V600 BRAF-mutated cancers.

Fore Bio, formerly known as NovellusDx, was founded in 2011 and is currently headquartered in Philadelphia, Pennsylvania, USA. It is an innovative oncology drug development company dedicated to providing ultra-targeted therapies for patients with rare cancer-driving mutations who lack effective treatment options.

In the early stages of the company’s establishment, its founders leveraged their extensive experience in synthetic biology, bioinformatics, and drug development to create an algorithm known as Foresight. This algorithm is capable of identifying rare cancer-driving mutations and functionally classifying them.

Foresight can recapitulate naturally occurring in vitro mutations and assess their impact on signaling pathway activity and responses to diverse compounds. This enables the identification of unique, molecularly defined patient subpopulations likely to respond to a given drug, thereby optimizing clinical trial processes and accelerating drug development.

In early 2021, NovellusDx was renamed “Fore Bio” and established its global headquarters in Philadelphia. These measures reinforced the company’s mission of “matching cancer patients with rare mutations to clinically validated therapies,” ultimately facilitating the smooth advancement of the plixorafenib pipeline.

The successful launch of the pipeline is underpinned by Fore Bio’s alignment with favorable timing, geographic advantages, and strong team synergy.

Timing: Selected the field of BRAF-mutant tumor therapy, which has a broad market, at the right time.

Currently, most anticancer drugs on the market target common cancer types. Therapeutic options for patients with cancers driven by rare mutations remain limited, leaving this patient population with few treatment choices. According to data from Orphanet, a rare disease database, 6,000–8,000 rare diseases collectively affect approximately 3%–8% of the global population. Although more than 500 orphan drug therapies have been approved in the United States, 95% of patients with rare diseases still lack appropriate treatment options.

Therefore, it is not without reason that Fore Biotherapeutics has chosen to focus on the field of BRAF-mutant cancers.

On one hand, current therapeutic approaches for V600 BRAF-mutant cancers still require improvement. A study conducted by Dr. Gianluca Mauri and colleagues indicated that approximately 8%–10% of patients with metastatic colorectal cancer harbor V600 BRAF mutations. However, among patients receiving treatment for BRAF-mutant colorectal cancer, radiographic disease progression is frequently observed at the first re-evaluation, owing to rapid clinical deterioration and poor sensitivity to standard cytotoxic regimens.

On the other hand, non-V600 BRAF mutations are also present in many cancers and are even more prevalent than V600 BRAF mutations in certain tumor types. However, there are currently no approved therapies for non-V600 BRAF mutations, and cancers harboring non-V600 mutations do not respond to currently approved BRAF inhibitors.

Geographic Advantage: Establishing the corporate headquarters and R&D centers in the biotechnology hubs of Philadelphia, USA, and Rehovot, Israel.

Prior to 2021, Fore Biotherapeutics completed a series of research and development activities at its biotechnology and biomedical research center in Rehovot, Israel. Rehovot is an industrial hub in Israel and is home to the Weizmann Institute of Science. The institute hosts approximately 2,500 scientists, postdoctoral fellows, Ph.D. candidates, and master’s students in science, along with staff responsible for scientific, technological, and administrative affairs. It also features state-of-the-art laboratory spaces and facilities for genomics, computing, and microscopy.

In May 2021, Fore Biotherapeutics established its global headquarters in Philadelphia. Philadelphia is emerging as one of the top life sciences markets and leading biotechnology research hubs in the United States. The city boasts a rich concentration of talent, major universities, renowned medical institutions, and laboratory spaces. GlaxoSmithKline’s (GSK) “The Discovery Labs” is located there. According to data from the Greater Philadelphia Chamber of Commerce, Philadelphia ranks fourth among U.S. cities for the density of higher education institutions, with annual R&D expenditures reaching $10.5 billion. Between 2019 and 2020, venture capital investment in the region’s life sciences sector increased by 350%.

Renhe: A Scientific Advisory Board (SAB) composed of industry experts in oncology, rare diseases, biopharmaceuticals, and other fields.

Dr. Steven Averbuch serves as Executive Clinical and Regulatory Advisor and Head of the Scientific Advisory Board at Fore Biotherapeutics. He is a medical oncologist and pharmaceutical industry veteran with over 35 years of experience in oncology drug development and more than 10 years of experience in the co-development of biomarkers and companion diagnostics.

The other three members are Dr. Filip Janku, who has many years of experience in researching new cancer treatments; Dr. David Solit, an oncologist and laboratory scientist; and Dr. Brian Schwartz, who has more than 10 years of drug development experience in the fields of oncology, hematology, and rare diseases.

In addition, members such as Shawn M. Leland (Chief Executive Officer and Board Director), Michael Vidne, Ph.D. (Chief Business Officer and Chief Strategy Officer), and Gabi Tarcic (Chief Technology Officer) have brought mature drug R&D capabilities and corporate operational strategies to Fore Bio.

Cancer occurs when cells in the body grow and spread uncontrollably.

The BRAF gene in human cells encodes the BRAF protein, which is involved in the regulation of cellular signaling, growth, and survival. As a macromolecule, the BRAF protein works in concert with other proteins to transmit chemical signals from the extracellular environment to the nucleus, thereby instructing cells when to grow and divide. When the BRAF gene undergoes alterations or mutations, it may cause the BRAF protein to constitutively retain this signal. The resulting constitutive activity of BRAF monomers, followed by the activation of MEK1 and MEK2 proteins, promotes cell proliferation and inhibits apoptosis. This implies that cells affected by this signaling pathway may proliferate uncontrollably, ultimately leading to the formation of malignant tumors.

First-generation BRAF inhibitors (BRAFi) can inhibit V600 BRAF mutations in various tumor types, but they target only the most common BRAF mutations. Paradoxically, while inhibiting these mutations, they may induce paradoxical activation of the RAF/MEK/ERK pathway. This pathway transduces extracellular signals into the cell, causing cell growth and division to spiral out of control once again. They can even amplify the oncogenic activity of certain mutant cells, ultimately leading to therapeutic resistance. “Cancer recurrence caused by cancer treatment” has become an unbreakable paradox for first-generation BRAFi.

Plixorafenib emerges as the paradox-breaker of first-generation BRAF inhibitors (BRAFi). Plixorafenib is a small-molecule targeted therapy designed to selectively target cancer cells harboring BRAF mutations while sparing cells with normal BRAF genes.

Unlike first-generation BRAF inhibitors (BRAFi), Plixorafenib slows tumor growth by locking and silencing mutant BRAF proteins, thereby shutting down the transduction pathways of abnormal cell division signals while avoiding paradoxical activation of the RAF/MEK/ERK pathway. Furthermore, it targets a broad spectrum of BRAF mutations, including both common and rare variants, and does not induce the drug resistance associated with first-generation BRAFi.

As a next-generation BRAF inhibitor (BRAFi), Plixorafenib not only effectively inhibits the constitutively active V600 BRAF monomers targeted by first-generation RAF inhibitors, but also disrupts constitutively active dimeric Class II BRAF mutants, fusions, and splice variants. Meanwhile, it preserves RAF function in normal cells where CRAF homodimers can drive signal transduction.

Furthermore, Plixorafenib has a more favorable side effect profile compared to conventional chemotherapy. Conventional chemotherapy employs synthetic chemical agents to kill tumor cells and inhibit their growth. While this approach acts rapidly and can alleviate patient symptoms in a short period, it readily damages or even destroys normal cells, ultimately leading to adverse reactions such as nausea, vomiting, and neurotoxicity.

Currently, Fore Biotherapeutics has conducted two clinical trials. The results of both trials demonstrated that Plixorafenib, as a monotherapy, exhibits robust antitumor activity, durable responses, and favorable tolerability in patients with BRAF-mutant tumors.

In June this year, Fore Biotherapeutics presented its Phase 1/2a trial data at ASCO 2023. The Phase 1/2a trial is a clinical study designed to evaluate the efficacy of Plixorafenib in treating patients with BRAF-mutated advanced solid tumors and central nervous system (CNS) involvement. As of March this year, 113 patients (including both adults and children) had received ≥1 dose of Plixorafenib under conditions of continuous dosing and fasting within 28-day cycles.

Trial data demonstrate that Plixorafenib exhibits a favorable safety and tolerability profile. Efficacy was observed in both MAPK inhibitor (MAPKi)-naïve and MAPKi-pretreated patients within the V600+ BRAF population, with overall response rates (ORR) of 37.5% and 16.7%, median duration of response (mDOR) of 32.3 months and 12.9 months, respectively, and median progression-free survival (mPFS) exceeding two years. The incidence and severity of treatment-emergent adverse events (TEAEs) were low. Unlike early monotherapy data for approved BRAF inhibitors (BRAFi), Plixorafenib was not associated with secondary cutaneous malignancies.

Furthermore, trial results indicate that patients aged 10 years and older can achieve target effective exposure with a total daily dose of 900 mg Plixorafenib plus Cobicistat, thereby maximizing the objective response rate (ORR).

Currently, oncology treatment is becoming an industry highly favored by enterprises and investment institutions. According to Frost & Sullivan’s projections, the global anti-tumor drug market is expected to reach $244.4 billion in 2024, with a compound annual growth rate (CAGR) of 11.2% from 2019 to 2024. By 2030, the global anti-tumor drug market is projected to reach $391.3 billion, representing an expected CAGR of 8.2% from 2024 to 2030.

As the population of cancer patients continues to expand, R&D technologies for anti-cancer drug pipelines advance, and patient demand for innovative therapies grows, emerging treatments representing future trends—such as targeted therapy and immunotherapy—are poised for significant growth.

Fore Biotherapeutics’ ongoing Phase 1/2a clinical trial is expected to be completed in April 2024. VCBeat will continue to monitor whether the company can successfully advance Plixorafenib into the next stage of clinical development, launch the product, and ultimately secure a foothold in the oncology drug R&D market.

References:

1. Nguengang Wakap S et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020 Feb;28(2):165-73.

2. Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.

3. Gianluca Mauri et al. The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer. Cancers (Basel). 2021 Jan; 13(1): 137. Doi: 10.3390/cancers13010137