Viewpoints: With KRAS in the spotlight, Kura takes on HRAS

FirstWord Pharma

By Becky Simon

September 10th, 2019

While the World Congress on Lung Cancer meeting brought in fresh foment over drug development against KRAS, Kura Oncology has been plugging away against its relative HRAS- hoping to use precision medicine and breakthrough biomarkers to resurrect a long-defunct Johnson & Johnson compound.

The backstory
Back in 2005, tipifarnib received a death knell from the FDA, with the agency’s Oncologic Drugs Advisory Committee voting to reject Johnson & Johnson’s application for the candidate to treat acute myeloid leukaemia (AML). The company’s NDA was based on outcomes from a single Phase II trial, where according to Kura CEO Troy Wilson, the agency’s discussion centred not on the drug’s activity, but on the fact that there were two patient populations, “one that benefits and one that doesn’t.”

Johnson & Johnson promptly abandoned development of the farnesyl transferase inhibitor, without the benefit of any knowledge of defining characteristics for the responding patients. While academic groups dabbled in investigator-sponsored trials of tipifarnib over the next nine years, Wilson says that he was motivated by his experience developing KRAS inhibitors at Wellspring Biosciences and Araxes Pharma, paired with the definitive, but inconsistent, efficacy seen in the earlier clinical programme, to try a precision medicine approach for the therapy.

Over the course of a year, Wilson negotiated a licensing deal with Johnson & Johnson to bring the candidate on board at Kura- which also came along with a sample set from 5000 treated patients that would prove pivotal to identifying biomarkers for responders.

Tipifarnib’s mechanism is based on its ability to prevent the translocation of HRAS- but not related isoforms KRAS or NRAS- blocking activity of both wild type and mutant copies of the oncogene. The oncogenic mutation isn’t as common as the KRAS profile that currently has investors and analysts foaming at the mouth, but is enriched in some cancers, including head and neck squamous cell carcinomas (HNSCC). The company has already shown proof-of-concept data in the indication, and recently started a registration-directed trial. (See ViewPoints: What’s all the fuss about KRAS inhibitors?)

What happened
Kura shared results from an investigator-sponsored study of tipifarnib on September 3, outlining the first results for the candidate in urothelial carcinoma. The company said that in 13 evaluable patients with a median of one prior therapy, five achieved an objective response. Four of the five achieved progression-free survival of at least six months- which met the criteria to achieve the study’s primary endpoint. All enrolled patients had an HRAS mutation, with 7.5% of its screened population in Korea coming up positive for the marker.

Next steps
Wilson says that the company isn’t banging down the door to begin its own registrational programme in the new indication, but it is certainly encouraged by signs of efficacy for its candidate in a fourth, biomarker-defined cancer setting.

While the company is committed to pursuing drug development in the appropriate, targeted populations, Wilson noted that a tumour agnostic approval pathway isn’t necessarily in the cards, citing the complexity of mutation and resistance profiles in the MAP kinase pathway, as opposed to more defined targets like NTRK.

The bigger picture
Some of that complexity is illustrated by a second patient population independently identified by Kura as tipifarnib responders- patients with high expression of CXCL12 and CXCL5, both members of a chemokine signalling pathway. A genomic analysis of those 5000 patient samples from Johnson & Johnson pointed towards enrichment of the biomarker in tipifarnib-responders, which was later validated in a Phase II trial- further deepening the bucket of genetic profiles that respond to the farnesyl transferase.

While there are other farnesyl transferase inhibitors in the competitive landscape, Wilson notes that they are primarily in development for progeria- and the company has been building out a patent portfolio based on the use of any farnesyl transferase inhibitor in oncology indications to protect its claim to the space.

Final thoughts
Kura’s first order of business is generating positive results from its pivotal trial, while it’s also extending its grip into biomarker-driven indications. One challenge for that strategy could be in patient identification, given the generally low prevalence of HRAS mutations; as Wilson says, “physicians don’t look for things until they have a reason to.”

That said, the oncogene is included in standard screening panels, easing the diagnostic burden, and physician awareness of HRAS mutations will likely begin to enjoy some of the same spotlight that is now beating down on KRAS.