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‘Quiz’ Question: FDA Endpoint Nix Slows Down Ambit’s Bid in AML


By Randy Osborne
Staff Writer

Ambit Biosciences Corp. remains “on our baseline plan” after the FDA disagreed about the right endpoint and questioned the dose in a planned Phase III trial with quizartinib, the company’s lead FMS-like tyrosine kinase-3 (FLT3) inhibitor for relapsed/refractory acute myeloid leukemia (AML), said CEO Michael Martino, during a conference call with investors.

Shares of the San Diego-based company (NASAQ:AMBI) closed Wednesday at $8.56, down $4.24, or 33 percent, on word that the agency wants overall survival as an endpoint for the Phase III trial, rather than a novel surrogate endpoint that might have supported accelerated approval.

The surrogate endpoint would have been complete remission with incomplete hematologic recovery, and the FDA’s refusal is “consistent with its historical stance,” but still disappointing, Martino said.

Talks are ongoing also about the appropriate dose. Athena Countouriotis, Ambit’s chief medical officer, noted that more than 400 patients have been tested in Phase II trials, which turned up a flat dose response curve across all five doses, ranging 30 mg to 200 mg daily.

Ambit first proposed a starting dose of 60 mg for the Phase III trial, and the company “continue[s] to believe this dose represents an acceptable benefit-risk profile,” she said, but either 30 mg or 60 mg likely would “deliver comparable clinical benefit.”

Ambit “provided quite a bit of information regarding our Phase III study,” Countouriotis said. “The only [Phase II] analysis they asked for was an efficacy analysis” – specifically, a breakdown of exposure response from the pharmacology portion of the Phase IIb trial – but nothing about safety.

“With that as a background, there are multiple drugs on the market in oncology, including Gleevec [imatinib, Novartis AG], Inlyta [axitinib, Pfizer Inc.], as well as others that start at initial dose, and allow escalation based on tolerability and/or lack of efficacy,” she said. “We essentially are in the same situation with the proposal we have discussed with the FDA, and we’re awaiting their feedback.”

The issue of QT prolongation came up during the call, and Martino allowed that differences were noted in the QT signal between 30 mg and 60 mg. Although the grade 3 incidences are “very comparable” between the doses, the combined rate of grade 2 and grade 3 incidences in terms of number of patients, is about 50 percent higher at the 60-mg dose than at 30 mg, he said. Also, the median deviation from baseline over 60 milliseconds is “much higher” at 60 mg, Martino added.

Apart from the Phase III endpoint, though, the agency apparently has no quibbles with the planned layout of the study, which Ambit aims to start early next year. Worst-case scenario, of course, would be if the FDA demanded a new Phase II trial first, possibly at a dose even lower than 30 mg.

“I’m not going to speculate on what the FDA’s answer is at this point,” Martino said. “We believe that we have studied this drug now extensively in nearly 500 patients in Phase II studies. We’re confident in the data that there is a path forward without studying additional patients.”

The company last met with the FDA in June, and not before or since has the agency “suggested that a lower dose may be appropriate,” he said. “We believe we’ve done extensive dose range-finding work here, work that most tyrosine kinase inhibitors have done after they’ve made it to market. We believe we’ve bracketed the pharmacokinetics on this pretty well.”

Novartis also in the Game

In March, just after Ambit filed for its initial public offering (IPO), partner Astellas Pharma Inc., of Tokyo, walked away from their deal for FLT3 inhibitors, which began in 2009.

Ambit went ahead with the IPO anyway, raising about $65 million through the sale of about 8.1 million shares at $8 each. The pricing ended up lower than Ambit had hoped – it set a $13 to $15 price range – but Ambit compensated by increasing the number of shares. (See BioWorld Today, Dec. 21, 2009, March 13, 2013, and May 17, 2013.)

If the FDA gives its blessing, the company is going ahead with the Phase III trial, too, based on Phase II results that will be detailed in four presentations next week at the American Society of Hematology (ASH) meeting in New Orleans.

Martino said the company “frankly, anticipates[s] a very high level of clinical enthusiasm” at ASH for the data. Looking ahead to the meeting, Leerink Swann analyst Howard Liang wrote in a research report that quizartinib is “one of the most interesting new agents for AML, although with an uncertain regulatory outlook.”

Mutations in the FLT3 gene have been found in about 30 percent of AML patients. FLT3 belongs to the same family as KIT and PDGFR, and Ambit is not alone in recognizing its potential as a target. Basel, Switzerland-based Novartis AG has midostaurin in Phase III development, though the drug has not proven very effective as a single agent and would be combined with chemotherapy.

Given no surprises from the FDA, Martino said Ambit has cash on hand “sufficient to fund our baseline plan through 2015.”