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BOSTON -- Daclizumab HYP cut relapse rates and disability progression in multiple sclerosis patients more effectively than interferon beta-1a (Avonex) in a phase III trial, but the liver toxicity seen in earlier studies with the interleukin-2 inhibitor remained an issue, researchers said here.

In the 1,841-patient DECIDE trial, patients with relapsing-remitting disease assigned to daclizumab HYP -- the letters stand for high yield process, distinguishing the drug from an earlier formulation sold as Zenapax for preventing organ transplant rejection -- had a 45% lower annualized relapse rate compared with those receiving the interferon product (95% CI 35-5%-53.1%), reported , of University Hospital Basel in Switzerland.

Also, the risk of 6-month sustained disability progression was lower by 27% (P=0.033) in those receiving daclizumab, Kappos told attendees at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, held jointly this year with its North American counterpart.

By every other efficacy measure included in the study, including MRI lesion counts and overall burden, daclizumab was either significantly superior or no worse than interferon beta-1a, according to the data Kappos presented.

Safety Still a Concern

But the adverse event data failed to dispel concerns that the drug is seriously hepatotoxic that emerged in earlier studies.

A separate poster presentation by the DECIDE investigators on the safety results indicated that more patients in the daclizumab arm developed alanine aminotransferase elevations to greater than five times the upper limit of normal -- 53 versus 30 in the interferon group. Elevations to more than 10 times the upper limit of normal were seen in 24 patients receiving daclizumab and 11 in the interferon group.

Also, seven of the daclizumab patients developed the combination of alanine and aspartate aminotransferase elevations above three times the upper limit of normal plus total bilirubin twice the upper limit of normal, compared with one in the interferon arm.

The risk of these abnormalities was still low -- more than 900 patients received daclizumab in the trial -- and only one daclizumab patient was determined by an independent committee to meet criteria for , as was one in the interferon arm.

But serious cutaneous reactions were also more frequent with daclizumab, seen in 14 patients versus one receiving interferon, although none were diagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis. Infections were also somewhat more common in the daclizumab arm.

Overall, serious adverse events excluding MS relapses totaled 141 in the daclizumab group versus 88 with interferon (P not reported). About 30% of both groups discontinued during the study -- adverse events were the most common reason given in the daclizumab group, accounting for half of all withdrawals.

Kappos pointed out that this was a 3-year trial. "For this length of study, I think this is a reasonable discontinuation rate," he said.

, of the Cleveland Clinic, who is scientific program chair for the meeting, said the safety issues were "concerning" but would not necessarily sink the drug's chances with regulators or clinicians.

"My view is that, if it's approved, it will be a useful addition to our armamentarium," said Cohen, who was not involved with the trial. The hepatic and skin effects "will have to be sorted out [in placing] where it will be in the sequence of medications," he added, noting that he would not consider it a first-line option.

Study Details

Daclizumab binds to the high-affinity alpha subunit of the CD25 receptor for interleukin-2, providing a partial blockage of signalling in this pathway, since the cytokine can still bind to a different intermediate-affinity part of the receptor complex, Kappos explained.

The net effect is to inhibit activated T cell responses, promote proliferation of so-called CD56^bright natural killer cells, and normalize inducer cell counts in lymphoid tissue, he said. This action helps to quiet immune attacks on foreign tissue (hence the organ transplant rejection indication) and also attacks on self tissues, such as in MS.

Patients from 28 countries participated in the current trial, with North and South America, Eastern and Western Europe, and India represented.

To qualify, patients had to be 18-55 years old, with scores on the Expanded Disability Status Scale of no more than 5, and at least two relapses within the past 3 years and at least one in the past 12 months.

Daclizumab was administered once monthly subcutaneous injection. Interferon was dosed weekly by intramuscular injection at 30 mcg. This was a double-blind, double-dummy trial, hence patients in each arm also received a placebo injection on the schedule of the other arm.

Patients were followed for 144 weeks with periodic MRI scans and clinical evaluations for relapses and EDSS scoring.

Key efficacy results were as follows:

• Annualized relapse rate: 0.216 for daclizumab, 0.393 for interferon (P<0.0001)
• Proportion relapse-free at 144 weeks: 67% for daclizumab, 51% for interferon (overall risk reduction 41%, P<0.0001)
• New and newly enlarging T2 lesions at 96 weeks: 4.3 for daclizumab, 9.6 for interferon (P<0.0001)
• Proportion with 6-month sustained disability at 144 weeks: 13% for daclizumab, 18% for interferon (P=0.033)
• Change in MS Functional Composite score at 96 weeks, median z-score: 0.091 for daclizumab, 0.055 for interferon (P=0.0007)
• Mean annualized change in brain volume, week 24-96: 0.52% for daclizumab, 0.56% for interferon (P<0.0001)

Kappos noted that, among other secondary outcomes, there was a significant benefit for daclizumab in performance on the 25-foot walk test and in the nine-hole peg test -- the latter assessing hand function, which is often neglected in MS drug studies.

Daclizumab HYP "has the potential to have a favorable benefit-risk profile as a once-monthly subcutaneous injection for relapsing MS," Kappos concluded, calling the safety issues "manageable with standard monitoring and medical interventions."

CORRECTION: This article, which was originally published Sept.12, 2014, at 10:30 a.m., has been corrected (Sept.12, 2014, at 19:00 p.m.).

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