Drug development and marketing partners Genentech Inc. and Biogen IDEC Inc. touted a number of positive findings related to Rituxan at this week's American Society of Hematology meeting in San Diego.
The drug was shown to be effective as a first-line treatment of aggressive and indolent non-Hodgkin's lymphoma (NHL), the disease for which it is approved. Among the positive findings, the partners said one trial ended two years early - a Phase III randomized study that evaluated Rituxan (rituximab) in combination with chemotherapy as a front-line treatment for aggressive lymphoma, which met its primary efficacy endpoint early.
An interim analysis of data found a statistically significant improvement in time to treatment failure for patients receiving Rituxan and chemotherapy, compared to chemotherapy alone. The study was conducted worldwide.
Dubbed the MabThera International Trial, the study enrolled about 800 patients in 18 countries and was sponsored by F. Hoffmann-La Roche Ltd. Rituxan is labeled MabThera outside the U.S., where it is marketed by Basel, Switzerland-based Roche. In the U.S. it is held jointly by Biogen IDEC and Genentech, which also reported plans to repurchase up to $1 billion of its common stock through Dec. 31. Rituxan is co-marketed in Japan by Roche and Zenyaku Kogyo Co. Ltd., of Tokyo.
Separately, initial results from another Phase III randomized study showed that NHL patients who received Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, followed by Rituxan maintenance therapy or observation, demonstrated a trend toward prolongation of time to treatment failure, the primary endpoint of the induction phase of the study, as compared to patients who received CHOP alone followed by Rituxan maintenance or observation. The addition of Rituxan to CHOP did not influence the overall response rate in the induction phase (78 percent for R-CHOP vs. 77 percent for CHOP alone).
With regard to the primary endpoint for the maintenance phase of the study, patients treated with Rituxan maintenance for up to an additional two years after completing induction therapy had a statistically significant prolongation in time to treatment failure, compared to patients who did not receive Rituxan maintenance therapy following induction. The advantage appeared predominantly confined to patients who received CHOP alone during the induction phase. Also, investigators found no difference in overall survival between the Rituxan maintenance and observation arms, though they said additional follow-up is necessary.
The E4494 trial was a U.S. Intergroup study led by the Eastern Cooperative Oncology Group, in collaboration with the Southwest Oncology Group and the Cancer and Leukemia Group B.
Initial Phase III results in patients with indolent NHL demonstrated that the addition of Rituxan to cyclophosphamide, vincristine and prednisone chemotherapy (R-CVP) prolonged time to treatment failure - the study's primary endpoint - to 26 months, compared to seven months for patients treated with CVP alone. The risk of an event (defined as disease progression, relapse, death, stable disease after cycle four or new treatment administered) was reduced by 66 percent in patients who received R-CVP.
Phase II results in indolent NHL patients showed that those who received Rituxan maintenance therapy experienced 31 months of progression-free survival as compared to eight months for those who were retreated with Rituxan at the time of disease progression. The study also demonstrated that duration of Rituxan benefit, the study's primary endpoint, can be prolonged by either maintenance therapy (31 months) or re-treatment (27 months).
In other news from the meeting:
• Amgen Inc., of Thousand Oaks, Calif., said interim data showed that after 12 weeks of treatment with Aranesp (darbepoetin alfa), administered every two weeks in correcting anemia in cancer patients not undergoing chemotherapy, the mean change in hemoglobin was 1.9 g/dL for the Aranesp group and 0.2 g/dL in the control group. The randomized, multicenter study also found that the Kaplan-Meier estimate (95 percent) of hematopoietic response was 81 percent for the Aranesp group and 26 percent for the control group. Findings from separate head-to-head studies showed that 200 mcg of Aranesp dosed once every two weeks provided similar results to 40,000 units of epoetin alfa dosed once weekly in boosting hemoglobin and reducing the need for blood transfusions in cancer patients undergoing chemotherapy.
• AnorMED Inc., of Vancouver, British Columbia, said treatment with AMD3100, its lead drug candidate for stem cell transplantation, helped poor mobilizers generate an adequate number of stem cells required for a transplant procedure. More specifically, Phase II results showed that when AMD3100 was used in combination with a standard agent called G-CSF, all 19 patients achieved the target number of stem cells for transplantation. But seven of the 19 did not reach the target number when G-CSF was used alone to collect their cells.
• BioCryst Pharmaceuticals Inc., of Birmingham, Ala., reported Phase I results showing that treatment with intravenous BCX-1777 resulted in a clinical effect in four of five patients with aggressive T-cell malignancies, as evidenced by a decrease in malignant cell counts. The drug was well tolerated, with few drug-related adverse events. The company added that it expects data from several additional ongoing trials of the product in the first half of next year. Its stock (NASDAQ:BCRX) dropped 86 cents Monday, or 10.2 percent, to close at $7.54.
• Biogen IDEC Inc., of Cambridge, Mass., said new data support the ability of Zevalin (ibritumomab tiuxetan) to induce long-term remissions in patients with relapsed, refractory or transformed indolent B-cell NHL. Also, preliminary results indicate that Zevalin has promising clinical activity in treating patients with mantle-cell lymphoma.
• Cell Genesys Inc., of Foster City, Calif., said interim Phase II data indicate that its GVAX cancer vaccine is well tolerated and might reduce residual leukemic cells that persist after chemotherapy, as indicated by decreased levels of WT-1, a leukemia-associated genetic marker, which is detectable in more than 95 percent of patients with active acute myelogenous leukemia. Patients with newly diagnosed leukemia were treated with chemotherapy, and, if responsive, subsequently received autologous bone marrow stem cell transplantation and GVAX.
• Cell Therapeutics Inc., of Seattle, said preliminary clinical data showed that following treatment with Trisenox (arsenic trioxide), in 28 of 120 myelodysplasia patients with sufficient data for evaluation, responses were observed in each of the cell lineages and were seen after about eight to 24 weeks of therapy. Also, Trisenox treatment led to transfusion independence in 12 patients and a decrease of 50 percent or more in transfusion requirements for an additional five patients. Responses to Trisenox lasted from just under eight weeks up to 46 weeks, with a median duration of about 15 weeks. Separately, the company said data from preclinical studies show that a new cancer target called LPAAT-beta is highly expressed in many cancers.
• Corixa Corp., of Seattle, and GlaxoSmithKline plc, of London, said results from several studies showed that Bexxar (tositumomab and iodine I-131 tositumomab) is active in a variety of patients with difficult-to-treat lymphomas, including patients with heavily pre-treated follicular NHL who have had multiple relapses, patients who initially responded but subsequently relapsed following the Bexxar therapeutic regimen, and patients with previously untreated mantle-cell lymphoma who received Bexxar as a component of sequential therapy. The product is approved for use in a single course for treating patients with CD20+, follicular NHL, with and without transformation, whose disease is refractory to the antibody treatment rituximab and has relapsed following chemotherapy.
• Cytogen Corp., of Princeton, N.J., said clinical data showed that Quadramet (samarium SM 153 lexidronam injection), in combination with zoledronic acid (Zometa, Novartis AG), provided pain relief in elderly patients with symptomatic chemotherapy-refractory multiple myeloma. Findings from another study suggested a benefit in using high-dose Quadramet in multiple myeloma patients, along with high-dose melphalan chemotherapy (200 mg/m2), prior to undergoing stem cell transplantation.
• EntreMed Inc., of Rockville, Md., said preliminary Phase II data demonstrated that Panzem is well tolerated and stabilized disease in patients with plateau or relapsed multiple myeloma. The company plans to continue evaluating the patients using a new formulation of the drug candidate, designed to increase and prolong exposure to Panzem. Separately, EntreMed said it developed compounds that specifically inhibit proteinase-activated receptor-2 (PAR-2), which is associated with inflammation and has been shown in preclinical models to play a critical role in tumor growth and formation of new blood vessels. The company said in vivo studies showed that a small-molecule peptidomimetic is more potent in blocking the signaling of PAR-2 than a peptide it also designed.
• Genitope Corp., of Redwood City, Calif., said Phase II results suggest that an accelerated schedule with more doses of MyVax Personalized Immunotherapy might be a safe and effective treatment following chemotherapy in individuals with aggressive lymphoma, including mantle-cell lymphoma. The median time to disease progression for mantle-cell patients who received five immunizations during 24 weeks was 254 days following completion of chemotherapy. In such patients who received eight doses over 18 weeks, the median time to disease progression was 477 days following completion of chemotherapy.
• Genmab A/S, of Copenhagen, Denmark, reported interim Phase II results showing that treatment with HuMax-CD4 in cutaneous T-cell lymphoma patients resulted in at least a partial response (more than 50 percent improvement) among 55 percent of early stage and 38 percent of advanced-stage patients. One early stage patient's disease was completely cleared, and 9 percent of early stage and 23 percent of advanced-stage patients achieved a minor response (25 percent to 50 percent improvement). Separately, Genmab reported preclinical findings showing that HuMax-CD20 binds to a unique site on CD20 target cells when compared to other known CD20 antibodies. Other data showed that HuMax-CD20 appears to stop growth of B-cell tumors grown from a laboratory cell line more effectively than placebo or Rituxan.
• Genta Inc., of Berkeley Heights, N.J., said results from several clinical studies pointed to the safety and, potentially enhanced activity, when chemotherapy was combined with its lead cancer drug, Genasense (oblimersen sodium), as initial therapy for acute myeloid leukemia patients older than 60. Other clinical results suggested that Genasense could be used to synergistically enhance the activity of Rituxan in NHL.
• Geron Corp., of Menlo Park, Calif., said preliminary Phase I/II results showed that treatment with its telomerase therapeutic vaccine for metastatic prostate cancer has resulted in telomerase-specific cellular immune responses among all but one of the patients evaluated to date. No patients exhibited any sign of treatment-related adverse effects, and in the three patients analyzed thus far from the high-dose group, stabilization of serum PSA values during the treatment phase was observed.
• Hollis-Eden Pharmaceuticals Inc., of San Diego, reported positive results with investigational immune-regulating hormones (IRHs) in models of radiation and chemotherapy-induced neutropenia. The findings included a second study in nonhuman primates showing beneficial effects with HE2100 (Neumune) in a model of radiation injury, as well as positive results from separate studies in nonhuman primates with both Neumune and a new IRH in carboplatin-induced neutropenia. Other data related to Neumune's mechanism of action showed that the compound acts directly on a number of important stem cell components.
• Immunomedics Inc., of Morris Plains, N.J., said unlabeled epratuzumab could be combined safely with rituximab and the CHOP chemotherapy regimen in patients with aggressive NHL. The study also showed that epratuzumab could be active when given as re-treatment after an earlier response in patients with indolent NHL who relapsed after chemotherapy. Other data showed that the pharmacokinetic behavior of rituximab and epratuzumab were not altered when the antibodies were given in a combination therapy. Its stock (NASDAQ:IMMU) dropped 81 cents Monday, or 15.1 percent, to close at $4.54.
• ILEX Oncology Inc., of San Antonio, said investigator-sponsored studies showed that Campath (alemtuzumab) cleared residual bone marrow disease in most patients following chemotherapy and a molecular remission was achieved in 11 of 29 patients in whom polymerase chain reaction results were available. The overall response rate was 53 percent. Researchers reported that the absence of minimal residual disease is the best predictor for prolonged survival of patients with chronic lymphocytic leukemia. Campath is approved for treating B-cell chronic lymphocytic leukemia. Separately, ILEX said adults with first relapsed and primary refractory acute myeloid leukemia or myelodysplastic syndrome who were treated with the combination of clofarabine and ara-C (cytarabine) achieved an overall response rate of 41 percent in a Phase I/II trial. The response rate from the Phase II study included seven complete remissions and five complete remissions without platelet recovery. Six weeks ago, ILEX submitted the first part of a new drug application for use of clofarabine for refractory or relapsed pediatric acute leukemia. The company obtained U.S. and Canadian development rights from Bioenvision Inc., of New York, which maintains rights outside those areas. (See BioWorld Today, Oct. 23, 2003.)
• Inex Pharmaceuticals Corp., of Vancouver, British Columbia, released results from three separate clinical trials indicating that its lead anticancer product, Onco TCS, is able to reduce the size of tumors in lymphoma patients with advanced disease. Among the findings, final pivotal data on 119 patients with relapsed aggressive NHL resulted in a 25 percent overall response rate after Onco TCS treatment. The findings included eight patients whose tumors were completely eliminated and 22 whose tumor volume was reduced by more than 50 percent. An additional 31 patients had their disease stabilized while being treated. Initial results of the study were reported during the summer, and the company began a rolling new drug application with an initial submission to the FDA two months ago. (See BioWorld Today, Oct. 1, 2003.)
• Novartis AG, of Basel, Switzerland, said new data demonstrated that at 12 months, newly diagnosed patients with Philadelphia chromosome positive chronic myeloid leukemia taking 800 mg/day of Gleevec (imatinib mesylate) achieved higher complete cytogenetic responses compared to those taking the standard 400-mg/day dose. More specifically, 92 percent of evaluable patients taking 800 mg achieved a response, compared to 72 percent on the standard dose. More patients in the higher dose group also achieved a molecular response compared to those in the standard dose group.
• Seattle Genetics Inc., of Bothell, Wash., said Phase I data showed that its SGN-30 product was well tolerated and demonstrated antitumor activity. Also, preclinical data on SGN-40 showed activity in multiple models of hematologic malignancies and favorable pharmacokinetic properties. The company added that it expects to begin Phase II trials early next year to evaluate SGN-30 in patients with Hodgkin's disease or anaplastic large-cell lymphoma, and to begin a Phase I study of SGN-40 in multiple myeloma patients.
• SuperGen Inc., of Dublin, Calif., said data from five clinical studies demonstrated the activity of its cancer drug Nipent (pentostatin for injection), as part of combination therapy, in chronic lymphocytic leukemia. The company added that findings from two other clinical studies demonstrated the drug's activity in treating NHL patients through combination therapy. Nipent is approved as a single-agent treatment for patients with hairy-cell leukemia.
• Trubion Pharmaceuticals Inc., of Seattle, said its initial products demonstrated effectiveness in depleting normal and malignant B cells. Data from one study demonstrated that its TRU-016 small modular immunopharmaceutical (SMIP) binds to and effectively kills malignant B cells through apoptosis, complement-dependent cytotoxity and antibody-dependent cellular cytotoxicity. In a second study, injection of another SMIP labeled TRU-015 into macaques resulted in rapid and complete depletion of circulating B cells for more than 28 days following the second injection.
• VasGene Therapeutics Inc., of Los Angeles, reported clinical data showing that its Veglin product can be administered safely in a number of cancers and HIV-related malignancies through eight escalating dose levels. The company called the product a next-generation inhibitor of vascular endothelial growth factor (VEGF), which employs a three-prong approach to inhibiting tumor growth. There was no evidence of hypertension or other side effects seen with other VEGF antagonists. Used as a single agent, Veglin also demonstrated evidence of tumor response following one or two cycles of therapy in some patients.