Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium

Oblimersen is an antisense oligonucleotide developed by Genta for systemic use as an injection. It comprises a phosphorothioate backbone linking 18 modified DNA bases. Oblimersen targets the first six codons of Bcl-2 mRNA to form a DNA/RNA complex. The duplex is subsequently recognised as a foreign message and is cleaved enzymatically, thereby destroying the Bcl-2 message. The Bcl-2 protein, which is a potent inhibitor of apoptosis, is overexpressed in many cancers, including follicular lymphomas, breast, colon and prostate cancers, and intermediate-/high-grade lymphomas. By reducing the amount of Bcl-2 protein in cancer cells, oblimersen may enhance the effectiveness of conventional anticancer treatments. Genta has reported results from randomised phase III trials of oblimersen in four different indications: malignant melanoma, chronic lymphocytic leukaemia (CLL), multiple myeloma and acute myleoid leukaemia (AML). A negative opinion has been issued for the company's MAA for the product in the treatment of malignant melanoma in the EU; the EMEA has indicated an additional confirmatory trial is needed in this indication for approval. An NDA for CLL was deemed non-approvable by the US FDA; the company is appealing this decision. The phase III trials in multiple myeloma and AML did not meet their primary endpoints. Phase I and II trials are also underway or have been completed for a range of other cancer types. Genta and sanofi-aventis (formerly Aventis) entered into a collaboration agreement in 2002; however, this agreement was terminated by sanofi-aventis in May 2005. Genta became solely responsible for all costs relating to oblimersen at this time. Genta expanded its Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute in November 2001. The expanded collaboration was to investigate the use of oblimersen in combination with standard anticancer therapy in a broad range of cancers. This expansion occurred following the Gensynergy project, which showed that oblimersen was synergistic with other anticancer therapies. Genta signed a 5-year manufacturing agreement with Avecia Ltd in December 2002 to supply it with oblimersen. Genta's NDA was submitted to the FDA in December 2005 and accepted for review in March 2006. The application was based on data from a phase I/II trial (NCT00021749) of oblimersen alone in approximately 40 patients and a phase III study (NCT00024440) of 241 patients who received fludarabine and cyclo-phosphamide with or without oblimersen. Genta received a Special Protocol Assessment (SPA) from the FDA in October 2006 for a randomised, pivotal, clinical trial of oblimersen in CLL. The trial will be conducted in patients who have not received prior chemotherapy and who would be randomised to receive fludarabine and rituximab with or without oblimersen. This trial has not yet begun.Fast-track status was given to oblimersen for CLL in June 2003 by the FDA. Oblimersen previously obtained orphan drug status in the US and EU for CLL in September 2001. Genta previously submitted the MAA under the centralised licensing procedure and Spain and France were assigned as rapporteur and co-rapporteur countries, respectively. It was supported by an extended 24-month follow-up of patients from a phase III study (NCT00016263) of oblimersen plus dacarbazine. The EMEA validated the MAA for review in January 2006. Genta received a number of scientific questions from the EMEA in June 2006, which the company responded to. Genta intends to file a formal complaint and a request for correction of information with the FDA under the Federal Data Quality Act. The complaint is related to a key statistical analysis of the company's data for oblimersen in the treatment of melanoma used by the FDA at the Oncology Drug Advisory Committee (ODAC) in May 2004. Genta believes that analysis sought to discredit the finding that treatment with oblimersen significantly increased progression-free survival; ODAC previously agreed this endpoint would support full approval in the absence of a survival improvement in patients with advanced melanoma.A rolling NDA submission was submitted to the FDA in the third quarter of 2003; however, Genta and Aventis withdrew the NDA after the application failed to gain marketing approval from the FDA's Oncology Drug Advisory Committee (ODAC). In May 2004, ODAC voted that phase III trial results did not provide substantial evidence of effectiveness to outweigh toxicity of oblimersen treatment in patients with metastatic melanoma. Genta has the option to resubmit this application. The FDA gave oblimersen orphan drug status for malignant melanoma in August 2000. In October 1999, fast-track status was given to oblimersen by the FDA for malignant melanoma when used in combination with dacarbazine. In addition, oblimersen received orphan drug status for malignant melanoma in Australia in October 2006.A phase III study (NCT00016263) of oblimersen in combination with dacarbazine was conducted in patients with malignant melanoma. The combination treatment did not significantly increase overall survival time, but did significantly increase progression-free survival time, compared with dacarbazine treatment alone. The phase III trial enrolled 771 patients at 140 sites in 12 different countries. Patients were randomly assigned to receive dacarbazine alone or in combination with oblimersen. The primary endpoint of this trial was to compare the overall survival between the two treatment arms. Secondary endpoints included comparative analyses of progression-free survival and tumour response. Genta will conduct another phase III study of oblimersen in patients with advanced melanoma. The trial is designed to provide additional safety and efficacy evidence of the drug, in combination with dacarbazine, in patients who have not previously received chemotherapy. Approximately 300 patients are expected to be enrolled in the trial, which is planned to begin during mid-2007, at sites throughout Europe, Australia, and North and South America. Genta is conducting a phase I clinical trial (NCT00409383) to evaluate the combination of oblimersen, ABI 007, and temozolomide in chemotherapy-naive patients with advanced melanoma. This trial was initiated in November 2006 and is the first follow-on study to Genta's phase III trial of oblimersen plus dacarbazine. Oblimersen received orphan drug status in the US and EU for multiple myeloma in September 2001. In addition, fast-track designation was given to oblimersen by the FDA in the same month.A phase I/II clinical study (NCT00062244) of oblimersen was conducted by the NCI in patients with Waldenstrom's macroglobulinaemia, a disease that is similar to multiple myeloma. The study results indicated that oblimersen may be a useful treatment in this group of patients (all had high levels of Bcl-2 expression). In June 2003, Genta and Aventis announced the presentation of clinical data from a phase II trial of oblimersen in combination with docetaxel injection concentrate for patients with advanced HRPC. Researchers reported that these findings validated progression into phase III trials. Genta has licensed eight US patents relating to oblimersen and its backbone chemistry and these expire between 2008 and 2015. Genta has two pending US patent applications that relate to oblimersen. Corresponding patent applications have been filed in Canada, Europe and Japan. Genta owns three US patents relating to methods of using oblimersen that will expire in 2020, and also has approximately 45 corresponding foreign patent applications.