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Fore Biotherapeutics Enters Pharma Business With BRAF Inhibitor as Lead Product

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NEW YORK – Fore Biotherapeutics, which last month officially changed its name from NovellusDx, has transitioned to developing its own drugs and is advancing a targeted treatment for cancer patients with certain BRAF tumor mutations not addressed by available options.

The Israel-based company, which launched as NovellusDx in 2011, originally offered a functional genomics platform to pharmaceutical companies and researchers who wanted to gain deeper insights into the activity of their drugs. Now as Fore, this platform, dubbed Foresight, is central to its own drug development strategy, which involves licensing therapeutic candidates from other firms and identifying tumor mutations the agents have activity against. As with its lead compound, PLX8394, Fore is particularly interested in identifying drug development opportunities that address an unmet need in precision oncology.

"What we've developed in the diagnostic company was the ability to synthesize mutations fast, see how … they induce activity in different cells, and then test them with different drugs," said Michael Vidne, Fore's chief business and strategy officer.

NovellusDx began its transition to therapeutics in 2019, while Vidne was CEO and recognized the potential of the functional genomics platform to identify drug development opportunities for the company to advance internally.

"When we did the shift from diagnostic to therapeutic, it became apparent that there is a very large patient population that has very rare mutations, even on very well-known genes," he said. "We can really help these patients because we have the ability not just to [target] the hot spot mutations the way that others do, but really synthesize each individual mutation and test it with a drug and therefore identify specific mutations that respond to the drug."

With the rebrand as Fore, the company is hoping to establish a base of operations in the US, and Vidne has handed over the CEO position to Usama Malik, previously the chief financial officer and chief business officer at Immunomedics. The company's lead candidate, PLX8394, is a BRAF inhibitor, which Fore exclusively licensed from California-based Plexxikon, a Daiichi Sankyo subsidiary, last June for an undisclosed payment.

BRAF inhibitors are widely studied and represent a crowded market. However, with its drug, Fore is going after a largely unaddressed patient population: the large swathe of cancer patients whose tumors have non-BRAF V600 mutations. V600 mutations comprise about 50 percent of the mutations that occur in BRAF in cancer patients, but for the other half, different parts of the gene are altered. These patients often don't typically derive a clinical benefit from currently approved BRAF inhibitors, Vidne said.

Earlier-generation BRAF inhibitors, such as vemurafenib (Genentech's Zelboraf), encorafenib (Pfizer's Braftovi), and dabrafenib (Novartis's Tafinlar), target BRAF V600 mutations.

Vemurafenib was the first drug approved for metastatic or unresectable melanoma patients with BRAF V600E mutations. More recently, the anti-PD-L1 immunotherapy atezolizumab (Genetech's Tecentriq) also was approved in combination with vemurafenib and the MEK inhibitor cobimetinib (Genentech's Cotellic) for BRAF V600 mutation-positive unresectable or metastatic melanoma. Newer BRAF inhibitors, in combination with other drugs, have also been approved to treat a variety of advanced cancers beyond BRAF V600-mutated melanoma including colorectal cancer, non-small cell lung cancer, and thyroid tumors that also harbor BRAF V600 mutations.

The difference between BRAF V600 mutations and non-V600 mutations is that the latter are dimers. Currently approved BRAF inhibitors only inhibit V600 mutations and cannot break the non-V600 dimers and therefore don't work well against cancer cells driven by non-V600 BRAF mutations. By contrast, PLX8394 is able to break such dimers by inhibiting ERK signaling in tumors driven by non-V600 BRAF mutations, while sparing RAF function in normal cells, according to a 2018 study of PLX8394.

Fore explored non-V600 BRAF mutations using its CRISPR-enabled functional genomics platform, which can synthesize cells with mutations to see how they activate and how they interact with different drug mechanisms. The company decided to focus on these mutations as a drug target because of the large patient population and the well-understood mechanism of action for BRAF inhibitors. The company estimated that PLX8394 could treat about 17,000 patients annually who have non-V600 BRAF mutations, BRAF fusions, or BRAF-mutated tumor types not currently treatable by approved therapies, like glioma, ovarian, or thyroid cancers.

"It's very well accepted that if you're able to inhibit BRAF, you're going to have a clinical response," Vidne said. "The unmet need [in BRAF] is huge. Even though 50 percent of the patients with the BRAF [V600] mutation, which is 3 percent of the entire patient population, were addressed with the first generation of BRAF inhibitors, the other 3 percent of the patient population were not addressed, and it is mostly because they had these non-V600 mutations."

Fore has already begun a Phase I clinical trial of PLX8394 and has dosed about 70 patients, Vidne said. In initial data from this study, researchers have observed a 22 percent response rate, with one complete response in a patient with an AGK-BRAF fusion and nine partial responses out of 45 evaluable participants. Fore is enrolling patients with different tumor types and BRAF mutation types who currently lack targeted treatment options.

For example, there are cohorts with glioma, thyroid, and ovarian cancer patients who have a BRAF V600 mutation. The trial also includes a tumor agnostic cohort to explore the activity of PLX8394 in patients with non-V600 and non-fusion BRAF mutations.

The company hopes to move into a Phase II study by the end of this year after determining PLX8394's dose in the current trial. If successful, PLX8394 could fill the gap left by earlier-generation BRAF inhibitors.

Of course, Fore isn't the only company to recognize the unmet need in this regard. Others are developing products targeting similar non-V600 BRAF mutations, including BeiGene, which is studying lifirafenib; MapKure, which has an inhibitor that targets both BRAF V600 and non-V600 mutations; Takeda Pharmaceutical, which is developing a pan-RAF inhibitor as a treatment for glioma; and Kinnate Biopharma, which also has its own non-V600 drug candidate.

There are two areas where PLX8394 is differentiated from competitors and currently marketed therapies, Vidne said. First, PLX8394 is already in the clinic, while several of these other potentially competing drugs are still in preclinical phases. Second, PLX8394 has already shown a promising safety profile in its Phase I study that, according to Vidne, is "cleaner than anything else that we've seen."

In the initial Phase I data, most adverse events reported were manageable and only one grade 4 adverse event was reported. PLX8394 also does not appear to have the risk of skin lesions that have occurred with other BRAF inhibitors, like vemurafenib and dabrafenib, with only four patients reporting a grade 1 rash in the Phase I study.

Going forward, Malik, who previously spent many years in venture capital, held executive roles at Immunomedics, and oversaw Immunomedics's $21 billion sale to Gilead, plans to establish new headquarters in the US and guide PLX8394 and other products through the pipeline.

Last September, Fore raised $57 million in a Series C funding round to support the development of PLX8394 and bring more drugs into its pipeline. Vidne said the company is exploring further licensing agreements to build out its pipeline, but he did not disclose specifics.

The company will continue using its functional genomics and drug discovery platform to identify unaddressed mutations and screen small molecule oncology drug compounds against these targets. In the next two years, Malik hopes to have two to four clinical assets in registrational studies.

With its focus on advancing drugs in areas of unmet need, many of Fore's products may receive orphan drug designation or breakthrough therapy designation from the US Food and Drug Administration. That would allow the company to take its products to market in an accelerated time frame, Malik said.

"We're not going to be a single-asset company," he added. "Our strategy moving forward is to keep looking at high-quality compounds that we can bring into the clinic." With each compound in its pipeline, Fore expects to explore its activity simultaneously in multiple indications that can potentially reach registration-enabling trials.

"That really creates a balanced portfolio where you're risk-managing things across multiple oncogenes and targets," he said. "You're further de-risking them by having multiple shots on goal within a single asset."