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22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

Madrid, Spain / September 27-30, 2006

It is increasingly clear that once multiple sclerosis (MS) progresses beyond a certain disability threshold, further deterioration will be relatively unaffected by treatment. Priorities in MS management are therefore accurate measurement of prognostic markers and early intervention with therapies that effectively block relapse and disability progression. Interferon beta (IFNb) remains a powerful tool in the MS arsenal, but its effectiveness is limited. The alpha 4 integrin antagonist natalizumab offers a novel mode of action in the treatment of MS. The recently published results of extensive phase III clinical trials with this agent demonstrate that it is a highly effective treatment for relapsing-remitting MS (RRMS).

Identifying Patients at Risk of Relapse and Disability Progression

In the early stages of MS, the brain has a very good capacity to repair demyelination damage. However, as Dr. Hans-Peter Hartung, Heinrich Heine University, Düsseldorf, Germany, told the audience, “There is clear-cut evidence that once axonal loss goes beyond a certain threshold of compensation, this is always accompanied by an inexorable and relentless progression of clinical disability; hence preventing this is imperative in the treatment of MS.”

Ongoing longitudinal MRI studies in several centres show that the number and types of lesions predict the subsequent development of clinical disease. According to Dr. Mar Tintoré, Vall d’Hebron University Hospital, Barcelona, Spain, MRI profiles can also predict when subsequent attacks will occur. MRI can thus identify patients at risk of developing disease over a short time. The importance of early intervention in such cases is underlined by the finding that clinical risk factors for disability progression only apply during the early relapsing phase of the disease. Once a patient’s Expanding Disability Status Scale (EDSS) score exceeds 4, when walking is impaired but a cane is not yet required, progression becomes independent of the disease profile at onset. There is thus a need for timely intervention with effective therapies to prevent relapse and progression.

Clinical Trial Data

The monoclonal antibody natalizumab inhibits leukocyte migration into brain parenchymal tissue by binding to alpha 4 integrins on the surface of these cells. This blocks binding of these receptors to vascular cell adhesion molecule 1 on endothelial cells, thereby preventing trafficking and migration of circulating leukocytes into the central nervous system.

Dr. Howard S. Rossman, Medical Director, Multiple Sclerosis Center, Michigan Institute for Neurological Disorders, Farmington Hills, described the 120-week, phase III AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) and SENTINEL (Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis) trials, which included over 3800 patient-years, as “the largest and most rigorous of any of the approved MS therapies.”

In AFFIRM, a monotherapy study vs. placebo, the annualized relapse rate after one year of active treatment was reduced by 68% and was sustained at two years (P<0.001). When patients did have relapses, these were less severe, as there was a 69% reduction in the rate of steroid treatment compared to placebo, implying, according to Dr. Rossman, “that the relapse was not as severe and a greater number did not require steroid intervention.” The risk of progression of disability over two years was reduced by 42% (P<0.001), based on EDSS reductions sustained over a 12-week period. When measured over 24 weeks, the risk reduction increased to 54% (P<0.001), so the more stringent the diagnostic criteria is, the more significant the benefit is, he noted. Crucially, the monoclonal antibody reduced by 67% the risk of progression to the key milestone EDSS score of 4. Positive MRI measures included a 92% reduction in gadolinium (Gd)-enhancing lesions at one and two years (P<0.001) and an 83% reduction in the mean number of new or enlarging T2 lesions between baseline and year 2 (P<0.001).

Although this compound has not been tested directly with other MS therapies, the relapse rate data compare favourably to reductions of about one-third with IFNb. The higher treatment efficacy translates into significant benefits on quality-of-life measures. Dr. Rossman remarked, “Quality of life is one of the most important measures to our patients,” adding that natalizumab “is the first agent in any phase III MS clinical trial that has shown a significant benefit in patients’ quality of life using the Short Form 36, both in the physical and mental or cognitive measures. This is the first time this has ever been seen.”

A striking feature of the trial data for all end points is the consistency of the treatment effect between year 0 to 1 and year 1 to year 2. This consistency is also preserved over longer treatment periods. Dr. Paul O’Connor, St. Michael’s Hospital, Toronto, Ontario, presented data from 250 patients in the extension study who remained on natalizumab therapy for a total of three years. The relapse rate during year three was 0.23, the same as in year 2. “It is pretty clear that the treatment effect is consistent… and that there is a clear and strong treatment effect,” he told the audience. The extension study also showed that protection from relapse was sustained for two to three months after cessation of therapy with no evidence of any rebound effect.

Also encouraging was the finding that patients with more active clinical disease benefited even more from treatment. Patients in this subset had experienced at least two relapses in their pre-trial history or had at least one Gd-enhanced MRI lesion at baseline. For these patients, the annualized relapse rate reduction with natalizumab was 81%; in the stringent 24-week disability test, risk reduction was 64%. Dr Rossman commented that the agent “works across the spectrum of patients, but with the patients with the most active clinical disease, we appear to get even more benefit.”

Ensuring Safety with Clinical Vigilance

Trial data on safety end points show no significant differences between treated and non-treated patients in infection rates, hypersensitivity reactions, malignancy or tolerability. Most adverse events were mild and the risk remained stable over the two years. In February 2005, natalizumab use was voluntarily suspended after reports of three cases (two in MS) of progressive multifocal leukoencephalopathy (PML), a rare viral infection not normally associated with MS. It is now licensed for monotherapy in the US and Europe, and current risk estimates for PML are 1/1000 over eight months. Licensing authorities and neurologists agree on the need to minimize this risk through careful patient selection and appropriate clinical vigilance for symptoms consistent with PML. The recommended procedures, outlined by Dr. Frank Fazekas, Medical University of Graz, Austria, and Dr. Ludwig Kappos, University Hospital Basel, Switzerland, include pretreatment patient screening for immunocompetence, monitoring for characteristic PML MRI lesions and, should suspicions remain, PCR of cerebrospinal fluid to confirm infection. Hand-in-hand with this, Dr. Kappos stressed that it is essential that patients be fully informed of the benefits and risks associated with their treatment program at all times.

Summary

Treatment for MS requires timely intervention to prevent subsequent progression of the disease beyond the point where disability progression becomes unstoppable. Monitoring with MRI can identify patients at risk of rapid progression, and the monoclonal antibody has a role to play in the treatment of such patients. The shared view of presenters was that the agent is a safe and highly effective addition to the MS arsenal. “I see potential for natalizumab treatment for patients who continue to relapse with IFNb therapy, and additionally as a first-line therapy for patients with a severe and aggressive presentation from onset,” Dr. O’Connor concluded.