Kura harks back to its roots

Few might recall that when Kura went public 10 years ago its primary focus wasn't menin but farnesyl transferase inhibition. The latter mechanism has come into play again, with the group priming investors for the first clinical data, due to be revealed next month on a molecule called darlifarnib.

If that suffix rings a bell it's because darlifarnib is structurally very closely related to tipifarnib, a Johnson & Johnson castoff that was Kura's lead project back in 2015. Tipifarnib is still in Kura's pipeline, but is likely to slip into obscurity after the switch to the follow-up molecule, which the group claims has better pharmacokinetics and – crucially – patent protection.

It was lack of IP that was perhaps tipifarnib's biggest problem. J&J originated that farnesyl transferase inhibitor (FTI) back in the 1990s, and tested it in numerous solid and haematological cancers, but by 2015, when the molecule was sold to Kura for $1m up front, its US composition-of-matter patent had just one year left to run.

Despite this Kura continued studying tipifarnib, though the company's investment case switched to the menin inhibitor ziftomenib. With ziftomenib now filed, and facing a November PDUFA date for relapsed, NPM1-mutant AML, the time has evidently come to dust off the FTI approach.

Darlifarnib

This is where darlifarnib, which actually started a first-in-human trial two years ago, comes in. This molecule has been "optimised" for combination drug development, Kura claims, and has enhanced potency and selectivity versus tipifarnib.

Next month's ESMO conference will reveal whether such pharmacokinetic claims have clinical backing. The phase 1 solid tumour study is to feature in two ESMO posters, Kura said at an investor event on Tuesday. One will detail the safety and efficacy of darlifarnib monotherapy, while the other relates to a Cabometyx combo specifically in second-line or later kidney cancer.

Kura says the logic of FTIs lies in this mechanism's ability to overcome resistance to inhibitors of tyrosine kinase, PI3Kα and KRAS. It has preclinical backing for a Cabometyx combo in the post-Lenvima/Inlyta setting, and says darlifarnib enhances activity of PI3Kα inhibition as well as resensitising KRAS inhibitor-relapsed tumours.

Accordingly, it reckons phase 1 data will be most impressive in combination, and says monotherapy activity is expected in HRAS-mutant patients only. Since Cabometyx alone yields a 25% response rate in relapsed kidney cancer Mizuho analysts want to see 31-46% from a combo among the 20 or so patients in whom efficacy data are be presented.

Meanwhile, neutropenia is a common problem for FTIs, and should be closely watched given Kura's claim that darlifarnib's tolerability is manageable.

Undervalued?

Darlifarnib is unlikely to feature prominently in sellside analysts' current models for Kura, whose valuation still turns on the promise of menin inhibition.

Nevertheless, despite ziftomenib looking likely to be approved shortly the market values Kura at $725m, which is barely above the company's mid-year cash balance of $631m. Little wonder that Kura is trying to drum up interest in work beyond menin.

Though darlifarnib looks set to eclipse tipifarnib, Kura hasn't yet given up on the latter, whose phase 1 Piqray combo study in PIK3CA-mutated/amplified head and neck cancer is also to feature in an ESMO poster. Apart from the $1m up-front fee Kura issued J&J $1m of equity, and agreed to pay royalties and $75m in tipifarnib milestones.

Given how similar darlifarnib is to tipifarnib it might be possible for J&J to demand fulfilment of some of these future obligations in relation to the follow-on molecule.