Calithera buys itself a plan B

When your next big trial catalyst involves an asset that has already failed in the clinic it pays to have a back-up. This might be the reasoning behind Calithera’s purchase yesterday of two early Takeda assets, a move that could give Calithera something to pivot to should telaglenastat fail its Keapsake study in lung cancer later this year.

Telaglenastat’s lung cancer mechanism might differ from its mechanism in kidney cancer, where the Cantata study bombed in January, so Keapsake might not be an obvious bust. But investors have deserted Calithera; as the cash element of the Takeda tie-up is just $10m doing the deal makes sense – with some important caveats.

There is some clinical backing for the two assets Calithera has acquired, the mTOR complex 1/2 inhibitor sapanisertib (TAK-228) and mivavotinib (TAK-659), an inhibitor of Syk and Flt3. The former has shown activity in squamous NSCLC carrying the NRF2 mutation, where a 27% ORR was reported at Asco 2020, and in which Calithera wants to start a study early next year.

Mivavotinib, meanwhile, has yielded a 28% remission rate in diffuse large B-cell lymphoma, a result Calithera reckons was driven by mutations in MyD88 and CD79. These mutations occur respectively in 30% and 10-15% of DLBCL patients, the group says, and comprise a distinct genetic subtype associated with poor outcomes.

It also says these lymphomas rely on Syk activation, which is why a Syk inhibitor like mivavotinib might be relevant. However, Calithera’s planned study, also beginning early next year, will enrol DLBCL cohorts with and without MyD88/CD79 mutations, so it will be vital to see whether there is much activity in wild-type disease.

$10m in cash

Still, if these assets are promising why did Takeda let them go for just $10m in cash plus $35m in Calithera preferred stock? True, the Japanese company has been doing some housekeeping, separately scaling back a CNS-focused collaboration with Wave Life Sciences yesterday, and Calithera said sapanisertib had been explored in a biomarker-agnostic fashion.

But the much bigger clue lies in toxicities. In particular, the NSCLC trial saw an astonishing 47% rate of grade 3 hyperglycaemia, and though this was said to be “easily controlled” with metformin it could make sapanisertib a non-starter.

In mivavotinib’s trial there were some liver enzyme elevations, which might have made Takeda cautious about development. Other reasons might include DLBCL being a competitive space and the fact that the asset is not a clean Syk inhibitor, additionally hitting Flt3.

Mechanistically both areas have relatively limited competition. According to Evaluate Pharma the industry’s only other clinical-stage mTOR complex 1/2 inhibitor is Boehringer Ingelheim’s BI 860585, though this has not progressed since phase 1 data showed it to have some solid tumour activity in combination with Aromasin or paclitaxel.

Work on Syk inhibitors has been ongoing for years, but mostly outside oncology. Rigel’s Tavalisse was approved in 2018, for chronic immune thrombocytopenia, but the only success of sorts in cancer has come courtesy of Portola’s cerdulatinib – also an inhibitor of Jak – in follicular lymphoma, a relatively less aggressive cancer. In DLBCL Gilead’s entospletinib yielded zero remissions.

Keapsake and cash

Calithera now faces a couple of pressing issues. First it must weather the readout later this year of telaglenastat, its lead project, in the Keapsake study of Keap1/NRF2-mutated NSCLC of non-squamous histology. The asset failed the Cantata trial in renal cell carcinoma.

Then there is its cash position; the company had $92m of half-year cash, and though this was later supplemented with an undisclosed settlement of litigation against Incyte over a discontinued deal covering INCB001158 it seems not to have extended Calithera’s cash reach beyond the end of 2022.

Both planned studies of sapanisertib and mivavotinib will yield data in late 2022/early 2023. Investors are surely braced for a cash call even before Keapsake reads out.