Agency recommends conducting an additional trial to assess the therapeutic contribution of this AML drug.

EpiCept received a refusal to file letter from the FDA on the NDA for Ceplene® for the remission maintenance and prevention of relapse in patients with acute myeloid leukemia (AML) in first remission. The drug was approved in the European Union in 2008 and is co-administered with low-dose interleukin-2 (IL-2).

In a preliminary review FDA concluded that EpiCept’s NDA did not establish its therapeutic contribution in combination with IL-2. It recommended that an additional confirmatory pivotal trial assessing Ceplene’s contribution using overall survival as a primary endpoint be conducted.

The company’s stock took a steep nosedive going from $1.10 at Friday’s close to open trading today at $0.63, a 42.73% drop. As of June 30, EpiCept had $8.3 million in cash and cash equivalents.

“We are surprised and obviously very disappointed by the FDA’s decision on our application,” remarks Jack Talley, president and CEO of EpiCept. The company retains the right to file the NDA over FDA objections.

“The Ceplene/IL-2 regimen, which is being rolled out to patients in the European Union, is the only approved treatment that has been shown to prevent relapse of AML patients, of whom the majority will die within a year should a relapse occur,” according to Talley. “We believe that the results of the Ceplene Phase III AML study, which demonstrated a statistically significant improvement in leukemia-free survival without impacting patients’ quality of life and no treatment-related mortality, together with the supporting data we generated for the application, deserved a detailed review.”

The Phase III study was conducted in 10 countries and included 320 randomized patients in complete remission who received up to 18 months of treatment with Ceplene plus low-dose IL-2. In its NDA, which was submitted in June, EpiCept also included results of two meta-analyses to help isolate Ceplene’s efficacy. The first analysis confirmed the lack of clinical efficacy of IL-2 monotherapy as remission maintenance and the second demonstrated the contribution of Ceplene in this indication when given in conjunction with IL-2, according to the firm. These two meta-analyses were conducted by independent statisticians and support the conclusions of the pivotal Phase III trial.

“In addition,” Talley continues, “six randomized large-scale studies have shown that IL-2 alone is not an effective therapy for AML patients. We will meet with the FDA as soon as possible to explore whether a basis exists to resubmit the application without conducting a new clinical trial.”

Ceplene has been granted orphan drug status in the U.S. Marketing applications are under regulatory review in Canada and Israel. European marketing partner Meda has launched the drug in the U.K. and Germany and filed applications for reimbursement in France, Italy, and Spain. Ceplene is expected to be rolled out to other countries in the EU over the next 12 months.

In June the EMEA notified EpiCept that it accepted the conclusion of a panel of hematologists convened by the company that it is not feasible to conduct, in conjunction with cooperative groups in Europe and/or the U.S., a confirmatory Phase III study to evaluate the safety and efficacy of Ceplene with low-dose IL-2 versus a comparator arm of either no treatment or IL-2 alone.

In reaching its decision, the EMEA accepted the consensus opinion of the panel, which concluded, in part, that robust data on the safety and efficacy of Ceplene in conjunction with low-dose IL-2 had already been collected. A new clinical study of Ceplene/IL-2 in remission maintenance for AML versus a comparator without demonstrated efficacy would raise ethical and practical issues in obtaining required study approvals from institutional ethics committees and institutional review boards.

EpiCept is continuing enrollment in its post-approval clinical trial studying the effects of remission maintenance therapy with Ceplene/IL-2 on minimal residual disease (MRD) in adult patients with AML in first complete remission. This open-label, multicenter study is also assessing the quantitative and qualitative pharmacodynamic effects of Ceplene/IL-2 by monitoring T-cell and natural killer cell phenotypes and their functionality after the first and third treatment cycles. The study will enroll up to 150 patients at approximately 30 centers across Europe with sites in Sweden, Belgium, France, U.K., Spain, and Italy.

“It will take time for Ceplene’s adoption to become widespread throughout Europe, but we believe Meda is implementing a marketing strategy that ultimately will maximize Ceplene’s impact in Europe in the treatment of AML patients in first remission and provide meaningful financial returns to both Meda and EpiCept,” Talley noted in early August when the company reported its second quarter earnings. Ceplene sales are expected to be modest in 2010 and 2011 and to grow significantly thereafter.

In the U.K. Meda has deployed a team of medical science liaisons to call on key opinion leaders (KOLs) to educate them on Ceplene’s clinical benefits. The KOLs will help establish new treatment guidelines and include the product on national cooperative group studies that will provide exposure and credibility.

At several leading hematology centers in England, agreements have been completed to allow applications for inclusion of Ceplene/IL-2 on their respective formularies, which once accepted will allow hematologists to prescribe the drug. Meda says that it has made progress at both private and National Health Service hospitals.

It also applied to the Scottish Medicines Council for approval to sell Ceplene in Scottish medical centers. Formulary approvals are expected to occur over the rest of the year.

In Germany, the marketing strategy is similarly focused on KOLs. It requires the involvement of KOLs to use Ceplene initially in their clinical trials while key Meda account managers implement a sales and marketing program based on one-on-one meetings, placement of journal advertisements, and product presence at national and international congresses.

EpiCept also plans to conduct further research with Ceplene to expand its uses. It will examine the effects of Ceplene and low-dose IL-2 in combination with Vidaza to treat patients with higher risk myelodysplastic syndrome (MDS), a bone marrow disease that can progress to AML. These patients will already have demonstrated a hematological response to Vidaza.

The trial will be followed by a randomized Phase II study of the efficacy, safety, and tolerability of the addition of Ceplene/IL-2 to Vidaza compared to Vidaza alone in patients with higher risk MDS and who have achieved hematological response to Vidaza.

The firm will also undertake a Phase I/II trial combining Ceplene and IL-2 with Gleevec for the eradication of MRD in adult patients with chronic myeloid leukemia. The primary objective will be to assess the safety of the combination therapy given for six months and to assess the number of patients achieving and subsequently maintaining disease-free survival after discontinuation of Gleevec. Patients will be followed for a minimum of 18 months after discontinuation of Gleevec therapy.

Epicept’s oncology clinical pipeline contains two more drugs, which have reportedly been shown to act as vascular disruption agents in a variety of solid tumors. Azixa is in a Phase II brain cancer trial, and Crolibulin is in a Phase I solid tumor study.

The company also has a clinical candidate for pain, called EpiCept™ NP-1. It is a topical analgesic cream in Phase II development for long-term relief of pain associated with peripheral neuropathies.

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