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Kinnate Exiting Stealth Mode With Plans to Move Lead RAF Inhibitor Into Clinical Trials Next Year

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NEW YORK − Biotech company Kinnate is slowly exiting out of stealth mode with a pipeline that features two targeted drug candidates expected to enter clinical trials next year. The company is particularly eager to explore its lead product, a RAF inhibitor, in non-V600 BRAF-mutated non-small cell lung cancer, colorectal cancer, and melanoma.

Kinnate was founded in 2018 by Steve Kaldor and Eric Murphy with the goal of developing precision oncology drugs. That year, it raised $22 million in a series A funding round led by Foresite Capital. Last December, the company raised $74.5 million in a series B round led by OrbiMed, rounding out its collection of investors with Nextech Invest, Vida Ventures, and Eshelman Ventures. The proceeds from the fundraising will be directed towards advancing multiple drug candidates into the clinic.

The company's lead drug candidate is a RAF dimer signaling inhibitor that targets class II and class III BRAF mutations and is now undergoing preclinical toxicology screens.

"It targets atypical BRAF mutations, non-V600E [mutations], and we have a lot of knowledge in this in lung cancer, melanoma, [and] colorectal cancer," said Murphy, who is also Kinnate's CSO. "These pathways are active and there are strong vulnerabilities that we know of."

BRAF mutations can be divided into three classes. Between 1 percent and 2 percent of NSCLC patients, for example, harbor targetable BRAF V600 mutations, which are dubbed class I mutations. However, between 50 percent and 80 percent of BRAF-mutated lung cancers have non-V600 mutations that can be divided into class II and class III mutations.

Class II mutations result in continuously active, RAS independent dimers with high or intermediate BRAF kinase activity. Class III mutations tend to have low or no BRAF kinase activity. Patients with class II or class III BRAF mutations are also more likely to have RAS co-mutations, and NSCLC patients with these mutations tend to have poor prognosis.

Most BRAF inhibitors that have been commercialized to date, or are being studied, go after BRAF V600 mutations, according to Kinnate CEO Nima Farzan. "We are looking after these class II, class III, or atypical mutations where the current drugs just do not work, and it's a more complex problem to solve," he said. "Our efforts have led us to believe that we can be effective in these other situations, where there are no approved drugs."

In the absence of treatments targeting their specific tumor mutations, these patients are receiving potentially more toxic standard-of-care options. "Those patients are getting no treatment today other than chemotherapy, or possibly immunotherapy, if they're eligible," said Farzan.

This is where Murphy envisions Kinnate's RAF inhibitor could come into play. "[Kinnate's RAF inhibitor] can really up the target coverage [and] cover a BRAF fusion or an inactive mutant that is expressed with RAS," he said.

Additionally, the team has been working to ensure that the molecule can overcome challenges associated with currently marketed BRAF inhibitors, such as "paradoxical activation." Researchers have found that one of the paradoxical features of BRAF inhibitors vemurafenib (Plexxikon's Zelboraf) and dabrafenib (Novartis' Tafinlar) is they activate the MAPK pathway in cells with oncogenic RAS and promote cancer growth. Drugmakers and oncologists have attempted to get around this problem by combining these BRAF inhibitors with a MEK inhibitor, which has been effective in BRAF V600E-mutant melanoma. 

Since Kinnate's molecule is designed to equally inhibit both the RAF and RAS dimers, this could alleviate the paradoxical activation problem, said Murphy.

Kinnate plans to start testing its RAF inhibitor in tumor types known to acquire class II and III BRAF mutations, such as NSCLC, colorectal cancer, and melanoma. But, eventually, the company hopes to take a tumor-agnostic approach and investigate the drug's activity in a variety of cancers with RAF mutations.

Murphy said that the BRAF mutations the company is focusing on in patients are detectable through central laboratory testing. Since commercial next-generation sequencing tests can gauge class II and class III BRAF mutations, Kinnate isn't expecting to develop its own companion diagnostic.

The second drug candidate the company hopes to bring into clinical trials next year is an FGFR inhibitor, which it will initially explore in patients with resistance mutations in FGFR2 fusion-positive intrahepatic cholangiocarcinoma and FGFR3-altered urothelial carcinoma. Farzan said that since the drug can inhibit the initial alteration or fusion in addition to the resistance mutations, Kinnate is interested in exploring it in the first-line setting down the line.

Kinnate also recently unveiled an earlier-stage program of a first-in-class CDK12 inhibitor, which it will study in ovarian cancer, triple-negative breast cancer, and metastatic castration-resistant prostate cancer characterized by mutations in DNA damage repair genes, either alone or potentially in combination with a PARP inhibitor or an immune checkpoint inhibitor.

The funds Kinnate has are adequate to take all three programs into the clinic, and the company is evaluating future financings based on market conditions.