From rxpgnews.com
FDA Fully Approves Bortezomib for Treatment of Relapsed and Refractory Multiple Myeloma
By Akanksha, Pharmacology Correspondent
Mar 26, 2005, 10:02
Millennium Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved the Company's supplemental New Drug Application (sNDA) for VELCADE(Bortezomib). This approval expands the label to include the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.
Bortezomib is the only drug therapy that has demonstrated a significant survival advantage as compared to a standard therapy in relapsed MM. Initial accelerated approval for relapsed and refractory MM was granted in May 2003.
Bortezomib is now fully approved in relapsed MM.The approval was based on data from the randomized phase III APEX study that compared single-agent Bortezomib to a traditional MM therapy, high-dose dexamethasone. The study demonstrated a significant survival advantage with
Bortezomib (p less than 0.05) in patients who had received one to three prior therapies.
Importantly, this pronounced survival advantage was also observed in the second-line MM patients. The safety profile of Bortezomib remained consistent with previous phase II findings. This indication doubles the number of U.S.
patients who could potentially benefit from Bortezomib to approximately 22,000.
"We are thrilled that more patients will have access to Bortezomib earlier in their treatment where Bortezomib has shown a significant improvement over a standard therapy in improving survival and delaying disease progression," said
David Schenkein, M.D., senior vice president, clinical research at Millennium.
"Millennium is committed to making a difference in patients' lives and will continue, in partnership with Johnson & Johnson Pharmaceutical Research and
Development L.L.C., to explore extensively the benefits of Bortezomib across the multiple myeloma treatment paradigm as well as in other hematologic and solid tumors."
The approval of this supplementary filing comes approximately 22 months after the initial FDA approval of VELCADE(R) (bortezomib) for Injection.
Bortezomib, the first of a new class of medicines called proteasome inhibitors,is the first treatment in more than a decade to be approved for patients with multiple myeloma, a cancer of the blood.
The sNDA submission was based primarily upon the results of the phase III APEX study, which compared Bortezomib to high-dose dexamethasone. The APEX trial enrolled 669 patients with relapsed multiple myeloma (patients had received one to three prior therapies) at 93 centers in North America, Europe and Israel.
This study was conducted under the direction of Paul Richardson, M.D.,clinical director, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute. The APEX trial was halted one year early after an independent data
monitoring committee concluded the findings of a pre-specified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of Bortezomib.
In the overall study population, Bortezomib was superior to high-dose dexamethasone based on time to progression (p less than 0.0001), overall survival (p less than 0.05) and response rate (p less than 0.0001).
Additional findings include the following:
-- Overall, 40 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate of 38 percent with Bortezomib, with a median duration of response of 8.0 months compared with a response rate of 18 percent, with a median duration of response of 5.6 months for dexamethasone;
-- Six percent of Bortezomib patients had a complete response and 7 percent had a near complete response as compared to less than one percent each with dexamethasone;
-- After a median of 8.3 months of follow-up, improvement in median time to progression was 78 percent with Bortezomib relative to dexamethasone.
Among the 251 second-line multiple myeloma patients (those who had only one prior therapy), Bortezomib was superior based on time to progression (p=0.0019), response rate (p=0.0035) and overall survival (p less than0.05).
Additional findings include the following:
-- Overall, 55 percent fewer patients died in the Bortezomib arm relative to the dexamethasone arm;
-- Overall response rate with Bortezomib was 45 percent (median duration of response was 8.1 months) compared with 26 percent for dexamethasone (median duration of response 6.2 months); and
-- Six percent of Bortezomib patients had a complete response and 6 percent had a near complete response as compared to two percent each with dexamethasone.
Adverse events on the Bortezomib arm were predominantly grade one or two,were similar to those previously observed in other trials and were considered manageable by the investigators.
-- The most commonly reported adverse events were asthenic conditions,diarrhea, nausea, constipation, peripheral neuropathy, vomiting,pyrexia, thrombocytopenia, psychiatric disorders and anorexia and appetite decreased;
-- The most commonly reported serious adverse events were pyrexia,diarrhea, dyspnea, pneumonia and vomiting.
Bortezomib is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Bortezomib is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
Bortezomib is being co-developed by Millennium and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of Bortezomib in the U.S.; Ortho Biotech and Janssen-Cilag are
responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for Japan.
Risks associated with Bortezomib therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events,thrombocytopenia and tumor lysis syndrome.
Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.
In 331 patients who were treated with Bortezomib 1.3 mg/m2 dose in the phase III APEX study, the most commonly reported adverse events were :
-asthenic conditions (61%),
-diarrhea (57%),
-nausea (57%),
-constipation (42%),
-peripheral neuropathy (36%),
-vomiting (35%),
-pyrexia (35%),
-thrombocytopenia (35%),
-psychiatric disorders (35%) and
-anorexia and appetite decreased (34%)
Fourteen percent of patients reported at least one episode of grade 4 toxicity;the most common grade 4 toxicities were:
-thrombocytopenia(4%),
-neutropenia(2%)
-hypercalcemia(2%).
A total of 144 patients on Bortezomib(44%) reported serious adverse events (SAEs) during the study.The most commonly reported SAEs were pyrexia(6%),diarrhea(5%), dyspnea and pneumonia(4%) and vomiting(3%).
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