New Medicines

CepleneAcute myeloid leukaemia (AML)


New molecular entity

Development and Regulatory status

Licensed but not launched
Not approved
Jun 20EU orphan drug status removed in Oct 18 at the end of the 10-year market exclusivity period [30].
Feb 19Immune Pharmaceuticals files for bankruptcy [29].
Nov 18Although previously launched in the UK, Ceplene is only available on a named-patient basis [27].
Nov 18Immune Pharmaceuticals and Vector Therapeutics announce an agreement that gives Vector an option to acquire worldwide rights to Ceplene. Vector is planning to launch Ceplene, as the first therapy approved for AML remission maintenance, in Europe in Q1 19 and to accelerate its development toward approval in the US, China and Japan [28].
Jul 18EMA confirms the approval of Ceplene for maintenance of first complete remission in patients with AML following the review of additional clinical studies that had been requested by the EMA [28].
Aug 10EpiCept is considering filing its NDA under protest after the FDA refused to accept the [22].
Aug 10Refusal to file letter from the US FDA on the New Drug Application (NDA) for histamine dihydrochloride, for the remission maintenance and prevention of relapse of patients with AML in first remission. In its preliminary review the FDA concluded that the application did not establish histamines therapeutic contribution in its combination with IL-2, and recommended that an additional confirmatory pivotal trial assessing its contribution and using overall survival (OS) as a primary endpoint be performed [21].
Jun 10Filed in US [20].
Jun 10Regulatory decisions regarding US approval anticipated 2H 2010 [19].
May 10Launched in Germany for remission maintenance therapy and prevention of relapse in adult patients with Acute Myeloid Leukaemia [18].
Apr 10Launched in the UK [19].
Feb 09Filed in Canada Dec 08 [16].
Feb 09US filing expected 2H 2009 for use in conjunction with interleukin-2 as a remission maintenance treatment of AML. FDA have indicated that available pivotal data are sufficient but have requested some additional information and analyses [15].
Oct 08Approved in EU, in conjunction with low-dose interleukin-2 (IL-2), for the prevention of relapse in adult patients with acute myeloid leukemia (AML) in first remission [14].
Oct 08EU Positive Opinion, Oct 08 , for the remission maintenance and prevention of relapse in adults with AML in first remission [13].
Jul 08MAA filed in EU in Oct 2006 for AML but negative opinion March 2008. Dossier resubmitted with additional information [12].
Mar 08EU negative opinion issued Mar 03, further data are required. Company has requested re-examination of the data [11].
Nov 03Filed in EU for advanced malignant melanoma (Nov 03)(6). FDA submission withdrawn Nov 04 (7). Positive opinion in EU (orphan status) Mar 05(8) for AML. Company plan to file in EU in 2006 for remission maintenence therapy for pts with AML (9). Filed in EU Oct 06 in conjunction with IL-2 for maintainance of 1st remission in pts with AML [10].


Histamine 2 agonist
The UK prevalence of AML is 3 per 100,000 people. 60 to 70% achieve remission but there is a high rate of relapse.
Acute myeloid leukaemia (AML)

Further information


Trial or other data

Aug 16Immune Pharmaceuticals releases positive data from the phase IV RE:MISSION European trial for histamine dihydrochloride/IL-2 in AML patients, which it intends to use for filing the planned pivotal study in AML supporting the potential submission of NDA in the US [27].
Sep 11The FDA has indicated that the required PIII study should compare Ceplene + IL-2 vs IL-2 monotherapy. The primary endpoint is overall survival; leukaemia-free survival can be a secondary endpoint provided that the bone marrow samples are collected at pre-specified and regular intervals [26].
May 11Company has filed a protocol for a PIII confirmatory trial with the FDA for review under the Special Protocol Assessment (SPA) programme. The proposed a two-arm trial will compare the efficacy of maintenance therapy with Ceplene + low-dose interleukin-2 (IL-2) to investigator´s choice, which is often no treatment. The target population is AML patients in first complete remission who have received consolidation therapy. The primary endpoint will be overall survival [25].
Mar 11EpiCept has identified a statistically significant survival benefit in a subgroup of patients with AML of monocyte origin in its previous PIII trial with Ceplene® given with low-dose interleukin-2 (IL-2). This finding is expected to influence the design of the new PIII trial to support resubmission for approval in the US. The trial is expected to start 2H 2011 [24].
Oct 09The FDA has asked for an additional study of Ceplene plus low-dose interleukin-2 (IL-2) vs standard of care in patients with AML in first complete remission and the company has agreed. The two-arm, randomized, open-label with a primary endpoint of overall survival will start in 2011. The Company recently filed an application with the FDA for fast track status [23].
Jul 09EpiCept is to start a post-approval study requested by the EMEA when marketed authorization was granted. The study will enroll 150 patients at 25 centres across the EU. The two primary objectives are to further demonstrate the clinical pharmacology of Ceplene by assessing certain immunologic biomarkers in AML patients in first remission, and to measure the effect of Ceplene/IL-2 on minimal residual disease. Secondary objectives are leukaemia-free survival after a follow-up period of up to 2 years. The study will take about 3 years to complete. The company said “ The commencement of this trial meets our post-approval commitment to the EMEA and underscores our determination to move forward as quickly as possible with the commercial launch of the drug in the EU” [17].
Feb 09At the pre-NDA meeting, the FDA requested that EpiCept provide additional information to the submission package, including statistical data further supporting the incremental effectiveness of Ceplene® given in conjunction with low-dose IL-2 and data showing the lack of significant efficacy of IL-2 as a monotherapy for remission maintenance of AML. The FDA also requested data supporting Leukemia-Free Survival (LFS) as an appropriate endpoint in the pivotal Phase III study,as compared with Overall Survival. Much of the requested data already has been generated in connection with the European MAA filing [15].
Oct 08EU approval based in part on the results of a phase III trial (n= 320) showing that Ceplene/IL-2 reduced the occurrence of relapse among AML patients in complete remission. Ceplene is designed to protect lymphocytes responsible for immune-mediated destruction of residual leukaemic cells by reducing formation of oxygen radicals from phagocytes [14].
Jul 01In trial in combination with alpha interferon for Hepatitis C. C3 trials in malignant melanoma. Company expects to launch in US 2001. Orphan drug status granted (Jan00). Preliminary C3 results show significant improvement in survival in stage IV melanoma. Filed -US (Jul00) as adjuvant therapy. US FDA's oncologic drugs advisory committee has voted unanimously not to recommend approval due to concerns over the trial design. Additional studies to be started. FDA submission withdrawn due to failure to reach primary endpoint in PIII study (7). EpiCept anticipate selecting a partner to market in EU following approval [10].

Evidence based evaluations