Positive phase 3 trial results of alemtuzumab support the need for early aggressive treatment of multiple sclerosis, Alastair Compston, MBBS, PhD, professor of clinical neurosciences at Cambridge University, said. But, he noted, that clinicians would need to weigh the benefits against potential safety risks.
ALEMTUZUMAB, the first fully humanized monoclonal antibody, works peripherally to disable circulating T and B cells.
BOSTON—Positive results from two recently completed phase 3 trials indicate that early treatment of multiple sclerosis (MS) with the monoclonal antibody alemtuzumab is significantly better than standard interferon treatment at reducing relapses in most patients for at least two years. But the treatment comes with a risk of provoking another, less serious autoimmune disease in up to 25 percent of patients.
As the MS therapeutic armory is poised to become yet more powerful, is it time for early aggressive therapy to become the standard of care? That argument was made by Alastair Compston, MBBS, PhD, professor of clinical neurosciences at Cambridge University, who discussed the results of the new trials here at the American Neurological Association annual meeting in October.
Alemtuzumab, the first fully humanized monoclonal antibody, works peripherally to disable circulating T and B cells, leading to profound and prolonged changes in the immune system. It was first tested in MS patients with advanced disease beginning in 1991, but after eight years, Dr. Compston said, the most important lesson “was that we did nothing whatsoever to help the disease, despite that the antibody more or less completely stopped inflammation within the brain. Practically without exception, patients continued to deteriorate from the disease they had at the time we treated them.”
That realization supported the growing notion that MS really comprises two distinct disease processes. “In the early stages, there is a great deal of inflammation and very little neurodegeneration, but as the disease moves forward into the progressive stage, the situation is reversed, and is predominantly a degenerative disease with little inflammation. So it followed, then, that the error we had made was to treat the disease too late,” he said.
DR. ALASTAIR COMPSTON: “In the early stages, there is a great deal of inflammation and very little neurodegeneration, but as the disease moves forward into the progressive stage, the situation is reversed, and is predominantly a degenerative disease with little inflammation. So it followed, then, that the error we had made was to treat the disease too late.”
That led Dr. Compston and colleagues to try using the drug much earlier, with much better results. “The majority of patients became stable or improved,” he said. In a recent follow-up analysis after a median of seven years treatment, half the original patients remained better than baseline, and 10 percent were unchanged. Of the remaining 40 percent, the majority had declined only slightly.
A phase 2 trial followed, which enrolled patients within three years of disease onset. Patients were randomized to daily interferon beta-1a (Rebif), or to two treatments of alemtuzumab, one given at baseline and the other at 12 months. After two years, alemtuzumab was superior to interferon in reducing relapses, disability progression, and imaging markers, the investigators reported in a 2008 paper in The New England Journal of Medicine.
That set the stage for the current phase 3 studies, called CARE-MS1 and CARE-MS2. Patients in the first trial were within three years of diagnosis and drug-naive, while those in the second trial were within 10 years of diagnosis, and had already had at least one relapse on a first-line therapy. In both trials, as in the phase 2 trial, patients were randomized to either daily interferon beta 1-a or two annual treatments with alemtuzumab.
In the first trial, alemtuzumab reduced the annualized relapse rate by 55 percent compared with interferon beta-1a, a highly significant difference. Eight percent of alemtuzumab patients, and 11 percent of interferon beta-1a patients, had sustained accumulation of disability, a non-significant difference that Dr. Compston attributed to an unexpectedly low level of disease activity in the interferon group, based on historical data. The number of alemtuzumab patients with gadolinium-enhancing lesions and new or enlarging hyperintense T2 lesions was modestly but significantly less, and brain volume loss was 40 percent less, than for interferon-treated patients.
In the second trial, alemtuzumab reduced the annualized relapse rate by 55 percent, the risk of sustained accumulation of disability by 42 percent, gadolinium lesions by 60 percent, T2 lesions by 32 percent, and brain volume loss by 20 percent — all strongly significant differences compared with interferon beta-1a.
DR. STEPHEN HAUSER: “We need biomarkers to use at an individual level, which may offer more nuanced information on individual risk. I think we are very close to that.”
Taken all together, Dr. Compston said, the results of the phase 2 and phase 3 studies show “broad superiority” over interferon beta-1a. However, he was quick to acknowledge that superior efficacy comes with risks.
The reconstitution of the immune system after alemtuzumab treatment evolves over years, he explained, “and it is just short of a decade before an individual will recover to their pre-treatment levels” of T and B cells. In the meantime, about 25 percent of patients develop autoimmune thyroid disease, which can be treated if necessary with a thyroidectomy and thyroid supplements. In the 40,000 person-years of experience with alemtuzumab so far, a few patients have developed more serious autoimmune diseases, including Goodpasture's syndrome and autolytic hemolytic anemia, leading to one death.
These conditions usually develop in the second year of treatment, and are likely due to an imbalance in the timing of cellular recovery. “What we want to see is a reconstitution that is represented by thymic cells, but that is sluggish,” Dr. Compston said. “What we see is the expansion of memory cells, bringing back some of the immune history of the individual.” Chance reaction of some of these expanding memory cells with antigens gives rise to the autoimmune disorder. Work is underway to better characterize this process, and to identify genetic factors that may predict which patients are most at risk for it.
“When we began in 1991, there were no treatments for multiple sclerosis,” he said. Shortly thereafter, the beta interferons were introduced, which proved very safe, but with less than satisfactory efficacy. The expectation in the field was that the trajectory in treatment development would be to maintain safety while improving efficacy. But that has not been the case, Dr. Compston said. Instead, treatments have been developed with “much greater efficacy but at the expense of much greater risk.” The consequence is that “we now have to have a debate” on how to balance the two, especially in regard to treatment initiation.
“I think everything we have learned about treating multiple sclerosis over the last 25 years around this program, makes clear that one has got to nail it early. Waiting five, ten, or fifteen years before using a highly effective therapy is not in the patient's interest,” Dr. Compston said. Safety concerns complicate the decision, but gradual escalation, the usual practice today, “is falling into the trap of waiting until the inflammatory process is in a sense waived, and you are dealing with an irretrievable degenerative disorder.”
“I have believed in early aggressive treatment for a long time,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco, in an interview with Neurology Today. The challenge, though, is how to advise the individual patient, especially one who is young, with minor signs and symptoms. “Do we commit a youngster like that to a major-gun therapy?” he asked, or hope that safer, less effective treatment will be sufficient? “We need biomarkers to use at an individual level, which may offer more nuanced information on individual risk. I think we are very close to that,” he said.
In praising the data from the two trials as “very exciting,” Dr. Hauser also noted how “reliably predictive” the phase 2 data were in forecasting the outcome of the phase 3 trials. “It shows how professional we are these days in performing trials. This could let us ask whether we could incorporate phase 2 designs in phase 3 studies,” using surrogate outcomes that could greatly speed drug development and reduce cost, he said.
• Coles AJ, Fox E, Compston DA, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. 2012;78(14):1069–1078. E-pub 2012 Mar 21.