Daclizumab’s efficacy against MS tempered by adverse events

Two to three years of monthly subcutaneous injections of daclizumab HYP were more effective at reducing the relapse rate and the number of new or worsening brain lesions in patients with relapsing-remitting multiple sclerosis than were weekly intramuscular injections of interferon beta-1a in the phase III, randomized DECIDE trial.

However, the percentage of patients whose disability progressed after 12 weeks of treatment did not differ significantly between the group given daclizumab HYP and that given intramuscular interferon beta-1a (Avonex), and the rates of infection, cutaneous adverse effects, and liver-test abnormalities were higher with daclizumab HYP. “The enhanced efficacy was accompanied by an increased frequency of adverse events, such that the net clinical benefit will need to be carefully considered by patients and their providers,” wrote Dr. Ludwig Kappos of the Neurologic Clinic and Policlinic, departments of medicine, clinical research, and biomedicine and biomedical engineering, University Hospital Basel (Switzerland), and his associates.

Dr. Ludwig Kappos

Daclizumab HYP (high-yield process), a formulation of daclizumab developed for long-term subcutaneous administration, has less antibody-dependent cytotoxicity than do earlier formulations of the drug. The researchers compared the two therapies in 1,841 patients aged 18-55 years who were treated at 244 sites in 28 countries. These patients were randomly assigned in a double-blind fashion to receive either 150 mg daclizumab HYP every 4 weeks and intramuscular placebo once weekly (919 patients) or 30 mcg intramuscular interferon beta-1a once weekly and subcutaneous placebo every 4 weeks (922 patients) for 2-3 years. The median duration of treatment was 108.7 weeks for daclizumab HYP and 111.4 weeks for interferon beta-1a. Overall rates of treatment discontinuation and withdrawal from the study were similar between the two groups.

The primary endpoint of the study – the annualized relapse rate over 144 weeks – was significantly lower (by 45%) with daclizumab HYP (0.22) than with interferon beta-1a (0.39). This result was confirmed in two sensitivity analyses. In addition, the number of new or newly enlarged lesions on cranial MRI at week 96 was a significant 54% lower with daclizumab HYP than with interferon beta-1a, Dr. Kappos and his associates noted (N Engl J Med. 2015;373:1418-28. doi: 10.1056/NEJMoa1501481).

However, the percentage of patients whose disability progressed at 12 weeks, as measured by scores on the Expanded Disability Status Scale, was not significantly different between the daclizumab HYP group (16%) and the interferon beta-1a group (20%), nor was the percentage of patients free from relapse at week 144 (67% vs. 51%). The proportion of patients who reported clinically meaningful worsening of the physical impact of MS, as measured by the physical subscale score of the 29-item Multiple Sclerosis Impact Scale, also was not significantly different between the two study groups (19% vs. 23%).

The overall incidence of adverse events was 91% in both groups, and there was no between-group difference in the rate of clinically significant hematologic abnormalities. However, patients receiving daclizumab HYP were significantly more likely to report developing infections (65% vs. 57%); serious infections (4% vs. 2%); or cutaneous events such as rash, eczema, seborrheic dermatitis, acne, erythema, and pruritus (37% vs. 19%). More patients discontinued daclizumab HYP because of adverse events, excluding MS relapses (14% vs. 9%).

In addition, hepatobiliary disorders developed in 3% of patients given daclizumab HYP and 2% of those given interferon beta-1a. Liver enzyme elevations more than five times the upper limit of normal occurred in twice as many patients taking daclizumab HYP (6%) than in patients taking interferon beta-1a (3%).

“Long-term follow-up studies will continue to be important in assessing the treatment effects of MS therapies on disability progression, because studies of even 2-3 years’ duration capture only a small fraction of the lifelong treatment that most patients with MS will require,” Dr. Kappos and his associates added.