Assistant Managing Editor

Shares of EpiCept Corp. plunged 38.3 percent Monday after the FDA refused to accept its new drug application for Ceplene (histamine dihydrochloride) in combination with interleukin-2 as a maintenance therapy for acute myeloid leukemia and, instead, recommended an additional pivotal trial.

EpiCept's stock (NASDAQ:EPCT) lost 42 cents, to close at 68 cents.

The news came as a surprise, given that the Tarrytown, N.Y.-based firm had complied with the agency's request for meta-analysis data intended to help clearly isolate Ceplene's efficacy. And coming in the form of a refuse-to-file letter was even more unusual, since they generally refer to technical issues with the application such as inconsistencies in the database or formatting problems identified during a superficial review.

So for the agency to "prejudge the merits of the NDA seems a bit abrupt to us," Jack Talley, EpiCept's president and CEO, told BioWorld Today.

It's not unheard of, though. The FDA questioned data underlying the submission of Pharmacyclics Inc.'s NDA for Xcytrin (motexafin gadolinium) in 2007, even though the company previously received a green light to file from FDA staffers. A year later, the agency sent back Introgen Therapeutics Inc.'s biologics license application for gene therapy candidate Advexin. Though specific details were not disclosed in that case, many analysts surmised that reviewers needed more data to be comfortable with an approval in the wake of earlier gene therapy disasters. (See BioWorld Today, Feb. 22, 2007, and Sept. 3, 2008.)

Regarding EpiCept's application for Ceplene, a drug designed to maintain the integrity of immune cells in cancer patients, the FDA was pretty clear in its recommendations. "The FDA is suggesting a trial testing Ceplene [in combination with] IL-2 and IL-2 alone as at least two of the arms," Talley said, with overall survival as the primary endpoint.

But EpiCept, which plans to schedule a meeting with the agency within the next 30 days, hopes to work out a pathway that will not require that additional study for approval. The company will "try to understand what [the FDA] may or may not be looking for and whether that can be found in the current documentation," he added.

This isn't the first time a confirmatory study has been suggested for Ceplene. That possibility has hung over the drug's development since before EpiCept's 2005 buyout of developer Maxim Pharmaceuticals Inc. In fact, it was that recommendation for a confirmatory Phase III trial that prompted cash-strapped Maxim to seek strategic options in the first place. (See BioWorld Today, Sept. 7, 2005.)

In its dealings with the FDA, Maxim had been told that its positive Phase III AML trial testing Ceplene in combination with IL-2 had failed to show Ceplene's benefit over IL-2 alone. (See BioWorld Today, Jan. 19. 2005.)

But that was then. At that time, there had been only one small, 80-patient trial testing IL-2 as a monotherapy, Talley said. When EpiCept met with the FDA more recently, there had been five such studies completed, involving a total of about 900 patients. And the results from all of them confirmed the lack of benefit of IL-2 alone in AML patients.

Based on those studies, the FDA "asked for the meta-analysis to isolate Ceplene's benefit, which we did," Talley said, adding that, in the interim, a sixth study was performed testing IL-2 "at a nearly identical dose" to the one used in the Phase III Ceplene study. Again, IL-2 alone showed no benefit. "So we thought all this new information since 2004 clearly showed that Ceplene and IL-2 were doing something over IL-2 alone," he said.

The IL-2 monotherapy data could also raise ethical issues for the FDA's proposed study design. "It might be very hard to get through an IRB," Talley noted.

There also are no currently approved therapies for remission maintenance in AML. "Relapse in AML is a death sentence," he said. "So it's not like there's a fulfilled medical need here."

If the agency refuses to budge on its recommendation for another trial, the firm, which ended the second quarter with about $8.3 million in cash, would have to consider its options, which would include partnering or raising additional capital. EpiCept had hoped to market the product on its own in the U.S. and had recently brought on board a senior director of marketing ahead of a hoped-for early 2011 launch.

Another possiblity is resubmitting the application over FDA objections. "We're not ruling that out," Talley said, "but we need to meet with them first."

The good news is that Ceplene's U.S. delay is not expected to have any effect on the drug's overseas launch. European partner Meda AB has been ramping up commercial activities and, under the firm's January deal, EpiCept is entitled to double-digit royalties on product sales. In its recent earnings report, the company said it expected Ceplene sales to be "modest" in 2010 and 2011 and to "grow significantly thereafter."

Part of Ceplene's 2008 European approval included postapproval study requirements, and EpiCept is continuing patient enrollment with a 150-patient trial to assess immunologic biomarkers in AML patients in first remission and to measure the combination of Ceplene and IL-2 on minimal residual disease in that patient population.

When asked whether data from any of the post-marketing studies might be acceptable to the FDA in lieu of another Phase III trial, Talley remained doubtful. But, he said, "we certainly intend to ask them."

In the meantime, the firm is moving ahead with plans for studies of Ceplene in additional indications, including a Phase I/II study in combination with IL-2 and Gleevec (imatinib, Novartis AG) on eradication of minimal residual disease in adult AML patients and a Phase II trial in combination with IL-2 and Vidaza (azacitidine, Celgene Corp.) vs. Vidaza alone in patients with higher risk myelodysplastic syndromes.

Also in the pipeline is EpiCept NP-1, a topical analgesic cream in a 400-patient study in chemotherapy-induced peripheral neuropathy, and crolibulin, a vascular-disruption agent slated to start Phase Ib in solid tumors.