US Food and Drug Administration (FDA) approved ZINBRYTA™ (daclizumab) as a new once-monthly injection for treating multiple sclerosis.
Daclizumab is a genetically engineered monoclonal antibody that binds to CD25, a receptor on T cells that is thought to become activated in response to MS. Daclizumab is believed to work by selectively targeting these activated T cells without causing general T-cell depletion. It is approved by the FDA for use in rheumatoid arthritis and other autoimmune diseases. Daclizumab high yield process (DAC HYP) is administered subcutaneously once every four weeks, rather than via intravenous infusion.
Participants in the Phase II CHOICE study had either RRMS or SPMS, with worsening disease activity while taking one of the approved interferon therapies. The study showed that DAC HYP was well tolerated when added to an interferon. A statistically-significant 72-percent reduction in the frequency of gadolinium-enhancing MRI lesions was seen in the high-dose group (300 mg every four weeks).
The Phase IIb SELECT trial, with 600 participants who have RRMS, was a one-year study of treatment with DAC HYP. This study was subsequently extended for a second year as the SELECTION trial. The study included three treatment arms, with two dose levels (at 150 mg and 300 mg) and a placebo group.
Results of the SELECT trial announced in August 2011 indicated that the annualized relapse rate was decreased by 54 percent in the 150-mg-dose group and by 50 percent in the 300-mg-dose group. It also met its secondary endpoints: the number of new gadolinium-enhancing lesions was reduced by 69 percent and 78 percent; the number of new or newly enlarging T2-hyperintense lesions was reduced by 70 percent and 79 percent; and the proportion of patients who relapsed was reduced by 50 percent and 51 percent. These results were all for the low- and high-dose groups respectively. Sustained disability progression at one year was reduced by 57 percent with the lower dose and 43 percent with the higher dose.
Participants who completed this trial were enrolled in an extended trial called SELECTION to evaluate long-term safety and efficacy. One-year results of the SELECTION trial were presented46 in 2012. Patients who were on placebo and began treatment with DAC HYP in the extension trial had a 59-percent reduction in annualized relapse rate compared to the year prior, while patients who continued on DAC HYP saw their low relapse rate from the prior year maintained.
In 2013, further data from this trial was presented;47 patients who received two years of treatment with DAC HYP in the SELECT trial and its one-year extension study, SELECTION, were evaluated to determine the rate of brain atrophy (brain-volume loss). During the second year of treatment, brain-volume loss was 27-percent lower in the treated groups compared with the placebo group at year one. The authors of the study note that this reduction in the rate of brain atrophy in people with MS may be consistent with neuroprotection.
DAC HYP was further studied in the DECIDE trial,48 a Phase III study of 1,841 participants with relapsing MS, comparing DAC HYP to Avonex. DAC HYP was admin-istered subcutaneously once every four weeks for 96 to 144 weeks in a dose of 150 mg. This was compared to a weekly 30-mcg intramuscular injection of Avonex. The study began in March 2010 and was completed in the spring of 2014. Outcome measures included relapse rate, functional decline, and disability progression, as well as quality of life.
Initial results of the DECIDE trial were presented in 2014.49 Treatment with daclizumab resulted in a 45-percent reduction in annualized relapse rate (ARR), a 54-percent reduction in new and newly enlarging T2 lesions, and a 65-percent reduction in new gadolinium-enhancing lesions in comparison to Avonex. Risks associated with daclizumab treatment included infections, rash dermatitis, and liver enzyme abnormalities, some of which were serious. More than a third of people on daclizumab reported cutaneous (skin) issues – twice as many as on Avonex – including some cases severe enough to warrant discontinuing the drug. One death in a daclizumab-treated patient from the Phase II study was due to complications of a muscle abscess, and a second death was due to autoimmune liver inflammation. The safety profile of this medication including the nature of the cutaneous side effects will be closely evaluated in further analyses of the Phase III trial.