Staff Writer

Ambit Biosciences Corp.'s potential $390 million deal with Astellas Pharma Inc. for FLT3 kinase inhibitors adds power to the push with oral small-molecule AC220, which just entered Phase II trials of the compound against acute myeloid leukemia in a patient subset that comprises about one-third of the newly diagnosed.

"We had several parties all the way to the end" of collaboration talks, said M. Scott Salka, CEO of San Diego-based Ambit, including a few that were heavy hitters in oncology with established pipelines.

"On one hand that's great, but it's a little scary for a small company that wants to play a role in the continued development of the agent," he said. "The risk is that you get squeezed out of the picture."

Astellas, of Tokyo, is still building its presence in cancer, under a five-year plan. "Ambit is one more piece of the picture," Salka said. "We get to be part of that story." Among Astellas' recent deals in the space is the October alliance that gave San Francisco-based Medivation Inc. $110 million up front for a Phase III prostate cancer drug. (See BioWorld Today, Oct. 28, 2009.)

Ambit's second-generation FMS-like tyrosine kinase-3 inhibitor was developed by way of KINOMEscan profiling technology, and moved from initial chemistry to clinical candidate selection for IND-enabling studies in 18 months, the company said.

With Astellas, Ambit will develop AC220 for AML in patients who have the internal tandem duplication mutation in the FLT3 kinase, as well as other indications. Behind the compound are other candidates in the class, known among scientists as "flit threes," for cancer and more, including autoimmune and inflammatory disorders, Salka said.

Responsibility for developing AC220 and others will be split along with costs between the firms in the U.S. and Europe, with Astellas taking full duties in other territories.

"This was very much part of the conversations with all of the companies - we were not interested in licensing the compound out," Salka told BioWorld Today, and Ambit knew we "had to be willing to put up half" of the development costs in order to retain a share of the value later.

AC220's Phase II trial is enrolling adult and elderly patients with relapsed/refractory AML that have the internal tandem duplication mutation in the FLT3 kinase, an indicator of a poor prognosis and decreased response to existing treatments, including chemotherapy and hematopoietic stem cell transplant.

"We will continue running the trials," with help from a joint steering committee, he said. Enrollment at 100 sites in the U.S. and Europe is ahead of schedule so far, with three up and running and two more to be added this week. All sites are expected to be enrolled early next year.

The $350 million in milestone payments from Astellas are all pre-commercial, rising as approval nears, but rewards if sales goals are met also come with the deal, as well as tiered, double-digit royalties. In the U.S., Ambit holds an option to co-promote under a 50/50 profit-and-loss-sharing arrangement.

AML has proven tricky for drug developers lately, especially given the FDA's dim view of single-arm trials, deployed by some firms in an attempt to win accelerated approval for compounds against the disease in the elderly, with an eye to broadening the label later. (See BioWorld Insight, Dec. 21, 2009.)

FLTs themselves have run into trouble. Frazer, Pa.-based Cephalon Inc.'s multikinase inhibitor lestaurtinib (CEP-701), which hits FLT3 among other targets, fizzled this summer in a Phase III trial when combined with chemotherapy. Novartis AG, of Basel, Switzerland, had PKC412, a multi-kinase inhibitor with FLT3 activity that also failed in a Phase III combo trial. Cambridge, Mass.-based Millennium Pharmaceuticals Inc. (now part of Japanese drug maker Takeda Pharmaceutical Co. Ltd.) didn't make it with MLN518, either.

None of that troubles Salka or, apparently, Astellas. AC220, he said, is the first FLT3 inhibitor that has shown single-agent efficacy "beyond the stray anecdote," and achieved "complete shutdown of signaling of the receptor over the entire dosing period, as long as the patient stays on the once-a-day pill."

Other compounds "got some modest to significant inhibition," but their effect pulsed - function would return for 12 hours, leading up to the next dose, he said, crediting the Ambit technology with yielding potency that is tenfold higher.