TYSABRI® TWO-YEAR MONOTHERAPY DATA SUPPORT POSITIVE ONE-YEAR EFFICACY FINDINGS AND SHOW SIGNIFICANT REDUCTION IN RISK OF DISABILITY PROGRESSION
Data Presented at American Academy of Neurology Meeting
Cambridge, MA and Dublin, Ireland - April 12, 2005 -Two-year data from the AFFIRM Phase III monotherapy trial presented today for the first time, showed that treatment with TYSBARI® (natalizumab) led to a significant reduction in disability progression, the rate of clinical relapses and brain lesions in patients with relapsing forms of multiple sclerosis (MS). These data were presented at the 57th annual American Academy of Neurology (AAN) meeting in Miami Beach, FL.
AFFIRM met all primary and secondary endpoints, including disability progression and relapse rate. TYSABRI treatment was also associated with a low level of immunogenicity.
TYSABRI treatment led to a 42 percent (p=0.0002) reduction in the risk of disability progression compared to placebo. TYSABRI also reduced the rate of clinical relapses by 67 percent (p<0.0001) compared to placebo, which was sustained and consistent with the previously reported one-year results.
On February 28, 2005, Biogen Idec and Elan Corporation, plc announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. This decision was based on reports of progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal, demyelinating disease of the central nervous system. Biogen Idec and Elan's comprehensive safety evaluation concerning TYSABRI and any possible link to PML is ongoing. The results of this safety evaluation will be discussed with regulatory agencies to determine possible re-initiation of dosing in clinical trials and future commercial availability.
"While an evaluation is underway to better understand recent developments with TYSABRI, these data confirm the efficacy of TYSABRI on clinical relapse and define its impact on disability progression," said Chris Polman, MD, PhD, lead investigator of the AFFIRM study, professor of Neurology at Free University Medical Centre, and clinical and scientific director of the Multiple Sclerosis Centre at the VU Medical Centre, Amsterdam. "Disability progression is an important consideration in managing MS. The efficacy of TYSABRI underscores its importance for MS patients."
Results From Two-Year AFFIRM
AFFIRM is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients conducted in 99 sites worldwide, evaluating the effect of TYSABRI on the progression of disability as measured by at least a one-point increase on the Expanded Disability Status Scale (EDSS) sustained for three months, and the rate of clinical relapses. Progression of disability is a sustained change that has a long-term impact on a patient's functional and ambulatory performance. Patients in AFFIRM were randomized to receive either a 300 mg IV infusion dose of TYSABRI (n=627) or placebo (n=315) every four weeks.
TYSABRI-treated patients were less likely to experience progression of disability. The risk of disability progression sustained for three months was reduced by 42 percent relative to placebo (p=0.0002), the two-year primary endpoint. Additionally, after two years, 29 percent of placebo-treated patients had progressed, while only 17 percent of TYSABRI-treated patients progressed, representing a 41 percent reduction in the proportion of patients progressing (p<0.0001).
TYSABRI also slowed the progression of disability as demonstrated by the mean Multiple Sclerosis Functional Composite (MSFC) score. The MSFC consists of three tests that evaluate ambulation, upper extremity dexterity and cognitive function.
A pre-defined sensitivity analysis of the primary endpoint defined progression as at least a one-point increase on the EDSS sustained for six months. Using this definition, the risk of disability progression was reduced by 54 percent with TYSABRI treatment.
Data also demonstrated a 67 percent reduction in the rate of clinical relapses relative to placebo (p<0.0001) over two years, which was sustained and consistent with the previously reported one-year results. The annualized relapse rate was 0.22 for TYSABRI-treated patients compared to 0.67 for placebo-treated patients. The proportion of patients who remained relapse free was 67 percent in the TYSABRI-treated group compared to 41 percent in the placebo-treated group (p<0.0001).
MRI analysis examining different types of brain lesions is used in the initial diagnosis of MS and is a marker of ongoing and previous disease activity and damage. TYSABRI treatment resulted in sustained and statistically significant reductions in the number and volume of gadolinium enhancing, T2-hyperintense and T1-hypointense lesions compared to placebo. The pre-specified secondary endpoint MRI measures were the volume of T2-hyperintense lesions and the number of new T1-hypointense lesions.
Over two years, there was a significant difference in the burden of disease as measured by change in T2-hyperintense lesion volume. Placebo-treated patients experienced an increase in burden of disease while TYSABRI-treated patients had a decrease. In addition, TYSABRI demonstrated a 76 percent reduction in the mean number of new T1-hypointense lesions compared to placebo.
AFFIRM Safety Summary
The two-year adverse event profile in AFFIRM was consistent with previously reported one-year results. Common events included headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, limb and joint pain, and pharyngitis. The rate and incidence of infections in TYSABRI-treated and placebo-treated patients were similar. Serious infections occurred in 3.2 percent and 2.6 percent of TYSABRI-treated and placebo-treated patients, respectively. TYSABRI has also been associated with hypersensitivity reactions, including serious systemic reactions that occurred at an incidence of less than 1 percent of patients.
All biologics have the potential to induce antibody formation. Analysis of the two-year data from the AFFIRM study indicated a low level of immunogenicity associated with TYSABRI. Patients were tested for antibodies every 12 weeks. Antibodies were detected in approximately 9 percent of patients at least once during treatment, with 6 percent of patients remaining persistently positive. Persistently positive antibodies were associated with a substantial decrease in efficacy and an increase in certain infusion-related adverse events. Almost all patients who tested positive for antibodies did so within the first 12 weeks of treatment.
"We believe in the significant therapeutic benefit of TYSABRI in MS, a disease with high unmet need," said Burt Adelman, MD, executive vice president, Development, Biogen Idec. "Biogen Idec and Elan are working diligently to evaluate extensive data from our clinical trials, consulting with leading experts and with regulatory agencies throughout this process. We hope to define a path forward for this product, and our future steps, as always, will be guided by our commitment to people living with MS."
"We are very encouraged by the two-year results which support the efficacy of TYSABRI in MS," said Lars Ekman, MD, PhD, executive vice president and president, Research and Development, Elan. "Patient safety is our top priority, and we are working closely with the regulatory agencies to define the appropriate benefit-risk profile for TYSABRI as a new option to treat MS."
Biogen Idec and Elan are collaborating equally on the development of TYSABRI in MS, Crohn's disease, and rheumatoid arthritis. On February 28, 2005, Biogen Idec and Elan announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. Worldwide regulatory agencies are being kept informed of developments related to TYSABRI.
Information about TYSABRI, including the voluntary suspension of marketing, U.S. prescribing information and support services, is available through a single toll-free number (1-800-456-2255), and via www.TYSABRI.com
About Multiple Sclerosis
MS is a chronic disease of the central nervous system that affects approximately 400,000 people in North America and more than one million people worldwide. It is a disease that affects more women than men, with onset typically occurring between 20 and 40 years of age. Symptoms of MS may include vision problems, loss of balance, numbness, difficulty walking and paralysis.