Zentalis doubles down on Wee1

Zentalis is hoping to buck the trend of disappointments in Wee1 inhibition, doubling down on development of its contender, azenosertib, a molecule that spent three months on US clinical hold last year. Key to its enthusiasm is a new focus, revealed on Wednesday, specifically on the cyclin E1 biomarker.

So confident is Zentalis that it is also cutting 40% of its workforce to stretch cash beyond the expected data readout from azenosertib's potentially registrational study. This, it now says, will enrol cyclin E1-positive, platinum-resistant ovarian cancer patients, and is expected to start this year, with data readout due by the end of 2026.

These developments have come two months after a leadership shake-up. Last November Zentalis replaced its chief executive, Kimberly Blackwell, and chief medical officer, Diana Hausman, with Julie Eastland and Ingmar Burns respectively. At the time the company had around $390m in the bank, enough to last into mid-2026; with the cuts its cash is now expected to last until late 2027.

Accelerated approval?

On Wednesday Zentalis said it had "reached alignment" with the FDA on part of an uncontrolled registrational trial, Denali part 2a, which it hopes will be its first step to an accelerated approval of azenosertib.

This will enrol an initial 60 patients, spread across two doses, before part 2b focuses on one selected dose and enrols another 70 subjects, testing ORR and PFS among key endpoints. However, part 2b is still "pending FDA feedback", Zentalis said, as is a randomised phase 3 confirmatory study versus standard of care in cyclin E1-positive, platinum-resistant ovarian cancer.

Zentalis has previously talked about the importance of cyclin E1, for example presenting a poster at AACR 2023 that discussed how overexpression of this protein sensitised ovarian cancer cells to azenosertib. But it's only now that it has decided to zero in on this biomarker in the molecule's registrational clinical programme.

The move follows analysis of three studies in platinum-resistant ovarian cancer, in which response rates appeared to be markedly better in patients whose tumours were retrospectively found to be cyclin E1 positive. Perhaps most important among these was part 1b of the Denali trial, which has been revealed to have yielded a 31% ORR in this subgroup, versus 18% in the intent-to-treat population.

Selected azenosertib trials in platinum-resistant ovarian cancer

Note: *data cited are for azenosertib monotherapy, as a Zejula combo was scrapped for lack of efficacy. Source: Zentalis presentation.

One question now is how Zentalis deals with the implied reduction in azenosertib's addressable market. On an analyst call the company said about 50% of platinum-resistant ovarian cancers were cyclin E1 positive "based on Zentalis's proprietary immunohistochemistry cutoff".

This, it said, amounted to 21,500 patients in the US and key European countries. It also said development would be carried out with a companion diagnostic, and success will depend on such a diagnostic, and cyclin E1 expression testing, being accepted into medical practice.

After notable industry failures in Wee1 inhibition azenosertib is now the most advanced molecule in development with this mechanism. AstraZeneca, for instance, had long touted the Merck & Co-derived adavosertib as a key part of its approach to synthetic lethality, but discontinued it for lack of tolerability in 2022.

Azenosertib also has a safety profile that needs to be watched closely. All three studies cited included patient deaths, and the project was put on clinical hold last June after two sepsis deaths in Denali. However, this was lifted just three months later with no changes in the clinical development plan.

Perhaps in response to azenosertib's reduced potential market, or reflecting a general lack of confidence in the project's development plan, Zentalis stock fell 21% on Wednesday.