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Thursday, September 25, 2014

Understanding Daclizumab - another MS Medication on the Horizon for FDA approval

Phase 3 results show that daclizumab reduces disease activity in relapsing-remitting multiple sclerosis by half compared with interferon, as measured by brain imaging, with skin and other side effects. The drug works in surprising ways that are revealing new details about the pathogenesis of MS.

Three might be the lucky number for daclizumab, an investigational drug for relapsing-remitting multiple sclerosis (RRMS) with broad and unexpected immune effects.

Under the brand name Zinbryta (Biogen Idec/AbbVie), a newly patented version of the drug, called daclizumab high-yield process, or DAC HYP, recently captured headlines after researchers presented more efficacy and safety results from the phase 3 clinical trial (Kappos et al., 2014).

The unpublished results seem to sustain expectations that daclizumab may be as effective as the best MS drugs now approved but with lower risk (Pfender and Martin, 2014). Meanwhile, researchers have identified at least three ways the drug works to counter MS, a finding that is illuminating new details in disease pathology and may lead to novel therapeutic strategies (Bielekova, 2013Pfender and Martin, 2014).

The phase 3 study, called DECIDE, is “a pivotal trial,” said Ellen  Mowry, M.D., M.C.R., a neurologist at Johns Hopkins University in Baltimore, Maryland. She cited the notable drop in disease activity as measured by relapses, MRI, and disability progression, compared to a popular older drug, interferon β-1a (Avonex, Biogen). She also noted daclizumab’s signature skin side effects as well as a small increase in serious infections.

Ludwig Kappos, M.D.
Ludwig Kappos, M.D.
Daclizumab “deserves to be approved and to be one of the options” available to people with MS and their physicians, said Ludwig Kappos, M.D., chair of neurology and head of the MS Research Group at University Hospital Basel, Switzerland, and lead investigator for DECIDE. The relative effectiveness of the drug could be “at least” at the level of fingolimod (Gilenya, Novartis) or dimethyl fumarate(Tecfidera, Biogen), Kappos speculated in an interview with MSDF. He cautioned that results of this and other drug studies cannot be compared directly, due to differences in design, selection criteria, and other details.

Kappos presented the DECIDE findings earlier this month at MSBoston2014, shorthand for the joint meeting of the Americas and European committees for treatment and research in multiple sclerosis (ACTRIMS-ECTRIMS), held September 10-13 in Boston. In the closing session, Mowry cited the findings as a clinical research highlight of the meeting.

Other meeting reports confirmed and extended some of the surprising ways daclizumab pulls the strings of the immune system. One of the new mechanisms of action has shown promise as an early biomarker of how the drug is working.

In another finding from the meeting, an analysis of samples from blood and cerebrospinal fluid suggests that daclizumab nudges the abnormal numbers of innate and adaptive immune cells in RRMS back to more normal physiological levels found in people without MS (Lin et al., 2014).

Top-level clinical findings

The double-blind phase 3 DECIDE trial pitted monthly injections of daclizumab against weekly interferon injections in people with RRMS for a minimum of 2 years. Each group received placebo injections of the other drug. A little more than 1,800 people started the 2-year DECIDE study. About two-thirds were women. On average, participants had had RRMS for about 4 years and mild disability of about 2.5 on the Expanded Disability Status Scale. About 30% dropped out for various reasons, mostly because of adverse events and lack of efficacy.

In the main finding, daclizumab reduced the annualized relapse rate by nearly half compared to interferon. Translated to an evidence-based medicine figure called “number needed to treat,” each patient on daclizumab had a 1-in-5.6 chance of having fewer relapses. In secondary endpoints, several brain imaging techniques also showed about half the new and enlarging lesions in the daclizumab treatment arm compared to interferon (Arnold et al., 2014).

Many of the top findings were reported in a press release in June. A new 6-month analysis presented at the meeting showed a slightly lowered risk of disability progression. Another new graph showed a reduction, although not statistically significant, in patient-reported physical decline (Kappos et al., 2014).

Skin and other side effects

The opposite trend was true with daclizumab’s distinctive side effect: skin adverse events, mostly rash and inflammation. More than one-third of people on daclizumab reported cutaneous issues, twice as many as in the interferon group, including some cases severe enough to discontinue the drug. The skin effects were independent of the injection site and were mostly manageable by corticosteroid creams, Kappos said.

Both groups had similar rates of injection site pain, about 10%, and daclizumab came out ahead on influenza-like illness, with 10% compared to 37% of people in the interferon group (Selmaj et al., 2014).

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