NEW YORK (GenomeWeb) – With its initial foray into the use of next-generation sequencing technology, Kura Oncology aims to resuscitate a drug that the US Food and Drug Administration deemed not approvable a decade ago.
Last week, Kura announced that it had licensed from Johnson & Johnson's Janssen Pharmaceutica the exclusive rights to develop and commercialize the protein farnesyltransferase inhibitor tipifarnib (Zarnestra) in the field of oncology.
Kura CEO Troy Wilson told GenomeWeb this week that as it embarks on a Phase II clinical trial for the drug, it will collaborate with clinical organizations to perform NGS analysis to identify those patients who may benefit from the drug, joining a growing number of drug firms using the technology to develop new therapeutics.
Kura's trial will test the hypothesis that tipifarnib inhibits tumors with HRAS mutations, and aims to identify patients with solid tumors with documented mutations in the HRAS gene. The trial will have two cohorts, each with 18 patients. One cohort will comprise patients with documented HRAS mutations who typically present with thyroid cancer. The other is with patients with documented HRAS mutations who present with other cancers, including breast, prostate, urothelial, and salivary gland cancers.
Using NGS technology, Kura's clinical partners will screen patients and report to Kura those who have HRAS mutations. The company has identified the clinical sites for its trial and is in the process of finalizing agreements, Wilson said, though he declined to identify them. The collaborators will choose which sequencing platforms to use.
At this point, Wilson said, the La Jolla, Calif.-based firm is in a "drug discovery and development situation where we're trying to identify the patients and understand the biology, and if we get a good signal and we see signs of efficacy, then we'll start to think about … how [to] translate that into the development and commercial realm."
The work marks Kura's first foray into the NGS space, but Wilson said that the choice to use the technology was not made by the company as much as it was made for it as clinicians increasingly are incorporating NGS into the care of their patients.
"They are the ones who are responsible for patient care, and [NGS] is part of their caring for the patients," Wilson said. "What we're trying to do is provide them with a potential therapy … At the end of the day, the decision about which platform to use, which technology, rests with the clinical sites and the investigators."
Nonetheless, its entry into the NGS space is part of a growing trend among pharmaceutical firms to include NGS in their drug development work, a list that includes Regeneron Pharmaceuticals, Genentech, and Biogen Idec. Meanwhile, the two largest NGS platform companies, Illumina and Thermo Fisher Scientific, each recently announced collaborations with drug manufacturers to develop universal NGS-based companion diagnostic oncology tests.
Unlike many of the other efforts, though, Kura — which last week also said that it raised $60 million in gross proceeds from a private placement of its shares — is not developing a new drug from the ground up, but instead seeks to salvage one that has shown clinical promise but ultimately failed to pass FDA muster.
Tipifarnib was discovered and developed by J&J to treat acute myeloid leukemia patients 65 years of age and older. It works by inhibiting farnesylation, a cell signaling process that has been implicated in cancer initiation and development, Kura said, adding that preclinical and clinical data indicates that tipifarnib can benefit cancer patients with limited treatment options.
In early 2005, J&J submitted a new drug application to FDA for tipifarnib, but a few months later the agency issued a "not approvable" letter for the drug.
According to Wilson, tipifarnib has been used by thousands of patients, has been well-tolerated, is well-understood in safety profiles, and "has some encouraging signs of efficacy in different patient populations." But because the response rate has never been high enough for any particular indication, the FDA has passed on approving it.
In targeting tipifarnib at patients with HRAS mutations, Kura is seeking a potential market size of about 8,000 patients, though many of them may not respond to the drug.
"It's believed that if a patient presents with a mutation at either codon 12, codon 13, or codon 61 of HRAS, then the HRAS is constitutively active, and the hypothesis is that [the] activated HRAS is driving the tumor," Wilson said. The preclinical data supports the hypothesis, "but you never know until you get into [the] patients."
He added that "patients with mutations in HRAS will have activated HRAS. That will activate the signaling pathways downstream from HRAS," but by blocking HRAS activity with tipifarnib, "we can then interrupt that constitutively active state. … If the accelerator is pressed to the floor, we can sort of cut the line and take the foot off the accelerator, so that the cells stop growing."
Kura anticipates starting its clinical trial in the second quarter of this year. According to a document filed on clinicaltrials.gov, the study is anticipated to be completed in December 2017.
Though tipifarnib was developed to treat older AML patients, Wilson said that Kura is not working in that area, but instead will focus on thyroid, head and neck, urothelial, and salivary cancers.
Further down the road, if Kura decides to prospectively screen patients for the drug, it will need to settle on a technology for such work. Kura will not have to make a decision for some time, and while NGS could be used for such applications, Wilson noted that for KRAS mutations, current screening applications have relied on PCR-based technology.
Along with plans to seek FDA approval for tipifarnib, Wilson said the company anticipates seeking regulatory approval for a companion diagnostic for the drug "if it turns out that a companion diagnostic is useful in identifying these patients prospectively." In such a scenario, Kura would partner with a diagnostic firm to develop the CDx, he said.
Along with the HRAS clinical trial, Kura has a clinical trial planned for tipifarnib directed at patients with peripheral T-cell lymphoma, but there are no plans to use NGS for that trial.
Also, the company has a development program for an ERK kinase inhibitor that is in the preclinical stage. Specifically, the candidate drug inhibits protein-protein interactions called menin-mixed lineage leukemia and has shown "particularly good activity in tumors where the RAS pathway is mutated or otherwise misregulated," Wilson said. In this program, Kura will also look for patients with mutations to KRAS, BRAS, or NRAS. No decision has yet been made whether NGS will be used to ID those patients as Kura is still in the IND-enabling stage with the program, he said.