LYON, France — New trial results show that extending treatment with daclizumab (DAC) to 2 years in patients with relapsing multiple sclerosis (MS) has a beneficial effect similar to that of an earlier 1-year trial and that no rebound disease activity occurred after a 24-week washout period.

"This trial confirms the high efficacy of daclizumab, and that this efficacy was sustained in the population that received the drug for 2 years," said lead author Gavin Giovannoni, PhD, professor, neurology, Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine, United Kingdom.

However, the study uncovered some serious adverse events, including immune-mediated events and 1 death.

Dr. Giovannoni later told Medscape Medical News that the adverse events seen by the study are important in terms of moving forward with this drug. "It means that if the drug gets through phase 3, it will come with increased monitoring. As always, it will depend on the risk/benefit ratio and for the latter we need the phase 3 results."

The study, which included 517 patients, was presented here at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Placebo to Treatment

DAC is a humanized monoclonal antibody that selectively binds to and inhibits CD25, a receptor subunit that is expressed at high levels on T cells thought to be abnormally activated in MS. Researchers believe that daclizumab does not cause T-cell depletion.

Last year at this meeting, main results of the phase 3 SELECT trial were presented, and reported by Medscape Medical News at that time. The researchers, led by Dr. Giovannoni, reported that compared with placebo, both 150-mg and 300-mg doses of DAC high-yield process (Biogen Idec/Abbott) reduced annualized relapse rates by around 50% and reduced disability in patients with relapsing MS.

In the SELECTION study, an extension of the SELECT trial, patients who had been receiving placebo in the earlier trial were randomly assigned to 1 of 2 doses of the subcutaneous formulation of DAC (150 mg or 300 mg).

Those who had been receiving active treatment at either of 2 doses, administered once every 4 weeks, were randomly assigned to a 24-week washout period followed by active treatment or to continuous active treatment for a second year. 

In patients who shifted from placebo to active treatment, the annualized relapse rate was reduced by almost 60% compared with year 1 (59%; P < .001).

Although this could be due to regression to the mean, "it is more than you would expect for regression to the mean," said Dr. Giovannoni. "In other trials, you don't see much regression to the mean in year 2 compared to year 1."

In this placebo-to-active treatment cohort, the 3-month confirmed disability progression was reduced from 10% (17 patients) in year 1 to 5% (7 patients) in year 2. In this group, there were a 74% reduction in new and enlarging T2 lesions on magnetic resonance imaging and an 86% reduction in gadolinium-enhancing lesions.

In the patients who were receiving active treatment in the first year who continued this treatment for another year, the annualized relapse rate in year 2 was similar to that in year 1 (66% compared with the placebo group in year 1; 62% versus placebo in year 2).

The reduction in new or enlarging T2 lesions appeared to be slightly stronger in year 2 of daclizumab therapy compared with year 1 (79% reduction in year 1 vs 88% in year 2 in the high-dose group; 76% and 83%, respectively, in the low-dose group), and this difference was significant, said Dr. Giovannoni.

Washout Effect

As for the effect of the washout period after which daclizumab therapy was reintroduced, the study found an increase in the number of new gadolinium lesions, but this didn't return to the level seen at the start of the study (baseline mean, 1.2 in the high-dose group and 1.9 in the low-dose group). At 32 weeks after the drug was restarted, the mean number of lesions was 0.2 in both groups.

"In the washout phase, there was no evidence of rebound above baseline," said Dr. Giovannoni. "I think it's important to note that when the drug is restarted, the lesions are suppressed."

Researchers chose a period of 24 weeks for the washout because when daclizumab is stopped, it takes about that length of time for the number of CD56 NK cells to return to baseline, explained Dr. Giovannoni. "I wouldn't imagine that you’d ever allow a patient with active MS to be washed out for more than 6 months, so the 24 weeks was chosen pragmatically, to get information about whether or not there’s a rebound."

The researchers also looked at safety of this therapy. There were some serious adverse events, including immune-mediated events. Excluding relapses, "this rate was in the region of 5-8%," said Dr. Giovannoni.

Dr. Giovannoni reported that about 2% of patients taking daclizumab developed serious infections (the rate was similar to that in the SELECT trial) but stressed that these were not opportunistic infections. The rate of cutaneous events was about 1%, which again was similar to that in the earlier trial. Liver function test results were lower in the second year (1.5% vs 4%).

There was 1 death, from autoimmune hepatitis in a patient in the DAC 300-mg washout group, that was reported last year. "This death unfortunately occurred prior to us knowing about the hepatotoxicity" associated with daclizumab and wasn't part of the strict monitoring that was later put in place, he said.

"We feel that if this particular individual had been picked up earlier and treated more aggressively," there would have been a different outcome.

Increased Monitoring

Dr. Giovannoni also reported on pharmacodynamic outcomes. Cell populations seemed to take up to a year to increase and plateaued in year 2, a finding that may be important, he said. "This suggests that maybe the drug takes over a year to reach its maximum effect."

Responding to a query from the audience about whether the number of CD56 cells is low in this patient group to begin with and the therapy "normalizes" that number, Dr. Giovannoni pointed to extensive literature suggesting that there is a defect in the cell population and that daclizumab and other MS therapies increase that cell population.

Other delegates were concerned about clinical relapses during the washout period. Dr. Giovannoni.noted that the lack of good baseline data makes it difficult to compare the relapse rate during the washout to that in other periods.

However, he told Medscape Medical News that his research team plans to do another analysis comparing the data from the washout with data at baseline by using a paired analysis, which should provide additional information on relapses.

This study was supported by Biogen Idec and Abbott Biotherapeutics Corp. Dr. Giovannoni has received research grant support from Bayer Schering Healthcare, Biogen Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and sanofi-aventis and personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer Schering Healthcare, Biogen Idec, Eisai, Elan, Five Prime Therapeutics, Genzyme, Genentech, GSK, Ironwood Pharma, Merck Serono, Novartis, Pfizer, Roche, sanofi-aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals.

28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Paper 169. Presented October 13, 2012.

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