Genzyme Corporation today reported four-year follow-up data from its completed Phase 2 multiple sclerosis (MS) trial showing an estimated 71 percent of alemtuzumab treated patients remain free of clinically-active disease as much as three years after most patients received their last course of the investigational compound. The data were presented at the American Academy of Neurology annual meeting.
The CAMMS223 Phase 2 trial, first reported in the New England Journal of Medicine in 2008, compared alemtuzumab to the approved MS therapy Rebif (interferon beta-1a) in early, active, relapsing-remitting multiple sclerosis (RRMS) patients who had received no prior therapy. In the trial, alemtuzumab was given to patients in two or three annual cycles of not more than five days per cycle, while Rebif was given to patients three times per week, every week for three years.
Results of the four-year review found:
-- an estimated 71 percent of alemtuzumab-treated patients were free of clinically-active disease, compared to 35 percent of patients taking Rebif (p<0.001). To be free of clinically-active disease, MS patients in the trial were both relapse-free and without progression of disability as measured by the Expanded Disability Status Scale (EDSS) throughout the course of the study;
-- an estimated 91 percent of alemtuzumab-treated patients were free of sustained accumulation of disability compared to 68 percent of patients taking Rebif; and
-- an estimated 77 percent of alemtuzumab-treated patients were relapse-free compared to 49 percent of patients taking Rebif.
"These early data may set a new bar for clinical outcomes in multiple sclerosis," said Omar Khan, MD, Professor of Neurology, Wayne State University School of Medicine, site principal investigator in the CAMMS223 Phase 2 trial.
Post-hoc analyses of the patients free from clinically-active disease were performed using data obtained from patients participating in CAMMS223. The dataset analyzed consists of the originally-planned three years of patient follow-up, additional continuous post-three-year follow-up, and prospective follow-up of patients who initially discontinued but returned to the study to participate in the risk management program. Roughly 15 percent of patients participating in the post-three-year follow-up used non-study MS disease modifying therapies. A sensitivity analysis that censored these patients found that the risk of relapse, sustained accumulation of disability, and free from clinically-active disease status favored alemtuzumab.
Alemtuzumab Mechanism of Action Data
Research suggests that in multiple sclerosis, T- and B-lymphocytes mistakenly attack the myelin sheath that protects nerve cells. These attacks can lead to disease progression and irreversible disability. The first detailed depiction of pharmacodynamic data from a large cohort of alemtuzumab treated relapsing-remitting MS patients (n=216) provided at AAN showed that alemtuzumab, in a selective fashion, targets T- and B-lymphocytes while largely sparing other immune system elements. The analysis also found that the targeted immune system cells begin to repopulate following treatment.
"We believe that alemtuzumab targets the immune system cells responsible for the cellular damage found in multiple sclerosis, while sparing other immune system elements," said Alasdair Coles, MD, Senior Lecturer, Department of Clinical Neurosciences, University of Cambridge, a lead investigator of the Phase 2 clinical trial and author of the leukocyte dynamics abstract.
Updated Safety Findings
Immune thrombocytopenic purpura (ITP), an autoimmune disease, was identified in six alemtuzumab treated patients and one Rebif patient in the Phase 2 trial. Symptoms of ITP went unrecognized in the first alemtuzumab case and led to the onset of a fatal cerebral hemorrhage. Five other alemtuzumab-related cases were subsequently diagnosed and all five patients achieved durable remission, both with and without treatment during the Phase 2 study. New follow-up data presented at AAN show that these five patients continue to have normal platelet counts, and ITP has not been identified more than 16 months following the last alemtuzumab cycle. There have been no additional or recurrent events of ITP reported in the Phase 2 trial to-date.
"In this study, alemtuzumab treated patients who experienced an ITP event and achieved remission have had no recurring episodes of ITP. The remissions were complete and durable," said abstract author Edward Fox, MD, PhD, Director of the Multiple Sclerosis Clinic of Central Texas, and a clinical site director for the Phase 2 and 3 trials.
Additional new follow-up data presented at AAN show that the alemtuzumab-treated patients who experienced an autoimmune adverse event still experienced clinical benefits. Alemtuzumab patients with autoimmune adverse events had a 78 percent reduced rate of relapse, and 66 percent reduced risk for sustained accumulation of disability, compared to Rebif patients. Updated four-year data from the Phase 2 trial found that approximately 28 percent of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event. These events either normalized spontaneously or were managed using conventional therapies.
Genzyme is conducting two Phase 3 pivotal trials to evaluate alemtuzumab in the treatment of MS. Both trials completed enrollment in 2009. CARE-MS I, a randomized trial comparing alemtuzumab to Rebif, is studying early, active RRMS patients who have received no prior therapy. CARE-MS II, which also compares alemtuzumab to Rebif, is studying RRMS patients who relapsed while on other MS therapies. Patients who enrolled in those trials beginning in 2007 have completed the protocol-specified two years of follow-up and have begun to transfer into an extension trial. Data from the Phase 3 trials are expected to be available in 2011.
About CAMMS223 Phase 2 Study
In the Phase 2 trial, 334 patients with active RRMS were randomized to treatment with alemtuzumab at one of two dose levels, or Rebif. Patients were strongly encouraged to continue for two additional years of follow-up beyond the original three years of the study. Of the original sample, 158 patients completed a month 48 study visit (alemtuzumab n=122; interferon beta-1a: n=36). Alemtuzumab and Rebif were not provided by the study after the third year. Patients were allowed to continue Rebif or to receive other disease-modifying therapies during this follow-up period. The majority of patients last received alemtuzumab at Month 12.
Common adverse events in the trial included infusion-associated reactions in the alemtuzumab patients and flu-like symptoms in patients using Rebif. Alemtuzumab-treated patients were more likely than Rebif patients to experience infections, particularly of the upper respiratory tract; infections were predominantly mild to moderate in severity and there were no life-threatening or fatal infections. Patient monitoring for thyroid disorders, ITP, and anti-GBM disease is incorporated into all Genzyme-sponsored trials of alemtuzumab for the investigational treatment of MS.
Alemtuzumab is an investigational drug for the treatment of MS and must not be used in MS patients outside of a formal, regulated clinical trial setting in which appropriate patient monitoring measures are in place.
CAMMS223 AAN Abstracts
Alemtuzumab Reduces Disease Progression in RRMS: Long-Term Results of the CAMMS223 Trial. Omar Khan, MD, Professor of Neurology, Wayne State University School of Medicine, on behalf of the CAMMS223 study group.
Leukocyte Dynamics Following Alemtuzumab Treatment of RRMS in a Phase 2 Study (CAMMS223). Alasdair J. Coles, MD, Senior Lecturer, Department of Clinical Neurosciences, University of Cambridge, on behalf of CAMMS223 study group.
Detailed Analysis of CD52 Expression and Cellular Depletion/Re-population After Alemtuzumab Treatment in huCD52 Transgenic Mice. Bruce Roberts, PhD, Group Vice President, Genzyme Corporation.
Sustained Positive Effects of Alemtuzumab on Diverse Neurological Functions in RRMS Patients. Edward Fox, MD, PhD, Director of the Multiple Sclerosis Clinic of Central Texas, on behalf of the CAMMS223 study group.
Benefits of Alemtuzumab are Evident Even in RRMS Patients Who Experience Autoimmune Adverse Events. Vesna Brinar, MD, PhD, Professor of Neurology, Medical Faculty, University of Zagreb, on behalf of the CAMMS223 study group.
Long-term Follow-up of Immune Thrombocytopenia after Treatment of MS Patients with Alemtuzumab in CAMMS223. Edward Fox, MD, PhD, Director of the Multiple Sclerosis Clinic of Central Texas, on behalf of the CAMMS223 study group.
Exploring Alemtuzumab's Long Term Efficacy and Safety: Design of the CARE-MS Extension Study. Chris LaGanke, MD, on behalf of the CAMMS223 study group.
About Campath (alemtuzumab)
Campath is licensed in the United States as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), and outside of the U.S. for the treatment of B-CLL in patients who have been treated with alkylating agents and for whom fludarabine combination therapy is not appropriate. The product was launched in its oncology indication in 2001 in the US, where it is marketed as Campath, and in Europe, where it is named MabCampath.
Campath for B-CLL has a boxed warning that includes information on cytopenias, infusion reactions, and infections. The most commonly reported adverse reactions in patients with B-CLL were infusion reactions (fever, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), and infections (CMV viremia, CMV infection, other infections). Other commonly reported adverse reactions include vomiting, abdominal pain, insomnia and anxiety. The most commonly reported serious adverse reactions are cytopenias, infusion reactions, and immuno-suppression/infections.
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 12,000 employees in locations spanning the globe and 2009 revenues of $4.5 billion.
With many established products and services helping patients in approximately 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.
This press release contains forward-looking statements regarding Genzyme's future plans and business strategies, including its expectations about when data will become available from the two phase 3 trials, and the success of alemtuzumab to treat MS. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements, including: that the phase 3 trials are not successful; the timing and outcome of discussions with the regulatory agencies regarding approval of alemtuzumab for MS; the actual safety and efficacy of alemtuzumab for MS; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation the information under the heading "Risk Factors" in Genzyme's Annual Report on Form 10-K for the year ending December 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise these statements.
Genzyme, Campath, and MabCampath are registered trademarks and CARE-MS is a service mark of Genzyme Corporation. All rights reserved. Rebif is a registered trademark of EMD Serono, Inc. or affiliates.
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