Kronos seals pact with regulators to hunt AML with previously off-limits biomarker endpoint
As head of R&D at Gilead, Norbert Bischofberger shelved the SYK inhibitor entospletinib after it proved to need too lengthy a development cycle to win approval. The FDA heard those concerns and will now give entospletinib, once again under Bischofberger’s watchful eye at Kronos, a faster shot on goal.
Kronos has reached an agreement with the FDA to conduct a Phase III trial with a unique primary endpoint, the company announced Thursday, one that it hopes will accelerate entospletinib’s path forward in a certain type of acute myeloid leukemia. The endpoint is measurable residual disease (MRD) negativity, which Kronos says can paint a clearer picture when it comes to the study’s complete response rate.
“We’re pretty happy; now it’s full steam ahead,” Bischofberger told Endpoints News.
It’s the first time this endpoint has been used for a potential approval in a Phase III study for AML, he added.
The trial is expected to enroll about 180 newly-diagnosed AML patients with NPM1 mutations and will launch in mid-2021. It will be a randomized, double-blinded and placebo-controlled study, with those in the active arm receiving entospletinib in combination with chemotherapy. Topline data are expected by the second half of 2023.
Using MRD negativity as an endpoint will also help tamp down on the residual disease that can plague leukemia patients. Bischofberger said that a typical AML treatment usually involves administering chemo for a week and then waiting for a month to see how much cancer is left in the blood. If the cancer cells make up less than 5% after chemo (AML is diagnosed at levels of 20% or higher) that’s considered a complete response.
But with the new endpoint, Kronos can measure reductions of residual cancer down to the 0.001% level, or levels more than a thousand-fold lower than the standard CR threshold, Bischofberger said. And since about 40% of AML patients do have measurable residual disease, Kronos is testing to see how much entospletinib on top of two chemo cycles can reduce those levels. They’re hoping to cut that population in half.
“You essentially look at people who achieve a CR, 40% will still have measurable residual disease, and we’re now saying we can decrease that to 20%,” Bischofberger said. “That’s the assumption in the sample size of 180 patients.”
AML patients with NPM1 mutations don’t see much of a difference in disease severity or response to typical treatments. They actually fare a little bit better on average, but Bischofberger noted that AML is still a highly aggressive disease with therapies that are rough on patients.
Kronos’ motivation to study the NPM1 mutation population lies instead in its use as a biomarker. It occurs in about 30% of all AML patients, and Bischofberger said “you either have it or you don’t,” making it easier to apply MRD negativity as an endpoint. Kronos plans to assess MRD negativity by genetic sequencing and looking for these mutations after the treatment.
Thursday’s move means Bischofberger’s effort to revive one of the programs he set aside at Gilead has some confidence from the FDA. Though researchers had previously thought entospletinib would need a specific diagnostic tool to accompany it through studies — one that needed to be clinically validated on its own — that obligation turned out to be moot once Bischofberger realized the potential use for NPM1 at Kronos.
Ultimately, that could cut development time by a couple of years. Kronos acquired the program, along with another SYK inhibitor lanraplenib, for a “few million” in cash and a slice of equity back in July, Bischofberger said at the time.
Analysts appeared pleased by the development, with Piper Sandler’s Tyler Van Buren agreeing with Bischofberger’s development timeline. The move showed that Kronos can capably “flex” its regulatory muscles.
“Importantly, securing MRD-negativity as the primary endpoint allows Kronos to report topline primary endpoint data in a couple of years as compared to 4+ years for a trial based on survival as the primary endpoint,” Van Buren wrote to investors.
Should the NPM1 trial and its new endpoint prove successful, Kronos could potentially move entospletinib into two other populations: those with NPM1 mutations who aren’t fit for chemo, such as the elderly, as well as AML patients who are FLT3 positive. Those final decisions haven’t been made yet, though.