Volastra vies for the next big synthetic lethality target

Predicting the next big thing in cancer isn’t easy, but Volastra reckons it has a head start in a synthetic lethality target that's set to become hot, KIF18A inhibition. To back up this claim, the private company has attracted Bristol Myers Squibb as a partner and Lilly as an investor.

However, there are only a few other, predominantly Chinese companies looking at KIF18A inhibition. Furthermore, the group’s lead project, sovilnesib, is an Amgen cast-off. With no clinical data on a KIF18A inhibitor released publicly thus far, it might be a while before this mechanism catches on, if ever.

Cancer specific?

Volastra is focused on targeting chromsomal instability, also known as CIN, which the company’s chief medical officer, Scott Drutman, describes as an “important vulnerability” of cancer cells. More advanced examples of this kind of synthetic lethality include PARP, ATR and CHK1 inhibition. 

CIN refers to changes in the number and structure of chromsomes, and is seen in 60-80% of cancers, according to Volastra. KIF18A is a protein that binds to the microtubules involved in mitosis, and is said to be necessary for chromosomally unstable cancer cells, but not healthy cells, to divide. 

“If you inhibit KIF18A in normal cells they do just fine – but cancer cells, that have these abnormal numbers and structures of chromosomes, are unable to cope with the loss of KIF18A,” Drutman tells ApexOnco.

Volastra has two KIF18A inhibitors in clinical development, the Amgen-originated sovilnesib and the internally developed VLS-1488. Initially, the group is focused on high-grade serous ovarian cancer, which Drutman says is “universally enriched in CIN”, allowing the recruitment of all comers.

The picture in other cancers is more complicated, and here Volastra is investigating potential biomarkers to identify patients with CIN, via partnerships with Microsoft, Tailor Bio and Function Oncology.

Volastra ultimately hopes to progress either sovilnesib or VLS-1488, based on the data that emerge; Drutman estimates that the company should start getting clinical results later this year or early in 2025. Amgen has already completed a phase 1 trial, but has not yet disclosed any data – although this is expected to be released in future.

Amgen's goodbye KIF

Volastra is therefore ahead with a mechanism that has just seen the clinical entrance of China’s Genhouse Bio, as well as various preclinical presentations at the recent AACR meeting. “I think we’re on that upswing with a new and exciting target,” says Drutman.

However, if KIF18A inhibition is so promising, why did Amgen decide to exit the arena, in a deal announced last year?

“These prioritisations happen all the time. Big pharma companies have a lot of choices of what to pursue,” Drutman replies. Although he stresses that he can’t speak for Amgen, he notes that the big biotech is perhaps focused on its core oncology areas, such as KRAS inhibition and bispecific antibodies.

Elsewhere, Drutman says, Volastra has had “a lot of interest from strategics and large companies”. This might be seen as typical small company exuberance, except that two big players have already bought in. Last year’s in-licensing of sovilnesib was done in parallel with a $60m series A round in which Lilly participated – and Drutman points out that this was via the pharma giant’s Loxo division, rather than its venture financing arm.

Meanwhile, in 2022 Volastra announced a collaboration with Bristol Myers Squibb, under which the groups are working on two undisclosed CIN targets.

Volastra has enough cash to get into 2025, which should be long enough to get an early indication of whether KIF18A inhibition is as exciting as the company believes.

The KIF18A inhibitor pipeline

Source: OncologyPipeline.