Updated Bortezomib Evidence Further Strengthens Case for Millennium NDA

Millennium Pharmaceuticals announced the publication of updated results from a dual phase (phase I and phase II) clinical trial of injectable bortezomib (Velcade), its flagship oncology product. The trial assessed the efficacy and safety of bortezomib in newly diagnosed multiple myeloma (MM) patients who were ineligible for stem-cell transplantation, when employed as combination therapy in conjunction with melphalan and prednisone.

According to Millennium, study findings were notable in that results included one of the highest reported complete remission (CR) rates (an important indicator for long-term survival) ever attained in a trial of a prospective MM therapy. In addition, reported a Millennium spokesperson, the data demonstrated the highest three-year survival rate yet reported in the nontransplant MM treatment setting.

“These results support the strong relationship between high rates of durable complete remissions with long-term survival in patients with newly diagnosed multiple myeloma. We are confident that Velcade (bortezomib) will be a key component of the standard of care in this patient setting,” stated Nancy Simonian, MD, Chief Medical Officer, Millennium.

Haematologica

In the updated study, which was conducted by the PETHEMA Foundation in Spain and recently pre-published on-line in the journal , 60 patients received bortezomib at 1.3 mg/m² (N = 54) or 1.0 mg/m² (N = 6) twice weekly in weeks one, two, four and five for four six-week cycles (eight doses per cycle), followed by once weekly in weeks one, two, three and four for five, five-week cycles (four doses per cycle) in combination with melphalan (Alkeran) at nine mg/m² and prednisone at 60 mg/m² once daily on days one through four of each cycle. Treatment continued for a maximum of 49 weeks (52 vials) with a median number of 39 weeks (42 vials) reported in the trial.

The findings of the PETHEMA researchers were evaluated by criteria that were developed and designed by an independent, objective, third-party entity—the European Group for Blood and Marrow Transplantation (EBMT). The EBMT criteria were characterized by a Millennium spokesperson as “stringent.” Key highlights from the updated, revised results included the following:

• An overall response rate (ORR) of 89%;
• An immunofixation-negative complete response (CR) rate of 32%;
• The overall survival (OS) rate at 38 months was 85% with the bortezomib/melphalan/ prednisone (BMP) combination regimen compared with the 38% rate of OS observed in the historical control with melphalan and prednisone (MP) (P < 0.0001);
• The median overall survival for BMP has not been reached, compared with 26 months among the historical control with MP;
• The median time-to-disease progression (TTP) with BMP was 27.2 months, compared with 20 months for the historical control with MP (P = 0.001);
• The median event-free survival (EFS) with BMP was 25 months, compared with 15 months for the historical control with MP (P = 0.001).

Adverse events associated with the BMP combination included thrombocytopenia, neutropenia, and peripheral neuropathy. Incidence of serious adverse events, however, were relatively rare, especially when placed in the context of similar therapies. According to an analysis of integrated safety data pooled from phase II and III studies of single-agent bortezomib in 1,163 patients with multiple myeloma and mantle cell lymphoma, 20% of patients experienced at least one episode of toxicity that reached grade four or higher, most commonly thrombocytopenia (5%) and neutropenia (3%). Adverse events thought by the investigator to be drug related and leading to discontinuation occurred in 22% of patients. In total, 2% of the patients died within the time period in which the studies took place. Cause of death was considered by the investigator to possibly be related to the study drug.

The results of the dual phase I and II trial cited above provided the basis for the phase III VISTA (Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) trial. The VISTA trial randomized 682 patients with newly diagnosed MM who were ineligible for stem-cell transplantation. The large international study, conducted by Millennium and its co-development partner Johnson & Johnson Pharmaceutical Research & Development, compared bortezomib, melphalan, and prednisone (BMP) with the regimen of melphalan and prednisone (MP) alone (widely recognized as the current standard of first-line MM treatment).

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According to the findings of the research, BMP, compared with MP, demonstrated a statistically significant improvement across all efficacy endpoints, including complete response (CR) rates, TTP and survival (both progressionfree survival (PFS) and OS). The BMP combination regimen was associated with an immunofixation- negative (n)CR rate of 35% (compared with 5% in the MP arm) ( < 0.000001), which a Millennium spokesperson touted as “the highest (nCR) rate reported in a phase III trial in patients with newly diagnosed MM.”

Other highlights of the VISTA data were presented by Jesus San-Miguel, MD, Professor of Hematology and Hematology Department Head, University Hospital of Salamanca, Salamanca, Spain, and principal investigator of the trial, during an oral presentation at the American Society of Hematology (ASH) 49th Annual Meeting, held in Atlanta, Georgia, from December 8th through December 11th, 2007. These included:

• A median duration of response of 24 months for patients with CR in BMP, compared with 13 months with MP;
• TTP in the BMP arm of 24 months, compared with 17 months with MP (P = 0.0000001);
• BMP demonstrated statistical significance in OS with a 40% reduction in risk of death P = 0.0078);
• The median treatment duration was 46 weeks; discontinuation due to adverse events was low and similar in both arms.

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Armed with the VISTA results and a growing body of positive clinical data -- (i.e., the aforementioned phase I/II PETHEMA research; the GINEMA phase III trial conducted by the Italian Myeloma Network cooperative group which compared bortezomib, thalidomide (Thalomid), and dexamethasone (Decadron) to thalidomide and dexamethasone as first-line treatment in newly diagnosed MM patients, demonstrating improved pre- and post-stem cell transplantation results and a four-fold increase in complete remission rates; and a separate phase III trial comparing bortezomib and dexamethasone (BD) to vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (VDD), conducted by the Intergroupe Francophone du Myelome (IFM) cooperative group and CHU Nantes. As front line induction therapy in newly diagnosed MM patients prior to stem-cell transplant (SCT), the BD arm demonstrated a complete remission rate of 21%, compared with 8% with VDD ( < 0.0001). Of the 404 patients who proceeded to SCT, the BD arm demonstrated a post-transplantation complete remission rate of 41% compared with 29% with VDD ( = 0.0089). Millennium submitted a supplemental New Drug Application (sNDA) to the FDA on December 21, 2007, in an effort to expand the scope of bortezomib indications into the realm of newly diagnosed multiple myeloma. (Currently, bortezomib is approved for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma who have received at least one prior therapy.)

Roughly one month after Millennium’s initial sNDA submission, the FDA announced that it had granted priority review to the application. Priority review is granted by the FDA for a treatment that addresses an unmet medical need and demonstrates an improvement over existing therapies. The FDA expedites the approval process for applications granted priority review from 10 to six months.