BeiGene, SpringWorks to Study Combination Therapy for Advanced Solid Tumors

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BeiGene’s RAF dimer inhibitor lifirafenib (BGB-283)


BeiGene’s RAF dimer inhibitor lifirafenib (BGB-283) and SpringWorks Therapeutics’ MEK inhibitor, PD-0325901 will be studied as a combination therapy for patients with advanced solid tumors in a trial set to start next year, the companies said.

The value of the collaboration was not disclosed—though the companies did say that they will equally share all costs of their clinical studies and governance responsibilities. BeiGene has agreed to administer a Phase Ib trial that is expected to commence during the first quarter of 2019 in patients with advanced solid tumors that harbor RAS, RAF mutations, and other MAPK pathway aberrations.

SpringWorks Therapeutics has agreed to oversee fixed-dose formulation work as part of the collaboration, which aims to assess the safety, tolerability, and preliminary efficacy of combining lifirafenib with PD-0325901.

Discovered in BeiGene’s research facilities in Beijing, lifirafenib is a novel small molecule inhibitor with RAF monomer and dimer inhibition activities. Lifirafenib has shown antitumor activities in preclinical models and in cancer patients in tumors with BRAF V600E mutations, non-V600E BRAF mutations, and KRAS/NRAS mutations—where first-generation BRAF inhibitors have not shown to be effective.

“We believe that lifirafenib as monotherapy or in combination with other agents may have a potential for treating various malignancies, such as melanoma, NSCLC [non-small cell lung cancer], and endometrial cancer,” BeiGene states on its website.

To date, BeiGene said, lifirafenib has been dosed in more than 150 patients globally. Lifirafenib was the subject of a Phase Ia/Ib open label, multiple dose, dose escalation, first-in-human study in Australia (ACTRN12614001176651) launched in 2014.

“BGB-283 was generally well-tolerated during the Phase IB stage of the study. Antitumor activity was not only observed in subjects with B-RAF V600-mutated solid tumors including melanoma, PTC, and ovarian cancer, but also in subjects with K-RAS-mutated NSCLC,” Jayesh Desai, MBBS, FRACP, medical oncologist at Australia’s Royal Melbourne Hospital, and colleagues, reported at the American Association for Cancer Research (AACR) Annual Meeting 2017, according to the abstract of their presentation. 


‘Desirable’ Profile for Further Study

“When added to the efficacy data in the Phase Ia portion of this study, with objective responses noted in these tumor subtypes as well as in K-RAS-mutated endometrial carcinoma, BGB-283 demonstrated a desirable risk-benefit profile for further efficacy and safety investigation,” Dr. Desai and colleagues added.

PD-0325901 is a MEK 1/2 inhibitor originally discovered by Pfizer researchers, and under development for neurofibromatosis—a trio of genetic disorders (NF1, NF2 and schwannomatosis) that cause tumors to grow on nerves throughout the body, leading to blindness, deafness, disfigurement, cancer, bone abnormalities, learning disabilities, and severe pain.

PD-0325901 has been shown in clinical biopsies to block MEK phosphorylation, thereby arresting cellular growth and causing cell death to occur. Preclinical models have demonstrated significant synergy between MEK and RAF inhibition in RAS-mutant solid tumors. And MEK inhibitors have also shown encouraging activity in reducing tumor size in clinical Phase I/II studies in patients with plexiform neurofibromatosis, according to SpringWorks.

In the most recent study involving PD-0325901, published last month in Pharmacological Reports, Maksym Kopanitsa, Ph.D., lead for in vivo neurobiology, department of medicine, Imperial College London, and colleagues, reported that the MEK inhibitor was shown to normalize basal synaptic responses in vehicle-treated Syngap1+/- mice, but did not reverse their long-term potentiation (LTP) deficit.

By vertically inhibiting the MAPK pathway, SpringWorks and BeiGene reason, the combination of PD-0325901 and lifirafenib may potentially overcome feedback loops that have impeded therapeutic development for RAS-mutant solid tumors.

For SpringWorks, the clinical collaboration comes a day after it appointed Saqib Islam as CEO; he previously served as SpringWorks’ chief financial and chief business officer, and earlier held positions at Moderna Therapeutics and Alexion Pharmaceuticals.

The collaboration with BeiGene also comes a year after the company was spun out of Pfizer, which joined with three other investors to fund the new company’s $103 million Series A financing—the third-largest biopharma venture capital round of Q3 2017.

Separately, SpringWorks plans in 2019 to launch a Phase IIb trial designed to assess PD-0325901 as monotherapy for neurofibromatosis type 1 patients with plexiform neurofibromas.







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