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B-CELL REMOVAL SUGGESTED THERAPY FOR MS

ARTICLE IN BRIEF

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In early studies, rituximab depleted circulating B cells, which was associated with reduced disease activity.

Two preliminary studies add to the growing body of evidence supporting the role of B-cell depletion as a treatment strategy for multiple sclerosis (MS). In both studies, described in April at the AAN annual meeting in Chicago, rituximab (Rituxan) depleted circulating B cells, which was associated with reduced disease activity.

Rituximab is a chimeric antibody, comprising a hybrid human and murine sources, directed at CD-20-expressing B cells.

As a result of these studies, there is an emerging recognition of the importance of B cells in a disease that was previously presumed to be mediated largely by T cells, said Amit Bar-Or, MD, whose lab has been involved in much of this research. Dr. Bar-Or is associate professor of neurology and neurosurgery at McGill University School of Medicine and director of the Experimental Therapeutics Program at the Montreal Neurological Institute in Canada.

“After a decade or so of using rituximab for the treatment of B-cell lymphoma, it may have a role in removing B cells in autoimmune disorders, including MS,” he told Neurology Today.

“On one hand, B cells can become plasma cells that secrete damaging antibodies, but B cells can also activate the immune system and regulate responses of other immune cells, including T cells,” Dr Bar-Or explained. “While rituximab efficiently depletes B cells, it does not directly target plasma cells, since the latter do not express the CD-20 molecule.”

Studies thus far show that the benefit of rituximab is seen quite early; new disease activity is reduced by eight weeks — as evidenced by new gadolinium-enhancing lesions on brain MRI. This early onset of action suggests that the benefit of B-cell depletion is not simply related to the removal of potentially harmful antibodies.

“We think that B-cells also participate in MS in antibody-independent ways and are currently investigating those mechanisms,” he said.

PHASE 2 STUDY

At the meeting, Dr. Bar-Or presented follow-up pharmacokinetic and pharmacodynamic data from a 48-week phase 2 safety study of rituximab in relapsing-remitting MS; 24-week results were reported at last year's AAN annual meeting. Sixty-nine patients were assigned to rituximab and 35 to placebo, and the groups were matched at baseline for age, sex, and disease duration. The average age was 40 years, 75 percent were women, and symptom-duration was six to seven years from diagnosis. The main endpoint was new disease activity according to MRI criteria and clinical relapse rate. “The study was not powered to assess effects on progression of disability,” he explained.

Patients were treated with one course of rituximab (two infusions of 1000 mg of intravenous rituximab two weeks apart) and followed for 48 weeks. The average half-life of rituximab following the second infusion was 21 days, which is similar to studies of patients with rheumatoid arthritis, suggesting that MS patients metabolize the drug similarly to patients with other autoimmune disorders. In all treated patients, a single course of rituximab achieved a near-complete (greater than 99 percent) abrogation of circulating B cells, associated with significant reductions in new and clinical and imaging measures of MS disease activity.

Dr. Bar-Or noted that the B cells started to repopulate around six months after treatment, and that based on assays, they determined that most new B-cells were naïve based.

“As B cells repopulate, disease activity does not appear to return to pre-treatment levels. It is therefore possible that naïve B cells are less harmful than memory B cells,” he said. He added the caveat however, that by week 48 the B cells were not yet fully back to their baseline number, and it may therefore be too early to tell. “By week 48, B cells were reconstituted to around 30 percent of the baseline level, and most of them were naïve B cells,” he said.

Treatment with rituximab did not seem to change the frequency or number of circulating T cells or natural killer cells, consistent with the notion that immune cell depletion with rituximab is selective for B cells.

Five percent of treated patients had decreases in immunoglobulin (IgG) antibodies (typically associated with longer-term memory) below the limit of normal, and 10- to 15-percent had decreases in IgM antibodies (typically associated with shorter term memory) below the limit of normal. There was no evidence that these decreases in circulating antibodies led to more side effects or adverse events, he said. By week 48, 24 percent of treated patients developed human antichimeric antibodies (HACA) against rituximab. However, no relationship was observed between the development of HACA and safety or efficacy measures.

PHASE 1 STUDY

This open-label study was longer than the phase 2 study and had fewer patients. Twenty-six patients with relapsing-remitting MS were treated with two courses of rituximab (week 0 and week 2, and then again at week 24 and 26). After the second course of treatment, they were followed for an additional 48 weeks, for a total of 72 weeks. Characteristics of the patient population were similar to those in the phase 2 study.

Over 72 weeks, all patients experienced some adverse events. No serious adverse events (or grade 4 events) were reported. Only one patient discontinued the drug due to an adverse event (headache), which occurred after the third infusion. Grade 3 adverse events included muscle weakness (one), fatigue (one), headache (three), and tooth fracture (one). The other adverse events were all mild to moderate.

Most adverse events (reported in 65 percent of patients) appeared to be infusion-related. These included headache, chills, lowered blood pressure, and throat irritation. Infusion-associated adverse events tended to decrease in frequency over time. At week 0, 42 percent of patients experienced some adverse events with the first infusion and at week two, adverse events occurred in only 15 percent. At week 24, 19 percent of patients reported some adverse events with the first infusion and at week 26, only 8 percent had adverse events. “These decreases in the infusion-associated adverse events suggest that the body is getting used to the drug, rather than developing an allergic response to it,” Dr. Bar-Or noted.

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DR. AMIT BAR-OR said that as a result of these studies, there is an emerging recognition of the importance of B cells in a disease that was previously presumed to be mediated largely by T cells.

“Follow-up studies of B-cell depletion in MS are being planned,” Dr. Bar-Or said. “Investigators in the field are moving forward with enthusiasm.”

WHY USE A CHIMERIC ANTIBODY?

In a separate interview, Patricia Coyle, MD, professor of neurology and acting chair at Stony Brook University Medical Center in New York, was enthusiastic about the concept of B cell therapy for MS, which has come to the forefront over the past few years. The preliminary data in relapsing-remitting MS show clear activity for rituximab, she said, and results of another recently completed phase 2 trial of rituximab in primary progressive MS are “eagerly awaited.”

Dr. Coyle, who was not involved with the study, raised some concerns about the high rate of HACA that developed with only short-term use of rituximab, however. MS is a chronic disease requiring life-long therapy, she said, and 24 percent of patients developed HACA by week 48 in the phase 2 trial reported by Dr. Bar-Or.

“Although the investigators did not document any problems with HACA, the high rate raises a red flag that the antibodies might block the action of rituximab over time,” she said.

In the case of natalizumab (Tysabri), another humanized monoclonal antibody approved for treatment of RRMS, persistent neutralizing antibodies were shown to block the efficacy of the drug in MS patients, as well as raise the risk of infusion-related reactions. It follows, then, that similar antibodies could compromise the efficacy of rituximab as well.

She noted that a less immunogenic monoclonal antibody is in the early phases of development by Genentech for lupus and rheumatoid arthritis, but no studies have yet been done in MS.

She added, however, that going forward with a new anti-CD-20 monoclonal antibody would require that all the preliminary studies done with rituximab be repeated with the new drug, which may be a disincentive for the drug company.

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