SAN DIEGO – Emerging skin and liver issues mean that daclizumab, a humanized monoclonal antibody in phase III testing for relapsing-remitting multiple sclerosis, likely will be a second-line agent if approved by the Food and Drug Administration, predicted Dr. Gavin Giovannoni, a neurology professor at the University of London.
There’s been one death from autoimmune hepatitis; researchers now monitor liver values monthly. There also have been a low number of serious cutaneous events, although no cases of Stevens-Johnson syndrome have been reported.
"Because of the skin reactions and the liver, I can’t see it coming out as a first-line drug for people with relapsing-remitting MS," Dr. Giovannoni said. It might prove to be a good alternative to natalizumab, he added, noting that daclizumab, if approved, likely would be on the market in 2016.
"If you don’t develop the skin reactions and the liver problem – if you get through that hurdle – the tolerability of this drug is very good," he said in an interview.
So far, daclizumab appears to be particularly good at slowing MS progression.
"It’s having a real impact on progression. Subanalysis of people with just minor relapses still got an impact on progression. The way this drug works is by boosting the innate immune system, so its impact on progression is out of proportion to its impact on relapses," he said.
That finding was confirmed in 2-year data that Dr. Giovannoni presented at the annual meeting of the American Academy of Neurology.
In that study, 170 patients who were on placebo during the first year were randomized to monthly 150 mg or 300 mg subcutaneous injections during the second year. The 52-week annualized relapse rate (ARR) was reduced by 59% among the former placebo patients who began taking daclizumab during year 2, compared with those who remained on placebo during year 2 (0.18 vs. 0.43; P less than .001), and the proportion of patients with confirmed 3-month disability progression was reduced by 50% (5% vs. 10%; P = .033).
The study included an additional 347 patients who spent the first year on daclizumab and were randomized to either continue their dose or resume it after a 24-week treatment interruption.
Those who stayed on the agent after the first year maintained their ARR in the second year (0.148 vs. 0.165) and had fewer new/newly enlarging T2 lesions (1.2 vs. 1.85; P = .032); 88% were free of confirmed disability progression at the end of 2 years. The treatment-interruption group showed no evidence of disease rebound.
The incidence of serious infections was about 2% in both years, and the incidence of serious cutaneous events was similar (1.1% vs. 1.0%). Aspartate aminotransferase/alanine aminotransferase elevations five times above the upper limit of normal were less common among daclizumab treated patients in year 2 (1.5% vs. 4%).
"The efficacy of [daclizumab] was sustained through the second year of therapy and the safety profile was similar in years 1 and 2," the researchers, led by Dr. Giovannoni, concluded.
He said the autoimmune hepatitis death, which occurred in the 300-mg treatment-interruption group, could have been caught in time and prevented with routine liver function monitoring.
There was also a case of asymptomatic glomerular nephritis in the trial that resolved when daclizumab was stopped, and one case of ulcerative colitis, which can’t be pinned on the drug because MS patients are at risk for inflammatory bowel disease, he said.
The skin problems "present on their own because the patients report them," he noted.
The study was funded by Biogen Idec and Abbott Biotherapeutics. Dr. Giovannoni disclosed personal compensation and research funding from Biogen, among other companies.