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Antisense Oligonucleotides

Overview

No antisense oligonucleotides are on the market yet for cancer. Despite the compounds’ high specificity and low toxicity, this drug class has been plagued with disappointing results, such as those reported for ISIS-3521 (Isis Pharmaceuticals/Eli Lilly’s Affinitak) in non-small-cell lung cancer. Their appeal is further limited by the fact that they require long periods of intravenous administration.

Mechanism Of Action

Antisense oligonucleotides are short sequences of single-stranded DNA that bind to a specific region of target messenger RNA (mRNA). This binding, or hybridization, triggers enzymatic degradation of the mRNA, thereby blocking the translation of the mRNA and the generation of the corresponding protein.

Oblimersen

Genta/Aventis’s oblimersen (Genasense) is in clinical trials for a variety of cancers, including malignant melanoma, multiple myeloma, prostate, lung, breast, colorectal, and leukemia/lymphoma. Enrollment is complete for Phase III trials in multiple myeloma, malignant melanoma, and chronic lymphocytic leukemia; the FDA awarded both fast-track and orphan drug designations for all three programs.

Positive trial data from the malignant melanoma studies allowed Genta and Aventis to file the first part of a rolling new drug application (NDA) in December 2003 with a request for priority review status, and preregistration approval took place in February 2004. However, in early May 2004, the FDA Advisory Committee voted not to recommend oblimersen for marketing approval for malignant melanoma. The committee stated that the data presented did not provide substantial evidence for effectiveness, as measured by response rate and progression-free survival, to outweigh the increased toxicity endured by the patients receiving this in vivo drug. Genta subsequently announced that it was withdrawing the NDA for oblimersen therapy in malignant melanoma. It plans to meet with the FDA to discuss key issues and the next steps in developing oblimersen for malignant melanoma.

Oblimersen is an antisense oligonucleotide specific for mRNA transcribed from the bcl-2 gene. Bcl-2 is involved in the prevention of apoptosis and is over-expressed in chronic lymphocytic leukemia. Preclinical data have demonstrated that oblimersen induces apoptosis in primary chronic lymphocytic leukemia cells in vitro and its activity is potentiated when combined with rituximab, alemtuzumab, or cytotoxic chemotherapy. Ongoing trials are investigating these observations in chronic lymphocytic leukemia patients.

In July 2003, a randomized Phase III study comparing fludarabine and cyclophosphamide with or without oblimersen in patients with relapsed or refractory chronic lymphocytic leukemia completed enrollment of 200 patients at 60 centers in the United States, Canada, and Europe. Its objectives are to compare CR and nPR, overall response, response duration, survival, and time to progression. No data are yet available.

Other ongoing clinical trials include a two-part Phase I/II study analyzing oblimersen as a monotherapy in chronic lymphocytic leukemia patients who have failed a median of three prior therapies. Twenty-six patients, with a median age of 61, in Rai stages II-IV and two patients with Richter’s transformation entered the trial.

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