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.

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Anand Shah has served the American public in a unique way, crisscrossing over the last two administrations between serving as an attending radiation oncologist focused on prostate cancer at NIH, serving as CMO at the Center for Medicare and Medicaid Innovation, and most recently, leading the FDA’s operations on medical and scientific affairs from within the commissioner’s office.

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