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Investigators reported that in a placebo-double-blind trial ocrelizumab — a humanized monoclonal antibody that binds to and inactivates B cells — was superior to interferon beta 1a, but they said the findings should be considered “exploratory,” rather than definitive.
DR. STEPHEN HAUSER (left) in the lab with Pierre-Antoine Gourraud, PhD, at the University of California, San Francisco.
Ocrelizumab reduces multiple sclerosis (MS) lesions not only better than placebo, but also better than interferon beta 1a, according to a new phase 2 study of over 200 patients with the relapsing-remitting form of the disease.
The two-part trial, reported in the Oct. 31 online edition of The Lancet, compared ocrelizumab to placebo in a double-blind fashion, and with interferon beta 1a given open label. The results regarding superiority of ocrelizumab to interferon beta 1a should thus be considered “exploratory,” rather than definitive, according to lead study author Ludwig Kappos, MD, chair of neurology at University Hospital in Basel, Switzerland. But, he added, “the differences were so clear-cut” that the conclusion is justified.
Stephen Hauser, MD, chair of the neurology department at University of California, San Francisco, was the senior author of the study.
Ocrelizumab is a humanized monoclonal antibody that binds to and inactivates B cells. The results of the study further support a central role for B cells in MS pathogenesis, a role first confirmed through trials of a related antibody, rituximab.
Both ocrelizumab and rituximab deplete B cells by binding to CD20, a B-cell surface receptor. Unlike rituximab, derived from a chimera of human and mouse DNA, ocrelizumab is “humanized,” derived from DNA much closer to the human sequence. This difference is intended to reduce the risk of development of an immune reaction to the antibody.
DR. LUDWIG KAPPOS said the specificity of ocrelizumab's cytotoxic effect compared with other agents, such as mitoxantrone, “is really an advantage, because it allows us to preserve the potential for regeneration” in the CNS, even while depleting B cells.
“The results largely support what was seen with rituximab,” according to Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Cleveland, OH. “That was such a novel observation, it is reassuring the same thing was seen with a related monoclonal antibody.” Dr. Cohen was not involved in the study.
The trial enrolled 220 patients, ages 18 to 55 years, with relapsing-remitting disease. Patients were randomized into one of four arms: placebo, 600 mg ocrelizumab, 2000 mg ocrelizumab, or interferon beta 1a. Patients enrolled in the interferon beta 1a arm self-administered standard weekly intramuscular injections of the drug. Patients in the other three arms received intravenous infusions of either placebo or ocrelizumab on days 1 and 15.
Had the investigators chosen a double-placebo structure for the trial, Dr. Kappos said, patients in those three arms would have had to receive weekly placebo injections, a burden they chose not to impose at this stage in the drug's development. The primary endpoint was the total number of gadolinium-enhancing T1 lesions at weeks 12, 16, 20, and 24. All raters were blinded to treatment status, including for patients on interferon beta 1a.
All but two patients received at least one treatment, and were analyzed. Four patients in the low-dose, and seven patients in the high-dose ocrelizumab group, along with three patients in the interferon beta 1a group, discontinued treatment during the trial.
Ocrelizumab reduced the total number of enhancing lesions by 89 percent and 96 percent for the low-and high-dose groups, respectively, compared with placebo. No lesions were seen in 77 percent of those on low-dose ocrelizumab, 83 percent of those on high-dose ocrelizumab, 35 percent of those on placebo, and 48 percent of those on interferon beta 1a. The corresponding figures for number of relapses in each group were 5 percent, 7 percent, 30 percent, and 17 percent. For each comparison, the p value for each ocrelizumab dose versus placebo was less than 0.0001. The combined results suggest the two doses were equivalent, Dr. Kappos said.
Serious adverse events were equally spread among the four treatment arms, except that one patient in the high-dose ocrelizumab group developed a systemic inflammatory response syndrome (SIRS) and died at week 14 of the study. Because of several intervening factors, including the possibility of an underlying genetic disorder and a recent exposure to bee venom, “there is some uncertainty whether the death was related to treatment, or was due to circumstances that had nothing to do with treatment,” Dr. Kappos said. “Based on this unfortunate event, I don't see anything we can do in a different way.”
At the end of the 24-week double-blind trial, all patients received open-label ocrelizumab. Patients in both the placebo- and interferon-treated groups had reduced disease activity after switching, similar to that observed in the ocrelizumab groups already in the first 24 weeks, Dr. Kappos said. This “further support the advantage regarding efficacy” of ocrelizumab over interferon beta 1a. The magnitude of the benefit, however, is still not clear, given the open-label nature of the comparison, he said.
BINDING OF MONOCLONAL antibody to CD20 on the surface of a B cell
The results strengthen the case that B cells are important in the MS inflammatory process, and that targeting CD-20 on the surface of B cells with ocrelizumab is a potentially valuable therapeutic strategy. But the rapid reduction in disease activity from ocrelizumab treatment indicates that the effect is not by stopping the production of antibodies. Antibodies are very long-lived in the circulation, so that even after loss of B cells, they continue to exert an effect. Instead, Dr. Kappos suggested, inhibition of other B cell actions, including antigen presentation and cytokine release, may account for the benefit of treatment.
He also noted that the specificity of ocrelizumab's cytotoxic effect compared with other agents, such as mitoxantrone, “is really an advantage, because it allows us to preserve the potential for regeneration” in the CNS, even while depleting B cells.
Nonetheless, there are ongoing safety concerns about the use of anti-CD20 therapies, including ocrelizumab. Rare cases of opportunistic infections, including JC virus, have been reported in patients treated with ocrelizumab in other diseases, including lupus, rheumatoid arthritis, and lymphoma. Trials in the former two conditions were halted due to safety concerns, including patient deaths in the arthritis trial.
In their manuscript, Dr. Kappos and colleagues noted that patients in that trial were also receiving concomitant immunosuppressants. While the significance of the death in the MS trial is still unclear, it is likely to increase concerns about the risk/benefit ratio for ocrelizumab.
“This was a well done study, and the magnitude of benefit was very impressive,” said Dr. Cohen of the Cleveland Clinic. “The results largely support what was seen with rituximab,” which also targets CD-20. There are some reasons to think ocrelizumab may have some advantages over rituximab, he said. “It is hard to compare across studies, but there were some suggestions of some advantages. It is somewhat more potent and less immunogenic, meaning repeated dosing may be less likely to generate immunity to the antibody.”
One concern with both molecules is the long duration of effect, and therefore the prolonged time that would be needed to recover B cell function should a problem occur. “Where ocrelizumab fits in the treatment of MS will depend on that balance between efficacy and safety concerns,” he said.
Ocrelizumab now joins a large handful of other emerging therapies for relapsing-remitting MS that are moving closer to regulatory approval, including other monoclonal antibodies and oral therapies. In addition, the first oral therapy, fingolimod, is now on the market, and better risk stratification is likely to mean natalizumab will be more widely used. The effect on the MS treatment landscape is likely to be profound, Dr. Cohen said. “There will still be a population in whom the currently available injectables are appropriate, but I think their use is going to decrease dramatically in the next few years.”
Soon, he said, “We are going to have a pretty broad armamentarium to treat the inflammatory aspects of the disease, so the next big thing is going to be strategies to repair damage, and we are just starting to move into that,” with neurotrophic factors and stem cell strategies leading the way. These may be especially beneficial in progressive MS, he said, for which little is currently available.