New analyses of trial data with EpiCept’s acute myeloid leukemia (AML) drug Ceplene® (histamine dihydrochloride) have identified a subgroup of treated patients who exhibit particular survival benefit, a finding the firm says will help the design of a new Phase III study to support resubmission of its NDA. EpiCept hopes to submit the final trial protocol to FDA during the second quarter of 2011 and start the study later this year.
Ceplene was approved in the EU back in 2008, and in Israel in December 2010, for maintaining remission and preventing relapse in adult AML patients in first remission. However, FDA responded to EpiCept’s June 2010 NDA submission by issuing a refusal to file letter three months later. This stated that the application did not establish Ceplene's activity in combination with low-dose interleukin-2 (IL-2) and requested that the firm carry out an additional confirmatory pivotal trial using overall survival as a primary endpoint. EpiCept subsequently agreed on the outline of a proposed Phase III combination therapy study with FDA, and this will be carried out under a Special Protocol Assessment.
As part of its protocol preparation process for the new pivotal study, EpiCept conducted additional analyses of AML subgroups from its original 320 patient Phase III trial in AML patients in first remission. This study evaluated the effects of Ceplene plus low-dose IL-2 in terms of leukemia-free survival time and was not powered to determine overall survival. However, EpiCept says more detailed analysis of subgroup data suggests that patients with AML of monocyte origin achieve a statistically significant increase in overall survival when treated using Ceplene plus low-dose IL-2. The data also found a strong correlation between the administration of high-intensity consolidation treatment and improvements in overall survival. It is these findings that are being applied to design of the new pivotal study, the firm points out.
The European Commission granted Ceplene a marketing authorization under Exceptional Circumstances in 2008. Clearance on this basis means EpiCept is having to perform post-approval studies to further elucidate the clinical pharmacology of Ceplene by assessing certain biomarkers in AML patients in first remission and to assess the effect of combination therapy using Ceplene and IL-2 on the development of minimal residual disease in the same patient population. Ceplene is marketed in Europe by Meda under a 2010 licensing agreement with EpiCept. The deal in addition gives Meda marketing rights to Ceplene in Japan, China, and Australia. Roll-out of Ceplene in European countries was initiated in 2010.