BIO: Kura Oncology CEO Wilson on the power of biotech in the quest beyond KRAS

Troy Wilson’s company, Wellspring Biosciences, was working on a KRAS inhibitor with Johnson & Johnson when a thought struck him: Are there other ways to modulate the same pathway KRAS does? After spending “nights and weekends” poring over literature, he stumbled across a drug that his Big Pharma partner, despite all its resources, couldn’t take forward.

“I reached out to the head of oncology, Peter Lebowitz, and said: You have tipifarnib. It should work in HRAS-mutant cancers,” Wilson told Fierce Biotech. Lebowitz agreed but added that, even with J&J’s scope and resources, “we can’t do everything.”

Naturally, Wilson asked: “Can I have it?”

After much “pushing and pulling” to get it out of J&J and into Kura Oncology, the company zeroed in on HRAS-mutant solid tumors. J&J’s Janssen unit had tested tipifarnib in thousands of patients in “all sorts of different trials,” seeing tumor shrinkage across various cancers including lymphomas, leukemias and breast cancer, Wilson said. But it never produced a convincing signal. Wilson figures the Big Pharma was onto something, but didn’t have all the pieces of the puzzle.

“Five years on, we have a much better understanding on what the drug does. J&J didn’t have the perspective, the history or the tools, like next-generation sequencing,” he added. “They had an exquisitely potent and selective compound; they just didn’t know how to develop it appropriately.”

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Tipifarnib blocks an enzyme called farnesyl transferase, which plays a key role in multiple cancer processes, like the survival, growth and proliferation of tumor cells. Kura’s most advanced program targets HRAS-mutant head and neck cancers, but the drug could also be useful in patients who don’t have HRAS mutations but are HRAS-dependent, or even in patients who don’t express HRAS at all, Wilson said.

Its latest data, presented at this year’s virtual meeting of the American Society of Clinical Oncology, found that tipifarnib shrank tumors in half of 18 patients whose head and neck cancers had worsened despite undergoing prior treatment. The drug kept cancer at bay for nearly six months and extended patients’ lives for 15 months.

Though cross-trial comparisons are impossible to do, and the study wasn’t powered to show statistical significance, the company pointed to data for three FDA-approved second-line treatments—Merck’s Keytruda, Bristol Myers Squibb’s Opdivo and Eli Lilly’s Erbitux—to show tipifarnib’s potential. Those drugs shrink tumors in 13% to 16% of patients, stave cancer off for two to three months and extend patients’ lives by five to eight months, Kura said.

“It’s not fair to say without running a randomized study. But that’s a signal—in HRAS-mutant patients, it is now clear that inhibiting farnesylation, which is critical for the proper function of HRAS, can really arrest tumor growth and provide meaningful clinical benefit to patients,” Wilson said.

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Kura has tested tipifarnib is other HRAS-mutant solid tumors like vulvar, penile, skin and lung cancers, as well as in blood cancers that express the protein CXCL12. Blocking farnesylation in those blood cancers curbs CXCL12 production, leading malignant B cells and T cells to get destroyed.

“Once you understand CXCL12 and look at Janssen’s data in lymphoma and leukemia, it all begins to make sense,” Wilson said. “They didn’t understand what they had—once you understand it, you can design much better studies.”

The company wants to pursue those blood cancers but has put those programs on hold for now so it can concentrate on its head and neck program and an earlier-stage treatment for acute myeloid leukemia.

The latter program targets the menin-MLL interaction, a leukemia-driving mutation long thought to be undruggable. Kura aims to get to a dose for phase 2 studies this year and then test its treatment in patient groups where preclinical data predict it will be most successful.