Three monoclonal antibodies in development for relapsing-remitting multiple sclerosis show promise, but alemtuzumab (Campath) appears to be leading the pack, researchers reported here. Once-yearly alemtuzumab reduced relapse risk by 74% and risk of accumulation of disability by 71% compared with standard interferon (both P<0.0001), reported Alasdair Coles, Ph.D., of the University of Cambridge in England, and colleagues, here at the American Academy of Neurology meeting. The benefit continued for two years after the last dose in a subset of patients, according to three-year data from a randomized trial. Other monoclonal antibodies, including daclizumab (Zenapax) and rituximab (Rituxan, MabThera), also looked promising in studies presented here. However, the improvements with alemtuzumab were "probably greater than anything else that's currently on the market or any of the drugs that are being looked at," said Lily Jung, M.D., of the Swedish Neuroscience Institute in Seattle, who commented on the studies. The specific targets of the monoclonal antibodies may account for the differences, Dr. Coles said. Daclizumab is targeted against CD25 on T cells and rituximab is targeted to B cells, but alemtuzumab impacts both types of lymphocytes. "We think one reason why our efficacy is so much better than other more selective monoclonal antibodies is because it has this sort of broad range of action," he said. The phase II CAMMS223 trial included 334 patients with early, active relapsing-remitting disease. Participants were randomized to 44 mcg beta interferon-1a (Rebif) injections three times a week or to once-a-year treatment with either 12 or 24 mg intravenous alemtuzumab delivered every day for five days at baseline and then daily for three days at months 12 and 24. Cumulative relapse rates continued to diverge in favor of alemtuzumab through three years of follow-up for a 74% risk reduction (annualized relapse rate 0.10 versus 0.36, P<0.0001). The load of T2 lesions seen on MRI were reduced to a greater degree with the monoclonal antibody (-16.45 versus -13.3%, P=0.005) and T1 cerebral volume fell less with alemtuzumab as well (-0.5% versus -1.8%, P=0.049). The continued effects were notable because only 46 patients in the alemtuzumab groups received therapy at the 24-month stage. For most participants, dosing was suspended when one patient died of immune thrombocytopenic purpura (ITP) on treatment. ITP was seen in six of 216 patients on alemtuzumab and one of 107 patients on interferon, but all other cases were identified early and treated successfully if needed. Thyroid events were also elevated with the drug but could be monitored and easily treated, Dr. Coles said. Dr. Jung agreed that neither of the more serious adverse events were a deal breaker for the drug, because both can be monitored unlike the progressive multifocal leukoencephalopathy issues seen with natalizumab (Tysabri). Rather, she was impressed by the reversion of disability in the alemtuzumab group. Mean scores on the Expanded Disability Status Scale at three years decreased 0.39 points with the monoclonal antibody compared with an increase of 0.38 for the interferon group (P<0.0001). "We believe this to be unprecedented," Dr. Coles said. Long dosing intervals may be another advantage. Although patients will likely need two cycles of therapy, they may be able to go for three to five years thereafter without treatment, Dr. Coles said. "I think it's a significantly easier treatment for patients," Dr. Coles said. "That's potentially even more acceptable than a daily tablet because you can forget about your illness." For daclizumab, though, treatment will likely have to be given long term because of a rapid loss of efficacy after discontinuation, said Michael D. Kaufman, M.D., of the Carolinas Medical Center in Charlotte, N.C., and colleagues. Their phase II CHOICE study included 230 relapsing-remitting MS patients randomized to 20 weeks of treatment with beta interferon plus placebo, daclizumab 1 mg/kg, or daclizumab 2 mg/kg. For the previously reported primary endpoint findings, new or enlarged gadolinium-enhancing lesions were 25% fewer at 24 weeks with lower dose daclizumab and 72% fewer with the higher dose compared with placebo (3.6 and 1.3 versus 4.8, P=0.514 and P=0.004, respectively). However, these benefits faded within 10 to 20 weeks after stopping treatment. During the 48-week observation phase of the study, the number of new enhancing lesions seen on MRI at week 34 was not significantly different between treatments although there were 56% more with 1 mg/kg and 23% fewer with 2 mg/kg daclizumab compared with placebo (3.56 and 1.77 versus 2.29, P=0.22 and P=0.49, respectively). In another small study, rituximab reduced the frequency of inflammatory brain lesions and relapses through 72 weeks, reported Amit Bar-Or, M.D., of McGill University in Montreal, and colleagues. Their phase I, open-label trial included 26 patients with relapsing-remitting MS given in two courses of two 1,000-mg rituximab infusions six months apart. Patients had rapid, sustained B cell depletion through 48 weeks followed by partial recovery by week 72. Reductions in gadolinium-enhancing lesions and the number and volume of new T2 lesions were rapid, starting at week four, and sustained through week 72. Relapses were also reduced over 72 weeks compared with the year prior to study treatment. Although how these monoclonal antibodies will play out for clinical use remains to be seen, these findings suggest that alemtuzumab would be used as the initial therapy for newly diagnosed patients with the other agents serving as options for patients with a poor response to other therapies, Dr. Jung said. [Note that these studies were published as abstracts and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.]
