Maxim Files for European Approval to Market Ceplene for the Treatment of Advanced Malignant Melanoma
Friday November 7, 3:05 am ET
SAN DIEGO--(BUSINESS WIRE)--Nov. 7, 2003--Maxim Pharmaceuticals (Nasdaq NM: MAXM - News; SSE: MAXM) announced today that it has filed a European Centralized Procedure Marketing Authorization Application for Ceplene(TM) (histamine dihydrochloride), in combination with interleukin-2 (IL-2), for the treatment of patients with advanced malignant melanoma. Malignant melanoma is the most deadly form of skin cancer and is a growing health problem in Europe and the United States, where the incidence has more than doubled over the past twenty-five years. The Ceplene clinical results supporting the European application include multiple Phase 3 and Phase 2 trials demonstrating the potential of Ceplene to improve the survival of advanced malignant melanoma patients.
"This filing is an important milestone in the commercialization of our lead drug candidate Ceplene," said Larry Stambaugh, Maxim's Chairman and Chief Executive Officer. "Ceplene is a first-in-class drug candidate with the potential to meet a critical medical need in the treatment of advanced malignant melanoma, a disease for which no effective treatment currently exists. We look forward to bringing Ceplene combination therapy to European oncologists and their patients. In addition to Ceplene's potential to improve survival, we believe that it is important that the drug candidate is administered as an outpatient therapy with a good safety profile and with consideration for the patient's quality of life."
European Application for Approval
The Ceplene application is being filed with the European Agency for the Evaluation of Medicinal Products (EMEA) as an electronic Common Technical Dossier (eCTD) in compliance with the most recent International Committee of Harmonization (ICH) guidelines. The EMEA has confirmed to Maxim that this application represents the first official eCTD filed in Europe based on the July 2003 guidelines for fully electronic submissions. Ireland and Sweden have been assigned by the EMEA as the Rapporteur and Co-rapporteur, respectively, with responsibility to review the application on behalf of the European community.
"The EMEA and our Rapporteurs have been highly supportive and cooperative in our efforts to prepare the Ceplene eCTD submission," said Richard Lowenthal, Head, Worldwide Regulatory Affairs and Drug Safety at Maxim. "We believe in the approvability of our eCTD application based upon the most recent 36-month follow-up data from the MP-US-M01 Phase 3 trial (M01) in patients with advanced malignant melanoma coupled, with the single-arm MP-MA-0103 Phase 2 trial (M0103) reported earlier this year. The Rapporteurs' and EMEA's representatives have expressed an interest in this application based on the novel mechanism of action and potential to improve the treatment options for patients with advanced malignant melanoma, a growing health problem throughout Europe."
"An approval of Ceplene would provide a novel, safe and effective treatment option for patients with advanced melanoma, a deadly disease that currently has few treatment options," said Dr. Peter Naredi, Professor of Surgery, Umea University Hospital, Sweden. "I have worked with the Ceplene technology for over 12 years, and I am very pleased to see it reach this important point in development."
Maxim prepared the first fully electronic eCTD filed in the EU with the assistance of Datafarm Inc. (www.datafarminc.com), a provider of electronic submission solutions to the life sciences industry and regulatory authorities, and with the support of Parexel International. The eCTD format will allow the EMEA to electronically review the application in a more efficient manner.
Ceplene Clinical Results in Melanoma
Melanoma is reported to be the fastest growing among all cancers in the developed world and is the most deadly form of skin cancer. The prevalence of people diagnosed with melanoma in the United States and in the European Union is approximately 200,000 and 150,000 people, respectively. No approved treatment has shown a significant survival benefit in advanced malignant melanoma.
After 36 months of follow-up for the 305-patient M01 Phase 3 trial, the Ceplene/IL-2 combination demonstrated a statistically significant increase in survival (p=0.039, Log-Rank test, adjusted for multiple hypotheses) in the overall intent-to-treat population of advanced malignant melanoma patients compared to treatment with the same dose regimen of IL-2 alone. The increase in survival duration for patients treated with the Ceplene/IL-2 combination in the patients that entered the study with liver metastases was also statistically significant after 36 months of follow-up (p=0.0062, Log-Rank test, adjusted for multiple hypotheses).
Generally, melanoma patients with liver metastases have a very poor prognosis for survival, with a median survival of two to four months and with 3-6% of patients surviving for two years. In the M01 trial, two-year survival rates for patients with liver metastases were 18.2 percent for the group treated with the Ceplene/IL-2 combination versus 2.7 percent for the group treated with IL-2 alone. The 12 and 24-month follow-up results were published in the Journal of Clinical Oncology (JCO) and JCO Classic Papers in Melanoma in January and September 2002 respectively, and the 36-month results were presented at the EORTC: Perspectives in Melanoma meeting in October 2003.
The safety and side-effect profile of Ceplene combination therapy has allowed these advanced-stage cancer patients to administer treatment in their own homes. In the M01 Phase 3 trial, the incidences of treatment-emergent serious adverse events were comparable among patients treated with the Ceplene/IL-2 combination and those receiving IL-2 alone. The safety results were published in Melanoma Research, 2003 Jun; 13(3): 307-311. Also as part of the Phase 3 trial an independent health outcomes assessment group compared the quality-of-life effects of combination treatment with Ceplene and IL-2 versus IL-2 alone for patients with advanced metastatic melanoma. The researchers concluded that treatment with the combination of Ceplene and IL-2 resulted in a significant increase in median quality-adjusted survival versus treatment with IL-2 alone for the intent-to-treat population of all patients randomized into the trial (p=0.007, Mann-Whitney U-test) and also for the population of patients with baseline liver metastases (p=0.011). These results were published in Supportive Care in Cancer, 2003 May; 11(5): 304-312, Epub 2003 Jan 28.
The M01 Phase 3 results are supported by the results of the 163-patient, multi-center, single-arm, M0103 Phase 2 trial. Included among the clinical benefits of Ceplene was a comparison of survival results from the M0103 trial to historical controls (published trials) and to the survival curves from the control arm of the M01 trial. For example, a comparison of long-term survival (24-month) for patients with liver metastases treated with the Ceplene/IL-2 combination in the M0103 trial (n=80) with published trials suggests an improved long-term survival benefit. Long-term survival at 24 months in the M0103 trial was 12% compared to 3-6% survival reported for other published clinical trials.
Maxim is also conducting the confirming MP-8899-0104 Phase 3 trial (M0104) in the US and EU in 230 patients. This trial will further define the benefit of Ceplene in the treatment of patients with advanced malignant melanoma who have liver metastases. Ceplene demonstrated the strongest statistically significant survival benefit in liver metastases patients in the completed M01 Phase 3 trial, despite the poor prognosis for this patient population. The primary endpoint of the M0104 Phase 3 study is survival, with secondary endpoints including tumor response rate, progression-free survival, and duration of response. The study protocol has been reviewed and accepted under the Food and Drug Administration's (FDA) "Special Protocol Assessment" procedures and is expected to be used to amend the Company's New Drug Application to seek approval of Ceplene in the US.
Maxim previously announced it expects to market its drug in Europe through a marketing partnership and is currently in discussions with potential partners for Ceplene. The Company intends to market Ceplene in the United States.
Maxim Overview
Maxim Pharmaceuticals is a global biopharmaceutical company with a diverse pipeline of therapeutic candidates for life-threatening cancers and liver diseases. Maxim's research and development programs are designed to offer hope to patients by developing safe and effective therapeutic candidates that have the potential to extend survival while maintaining quality of life.
Maxim's lead drug candidate Ceplene, based on the naturally occurring molecule histamine, is designed to prevent or inhibit oxidative stress, thereby reversing immune suppression and protecting critical immune cells. Ceplene has been tested in 17 completed or ongoing clinical trials in 20 countries, including four Phase 3 clinical trials. Ceplene is currently being tested in Phase 3 cancer clinical trials for advanced malignant melanoma with liver metastasis and acute myeloid leukemia. Phase 2 trials of Ceplene are also underway for the treatment of hepatitis C and advanced renal cell carcinoma. More than 2,000 patients have participated in the Company's completed and ongoing clinical trials.
In addition to Ceplene, Maxim is developing small-molecule inhibitors and activators of programmed cell death, also known as apoptosis, which may serve as drug candidates for cancer, cardiovascular disease and other degenerative diseases. Ceplene and the apoptosis inducers are investigational drugs and have not been approved by the U.S. Food and Drug Administration (FDA) or any international regulatory agency.
This news release contains certain forward-looking statements that involve risks and uncertainties. Such forward-looking statements include statements regarding the efficacy, safety and intended utilization of Ceplene and the apoptosis inducers, and the conduct, results and timelines associated with the Company's clinical trials. Such statements are only predictions and the Company's actual results may differ materially from those anticipated in these forward-looking statements. Factors that may cause such differences include the risk that the Company will not obtain approval to market its products, the risk that products that appeared promising in early research and clinical trials do not demonstrate safety or efficacy in larger-scale clinical trials and the risk that adequate financing might not be available. These factors and others are more fully discussed in the Company's periodic reports and other filings with the Securities and Exchange Commission.
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