Response

In their letter to Nature Reviews Drug Discovery, Mitsiades et al. question the accuracy of some of our statements made in an article on apoptosis-targeting therapies1, specifically regarding bortezomib. In their letter they assert that “...bortezomib was determined to be an effective therapy for advanced multiple myeloma on data from a large multi-center Phase II trial of 202 heavily pre-treated patients with relapsed and refractory multiple myeloma2; in which not only the response rates (35%) was encouraging but also the time-to-disease progression (TTP) of patients while on bortezomib therapy (median 7 months) was superior to the TTP of the same patients (median 3 months) while receiving their last line of salvage therapy prior to study entry.” We do not dispute the findings of this study in our article. Indeed, we were fully aware that it served as the basis for approval of Velcade by the FDA. However, we would like to quote from a press release issued by the FDA on 13 May 2003 announcing approval of Velcade that influenced our position: “FDA evaluated the safety and efficacy of Velcade based on a study of 202 patients who had received at least two prior therapies and demonstrated disease progression on their most recent therapy. Altogether, out of 188 patients evaluated for response, twenty eight percent showed a response to Velcade. The response lasted a median time of one year. Another trial in 54 patients with relapsed multiple myeloma showed similar responses. As of yet, there are no controlled trials of Velcade demonstrating clinical benefit, such as improvement in survival.”

Mitsiades et al. also reference results of the Phase III APEX trial of bortezomib presented at the ASCO 2004 meeting in June of last year3. We would like to point out that this conference abstract presented interim analysis of the trial results. Moreover, the abstract stated that “Further evaluation of survival, response duration, response rate, and safety are ongoing.” At the time we were completing our article we did not feel that these interim data provided conclusive evidence of a survival benefit offered by bortezomib. Final analysis of the APEX study was presented at the 46th Annual Meeting of the American Society of Hematology in December of 2004, a month after our article was published. The Phase III APEX trial was the first and largest randomized study to achieve a survival advantage with bortezomib in patients with relapsed multiple myeloma. Based in part on the results of this Phase III APEX trial, in December 2004 Millennium Pharmaceuticals submitted a supplemental New Drug Application to the FDA and was granted a Priority Review designation. Therefore, we maintain that at the time we wrote our article (October 2004) we accurately represented publicly available information on bortezomib. In summary, we continue to be excited about bortezomib and view it as an important therapeutic option for the treatment of haematological malignancies. We applaud the ongoing commitment of Millennium, as well as efforts of independent investigators, to fully explore therapeutic potential of this drug.