Shares of Talon Therapeutics Inc. fell 22.7 percent Monday after the FDA released briefing documents ahead of Wednesday's Oncologic Drugs Advisory Committee (ODAC) meeting to discuss a new drug application (NDA) seeking accelerated approval for Marqibo (vincristine sulfate liposomes injection) based on a single-arm study in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL). The stock (OTCQB:TLON) lost 22 cents to close at 75 cents.

Approvals based on single-arm trials have been an iffy prospect at the FDA lately, though Seattle Genetics Inc. managed to get antibody-drug conjugate Adcetris (brentuximab vedotin) cleared in two lymphoma indications last year with single-arm data. But the fact that the FDA declined to grant Marqibo's NDA priority review might not bode well for the San Mateo, Calif.-based biotech.

Nor does the fact that Marqibo was rejected in a previous trip to the FDA under the accelerated approval pathway. Back in 2005, the drug earned a not-approvable letter in non-Hodgkin's lymphoma two months after ODAC said a randomized trial would be needed for approval. (See BioWorld Today, Dec. 2, 2004, and Jan. 20, 2005.)

Up for discussion at Wednesday's meeting is Marqibo's risk/benefit profile, as well as the available treatment options for ALL patients in second or greater relapse or whose disease has progressed following two or more lines of therapy.

Talon executives are expected to emphasize the scarcity of drugs for third-line treatment. The company has pointed out that existing third-line, single-agent therapies typically have response rates of less than 4 percent. In the pivotal Phase II RALLY study, Marqibo demonstrated a 35 percent response rate in patients who were in their third- to seventh-line of treatment. (See BioWorld Today, March 4, 2009.)

FDA reviewers noted that about 60 percent to 70 percent of patients relapse after, or are refractory to first-line treatment and there is no definitive standard for first salvage therapy regimens. Even then, the majority of patients – about 70 percent – who respond to first salvage therapy end up relapsing.

Yet Talon still has the challenge of convincing ODAC that Marqibo's efficacy is impressive enough to override safety issues, most notably neuropathy-associated adverse events, which were reported in 86.7 percent of patients. Eleven of 83 patients (13.3 percent) reported serious adverse events related to neuropathy.

Per FDA review, the response rate in the RALLY trial was 15.4 percent (10 of 65 patients). Going by past precedent, that might be too low for FDA consideration. Clolar (clofarabine, Genzyme Corp./Sanofi SA), which initially won accelerated approval in 2004 for pediatric relapsed or refractory ALL patients based on single-arm studies, had an overall response rate of 20 percent. (See BioWorld Today, Dec. 30, 2004.)

Marqibo is an encapsulated version of widely used cancer drug vincristine, designed to provide prolonged circulation of the drug in the bloodstream and greater accumulation at the tumor site. It originally was developed by Burnaby, British Columbia-based Inex Pharmaceuticals Inc. and was acquired by Talon (formerly Hana Biosciences Inc.) in 2006. (See BioWorld Today, March 20, 2006.)

Talon filed the NDA in July under the 505(b)(2) pathway. The PDUFA date is May 13, 2012. The drug has orphan status in the U.S. (See BioWorld Today, July 19, 2011.)

In addition to ALL, Talon also continues work in NHL, with an ongoing Phase III study testing Marqibo against conventional vincristine in the R-CHOP regimen in adults, 60 and older, with newly diagnosed aggressive NHL.