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In this issue: Bortezomib (Velcade) Granted Priority Review Status for Patients With Newly Diagnosed Multiple Myeloma Reports from American Society of Hematology: Advances in Thrombosis: (1) AMG 531 Demonstrates Efficacy in Sustaining Platelet Counts in Splenectomized Patients With Chronic Immune Thrombocytopenic Purpura in Phase III Study (2) Lowâ€“Molecular-Weight Heparin Reduces the Cost of Venous Thromboembolism Treatment Compared With Unfractionated Heparin
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NEWS BRIEFSBortezomib (Velcade) Granted Priority Review Status for Patients With Newly Diagnosed Multiple Myeloma
The U.S. Food and Drug Administration (FDA) has granted priority review of Millennium Pharmaceuticals Inc.'s drug Velcade (bortezomib) to treat new cases of multiple myeloma (MM). The priority review puts the new use of Velcade on track for possible approval in the first half of 2008, company officials said.
Oncology & Biotech News
The supplemental New Drug Application (sNDA) submitted to the FDA for this indication included data from the Phase III VISTA study (covered in February’s issue of ), a large, well-controlled international clinical trial, comparing a Velcade-based regimen to a traditional standard of care. Velcade is currently indicated for MM and mantle cell lymphoma patients who have received at least one prior therapy. With priority review status, the FDA will make its decision on whether to approve the application within six months, rather than within the usual 10- to 12-month review period. Millennium says that a decision on the application is expected by June. Velcade is currently approved to treat patients with MM who have received at least one prior therapy.
The VISTA trial randomized 682 patients with newly diagnosed MM ineligible for stem cell transplantation and was conducted by Millennium and its co-development partner Johnson & Johnson Pharmaceutical Research & Development. The trial compared Velcade, melphalan, and prednisone (VcMP) to the standard regimen of melphalan and prednisone (MP) alone. VcMP achieved a statistically significant improvement across all efficacy endpoints, including complete remission rates, time-to-disease progression (TTP) and survival (progression-free survival and overall survival). Included in these results, VcMP demonstrated an immunofixation -negative complete remission rate of 35%, which is the highest rate reported in a Phase III trial in patients with newly diagnosed MM compared with 5% in the MP arm.
Multiple myeloma is the second most common hematological malignancy and, although the disease is predominantly a cancer of the elderly (the median age of onset is 70 yr), recent statistics indicate both increasing incidence and younger age of onset. In the United States, more than 55,000 individuals have MM and approximately 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.
Reports from American Society of Hematology: Advances in Thrombosis
The association between cancer and thrombosis is well recognized. Historically, bleeding disorders have been a key area of concern for hematologist oncologists.
At an on-site press conference detailing an overview of major blood clotting and bleeding disorder findings presented at ASH 2007, Andrew Schafer, MD, President, American Society of Hematology, and Chairman, Department of Medicine, New York Presbyterian-Weill Cornell Medical Center, New York City, affirmed “exciting breakthroughs in the treatment and approach to mitigating the risk of thrombosis and bleeding disorders, which will directly impact the quality of treatment for many patients.”
Dr. Weiss, Scientific Co-Chair of ASH 2007, asserted that “the most major news in the platelet field” delivered at ASH 2007, was comprised of “pretty important data relating to ITP (therapy),” which “has been difficult to treat by standard methods.” According to Dr. Weiss, a handful of potential new treatments “were talked about a lot.” One example cited by Dr. Weiss was product candidate AMG 531(Romiplostim/N-plate). The investigational drug AMG 531, explained Dr. Weiss, is thrombopoietin mimetic, acting by stimulating platelet production at the thrombopoietin receptor. Several presentations were devoted to promising AMG 531—related findings.
AMG 531 Demonstrates Efficacy in Sustaining Platelet Counts in Splenectomized Patients With Chronic Immune Thrombocytopenic Purpura in Phase III Study
Terry Gernsheimer, MD, University of Washington School of Medicine, Seattle, presented the results of a randomized, doubleblind, placebo-controlled phase III study, in which investigators evaluated the efficacy and safety of AMG 531 (Romiplostim/ N-plate) in previously splenectomized patients with chronic immune thrombocytopenic purpura (ITP) per ASH guidelines and baseline platelet counts <30,000/AμL.
Sixty-three splenectomized patients were enrolled (placebo, 21; AMG 531, 42), with a median age of 52 years (range 26—88) and a mean baseline platelet count 14.7x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50-200x109/L.
The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last eight weeks of the 24-week treatment period in the absence of rescue medications. Sixteen of the 42 splenectomized patients (38.1%) receiving AMG 531 achieved a durable platelet response compared with 0/21 (0.0%) receiving placebo ( = 0.0013). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 33/42 (78.6%) patients receiving AMG 531, compared with 0/21 (0%) placebo patients. The mean number of weekly platelet responses (platelet count ≥ 50x109/L) was significantly greater in patients receiving AMG 531 (12.3/24 weeks, 51%) compared with placebo (0.2/24 weeks, 1%) ( < 0.0001).
AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent medication or use of new medication to increase platelet counts. Twelve of 21 (57.1%) placebo-treated patients received rescue medications compared with just 11/42 (26.2%) AMG 531-treated patients ( = 0.0175). In addition, 12/12 (100.0%) AMG 531-treated patients compared with 1/6 (16.7%) placebo-treated patients either discontinued or reduced their concurrent ITP medications by more than 25%.
There were two treatment-related serious adverse events; one patient with elevated bone marrow reticulin that returned to baseline three months after withdrawal of AMG 531, and one patient experienced thrombosis that was successfully treated allowing study continuation. No patient developed neutralizing antibodies against either AMG 531 or endogenous thrombopoietin.
The results indicated that AMG 531 was well tolerated and effectively increased and sustained platelet counts in patients. Dr. Gernsheimer and colleagues concluded that AMG 531—treated patients required less frequent rescue medications (medications needed in an emergency to restabilize platelet counts and prevent or treat bleeding) in comparison with those receiving the placebo, and were able to reduce their use of concurrent ITP therapies.
“The majority of available therapies for ITP decrease platelet destruction by the immune system, but we have been aware for some time that inadequate platelet production is also a problem in this disorder. Romiplostim is an investigational therapy that stimulates platelet production in a manner similar to the body's natural hormone thrombopoietin, and is currently being evaluated for its ability to increase the platelet count by increasing platelet production in ITP. The encouraging results of this study highlight the potential of this new therapeutic approach to the treatment of adult patients with chronic ITP,” said lead investigator Dr. Gernsheimer.
Low—Molecular-Weight Heparin Reduces the Cost of Venous Thromboembolism Treatment Compared With Unfractionated Heparin
Geno J. Merli, Thomas Jefferson University, Philadelphia, reported on a retrospective cohort analysis of discharge and billing records from a proprietary (Premier Perspective) database, which demonstrated that low—molecularweight heparin (LMWH) (Fragmin) is associated with reduced total direct medical costs for the acute treatment of venous thromboembolism (VTE) when compared with unfractionated heparin (UFH) (Calciparin).
The analysis included discharges of patients 18 years of age or older and with a primary diagnosis of VTE from January 2003 through June 2005. Discharges with prior VTE during the 12-month period prior to the index hospitalization or a pre-existing contraindication to anticoagulant therapy were excluded from the analyses. Total hospital direct medical costs associated with VTE treatment (including drug costs, hospital costs, and professional costs) were collected and compared for UFH and LMWH. Furthermore, VTE-related readmission rates at days 30 and 90 postdischarge were compared for each of these agents. Total direct medical costs (in U.S. dollars) were compared using generalized linear models (SAS 9.1 PROC GENMOD), adjusting for patient and hospital characteristics. Logistic regression was used to compare the likelihood of readmission within 30 and 90 days.
A total of 38,664 discharges surveyed met the inclusion criteria, 20,577 (53%) receiving LMWH and 18,087 (47%) receiving UFH. The two groups were broadly similar in clinical and demographic characteristics, although mean length of stay was 1.1 days longer in the UFH group (5.7 days [SD=2.9] vs. 4.6 days [SD=2.9] for LMWH, < 0.001). After adjustment for covariates, the mean total direct hospital costs were $3,618 for UFH and $3,068 for LMWH (difference $550, < 0.0001). LMWH was associated with reduced cost in most categories, although anticoagulation therapy costs were higher for LMWH ($242 versus $41 for UFH, < 0.0001). LMWH was associated with lower rates of VTE-related readmission at both 30 days (11.2% vs. 12.1%; odds ratio [OR] 0.89, 95% confidence interval [CI] 0.84—0.96; = 0.001) and 90 days (13.1% vs. 13.8%; OR 0.91, 95% CI 0.85—0.96;P < 0.001).
Dr. Merli and colleagues concluded that in a large, real-world population of patients from across the United States, LMWH is associated with reduced total direct medical costs for the acute treatment of VTE when compared with UFH. This reduction occurs despite higher drug-related costs for LMWH. In addition, patients receiving LMWH are less likely to be readmitted to hospital within 90 days with recurrent VTE.