The following article is a review of the current information about NAbs, as well as the great debate about what it all means. I will be providing more discussion at the end of the article on Page 5, as well as my Bottom Line.
This article, originally published in Applied Neurology and appearing on ConsultantLive.com, is made available to About.com users through a special collaboration with CMPMedica, publishers of this and other professional medical journals. For more information from journals your doctor may read, try searching on Search Medica, the search engine for medical professionals.
Neutralizing Antibodies to Interferon: Clinically Relevant to MS Treatment?
Article from Applied Neurology; October 01, 2005
Disease-modifying agents have been the mainstay of treatment for relapsing-remitting multiple sclerosis (RRMS) since the National Multiple Sclerosis Society Consensus Statement1 that recommended use of disease-modifying drugs was released in 1998.
The American Academy of Neurology,2 the Canadian MS Clinics Network,3 and an international consensus panel4 also have endorsed the use of disease-modifying agents for RRMS. These guidelines are continually updated as new information becomes available.5
The FDA has approved 4 immunomodulators: interferon (IFN) beta-1a intramuscular (Avonex, Biogen Idec), IFN beta-1a subcutaneous (Rebif, Serono and Pfizer), IFN beta-1b (Betaseron, Berles), and glatiramer acetate (Copaxone, Teva). In addition, mitoxantrone (Novantrone, Serono) has been approved as an immunosuppressant. Just how effective these drugs are in preventing attacks and slowing disease progression is not entirely clear. Despite compliance with disease-modifying-drug regimens, many patients still have relatively aggressive disease.
Would some exacerbations happen whether or not a patient was taking a medication? Are there some unknown biologic differences that account for patients doing poorly? Are attacks part of the normal waxing and waning of the disease? Is there something in the drugs themselves that prompts an adverse immune reaction that compromises their effectiveness in some individuals?
In looking for answers, investigators have been exploring immunology, genetics, molecular biology, and other factors. If these could be identified, they could help tailor available treatments. Better still, the researchers could tap this information to develop more targeted therapies that prevent attacks much earlier in the disease process than do today's disease-modifying treatments.
The search for molecular markers has been a very active area of research, according to Hillel Panitch, MD, professor of neurology at the University of Vermont in Burlington. "So far the only marker we have is MRI -- and that is pretty expensive," he said.
Numerous studies have been performed to evaluate the impact of neutralizing antibodies (NAbs) to IFN on clinical relapse, MRI relapse, and disability. The issue has been contentious, and neurologists have been debating it for close to a decade. In July, [i[Neurology published 2 research papers6,7 and an editorial8 that addressed the relationship between NAbs to IFN and relapse and disease progression outcomes. One of the articles published in [i[Neurology6 reported results of a post hoc analysis of the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial.9 When the manuscript was being prepared, the lead author, Gordon S. Francis, MD, was responsible for strategic direction and clinical development in neurology at Serono International, the manufacturer of Rebif. Francis is currently vice president of neurology at Elan Pharmaceuticals, a potential competitor.
The 2-year analysis of PRISMS trial data that examined the impact of NAbs to subcutaneous IFN beta-1a on clinical and MRI relapse revealed that use of IFN beta-1a correlated with significant positive outcomes.9 It also showed that the presence of antibodies was not associated with relapse. The 4-year reanalysis showed a different picture.6 Although similar relapse and disability rates were seen for patients who were either NAb-positive (NAb+) or NAb-negative (NAb2), once patients showed evidence of persistent NAbs, a decrease in pharmacodynamic response to IFN beta-1a developed and evidence of MRI relapse emerged.
Francis and his team found that the impact of NAb positivity was especially striking for MRI measures -- the study demonstrated that patients were functioning as well as they had been when receiving placebo. The impact on disability was less compelling. A one-point change in the Expanded Disability Status Scale was used to confirm clinical progression. Critics said that the impact on disability was marginal at best. In fact, it was only statistically significant (P < .03) for persons whose status was determined when the data were collected -- that is, for those with interval-positive status.
Francis acknowledged the study's limitations in documenting increasing disability. "The studies are really too short to show disability outcomes," he said. However, Douglas S. Goodin, MD, professor of neurology at the University of California, San Francisco, couched it differently: "The effect on disability was marginal at best."
Francis stressed that the findings pointed to the need for a change in treatment. "When you see that neutralizing antibodies limit the efficacy of interferon, keeping patients on interferon simply doesn't make biologic sense."