IDM Pharma, Inc. has announced that it received a not approvable letter from the U.S. Food and Drug Administration (FDA) after completing the review of the new drug application (NDA) for the investigational drug mifamurtide (L-MTP-PE), formerly known as Junovan, for the treatment of non-metastatic osteosarcoma, a rare and often fatal bone tumor that typically affects children and young adults.
The FDA has requested data from additional clinical trials to demonstrate the benefit of L-MTP-PE. Additionally, the FDA has requested information or clarification with respect to other sections of the NDA.
"We continue to strongly believe in the overall survival benefit and safety profile of L-MTP-PE for the treatment of osteosarcoma and are committed to obtaining regulatory approval to provide L-MTP-PE to the critically ill children and young adults who have not had a new treatment option in more than 20 years," said Timothy P. Walbert, President and Chief Executive Officer of IDM Pharma, Inc. "In anticipation of a not approvable letter from the FDA, in July we announced our intent to amend the current NDA with additional survival data with the goal of bringing L-MTP-PE to market as quickly as possible. While the FDA has asked for data from additional clinical trials, we believe that this decision was made in context of the lack of complete data in the submitted NDA and that capturing supplemental data will overcome the need for additional trials and further confirm the overall survival benefit of L-MTP-PE in osteosarcoma and provide evidence for approvability."
The Company will continue working with the cooperative groups and investigative sites involved in the study to collect vital status (information on whether the subjects remain alive or have died) on patients who participated in the Phase 3 clinical trial and for whom complete data were not available at the time of filing of the NDA in October 2006. When the additional follow up data have been collected, the Company will analyze the data and expects to submit an amendment to the NDA to the FDA by the first quarter of 2008. In addition to collecting supplemental Phase 3 data, the Company will address the other points raised in the FDA action letter.
"While we believe the evidence demonstrating the overall survival benefit of L-MTP-PE exists, we commend IDM Pharma for their continued investment in and commitment to working with investigators to collect the most recent data available," said Matthew Alsante, executive director, Sarcoma Foundation of America. "As the survival in children with osteosarcoma has not improved in the last twenty years, gaining approval of investigational agents with demonstrated improvement in survival is critical."
The L-MTP-PE NDA includes efficacy and safety data from 678 patients with non-metastatic resectable osteosarcoma, 332 of whom received L-MTP-PE, and from 115 patients with metastatic or unresectable osteosarcoma, 39 of whom received L-MTP-PE, in the controlled Phase 3 trial conducted by the Pediatric Oncology Group (POG) and the Children's Cancer Group (CCG), now the Children's Oncology Group (COG), sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Also included are safety and efficacy data from 51 patients with metastatic osteosarcoma treated in earlier Phase 2 studies. The biological effects and safety of L-MTP-PE are further supported by data from 7 other Phase 1 and 2 clinical studies performed under IND, in which an additional 197 patients received at least one dose of L-MTP-PE.
L-MTP-PE stimulates the innate immune system (the body's first line of defense) to kill tumor cells. When administered in combination with chemotherapy and after tumor resection to osteosarcoma patients in the Phase 3 trial, L-MTP-PE provided a significant improvement in Disease Free Survival (DFS) (p = 0.0245) and Overall Survival (OS) (p = 0.0183). At 6 years, the probability of survival when L-MTP-PE is combined with adjuvant chemotherapy is 77% (95%CI: 72-83%) compared to 66% (95%CI: 59-73%) without L-MTP-PE, a clinically meaningful finding in a pediatric population where the longer the survival, the greater the chance the patient is cured of cancer.
Treatment with L-MTP-PE was generally well tolerated in all phases of study. Adverse events were mild to moderate in severity and included chills, fever, nausea, vomiting, myalgia, headache, tachycardia (fast heart rate), hypo- and hypertension, fatigue and shortness of breath, all of which are consistent events with the activation of monocytes and macrophages by L-MTP-PE and the flu-like symptoms that follow cytokine release.
L-MTP-PE was granted orphan drug status in the United States in 2001. The NDA for L-MTP-PE was submitted to the FDA in October 2006 and was accepted on December 26, 2006.
In May 2007, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 12 to 2 that the data in the NDA do not provide substantial evidence of effectiveness of L-MTP-PE in the treatment of patients with non-metastatic, resectable osteosarcoma receiving combination chemotherapy.
IDM Pharma also is seeking marketing approval from the European Medicines Agency (EMEA) for the use of L-MTP-PE, or MEPACT as it is known in Europe. L-MTP-PE was granted orphan drug status in Europe in 2004. The Marketing Authorization Application (MAA) for L-MTP-PE was submitted to the EMEA on November 1, 2006 and accepted for review on November 27, 2006. The EMEA application is currently under review and the Company continues to work closely with the regulatory body to ensure it has the information needed to approve L-MTP-PE
About 3% of all childhood cancers are osteosarcoma. Because osteosarcoma usually develops from osteoblasts, it most commonly affects children and young adults experiencing their adolescent growth spurt. Boys and girls have a similar incidence rate until later in their adolescence, when boys are more commonly affected. While most tumors occur in larger bones, such as the femur, tibia, and humerus, and in the area of the bone that has the fastest growth rate, they can occur in any bone. The most common symptom is pain, but swelling and limited movement can occur as the tumor grows.
Osteosarcoma is an orphan disease with fewer than 1,000 new cases diagnosed in the U.S. each year. A similar incidence of the disease exists in Europe. According to the Children's Oncology Group, the survival of children with osteosarcoma has remained at 60-65% since the mid-1980s. The standard treatment for osteosarcoma is tumor resection with combination chemotherapy before and after surgery.