Top-line results from a Phase IIb trial of Biogen Idec Inc./Abbott Laboratories Inc.'s daclizumab in relapsing-remitting multiple sclerosis are impressive, but data from an ongoing Phase III trial may clear up lingering questions about the drug's safety profile.

In the one-year, 600-patient SELECT trial, daclizumab met its primary endpoint of lowering the relapse rate, met key secondary endpoints and posted a surprising effect on disability progression, a tertiary endpoint, compared to placebo, the firms announced Aug. 9. But it is the safety data, including liver toxicity and two deaths, that have analysts holding back.

While the efficacy data are "impressive" and daclizumab's once-a-month self-injections would provide a dosing convenience, "the unmet need in MS is for strong efficacy, desirable dosing, and good safety," UBS Investment Research analyst Matthew Roden, pointed out in same-day comments on the SELECT data.

The overall incidence of adverse events and discontinuations were similar across study arms, the companies reported. However, 2% of patients in the treatment arms experienced a serious infection compared to none for placebo, serious cutaneous events were reported by 1% of the treatment group versus none on placebo, and "liver function test abnormalities greater than five times the upper limit of normal" occurred in 4% of patients taking daclizumab versus less than 1% of the placebo arm.

One of the deaths was due to a complication of a muscle abscess in a patient recovering from a serious skin adverse event and the other, which occurred during an extension study, was due to possible autoimmune hepatitis, the companies said.

"Despite encouraging efficacy, safety could be a matter of concern and needs a closer look, in our view," J.P. Morgan analyst Geoff Meacham concluded.

Getting the complete safety picture might take a while, though. In fact, it might not be entirely clear until daclizumab has been on the market for two to three years, ISI analyst Mark Schoenebaum observed. In the meantime, "the sales ramp might be slower than some anticipate," he said in a note to investors.

SELECT is designated a registrational trial, as is the Phase III DECIDE, which is comparing daclizumab to interferon-beta 1a over two to three years of treatment in 1,500 patients. It is expected to wind up in January 2014, and both the companies and analysts are looking to those results for clarification and confirmation.

Daclizumab Is A Contender On Efficacy

Meanwhile, daclizumab's annualized relapse data projects it into the efficacy category now occupied by Biogen/Elan Corp. PLC's Tysabri (natalizumab), Novartis AG's oral drug Gilenya (fingolimod), and Biogen's oral hopeful BG-12, which has demonstrated good efficacy and a clean safety profile (Also see "Biogen Idec's BG-12 Results Up The Ante In The Oral MS Market" - Pink Sheet, 21 April, 2011.).

Daclizumab significantly reduced the annualized relapse rate by 54% in the 150 mg arm (p=0.0001) and by 50% in the 300 mg arm (p=0.0002) -a dosing option that was not carried into Phase III. And on disability progression, measured by the expanded disability status scale, daclizumab reduced the risk of sustained disability progression at one year by 57% in the 150 mg dose and by 43% with 300 mg.

Both dosing arms also reportedly produced a "highly statistically significant" reduction, though no p-values were provided, in the cumulative number of new gadolinium-enhancing lesions between weeks 8 and 24 (69% and 78%, respectively), compared to placebo.

The number of new or newly enlarging T2 hyperintese lesions at one year was reduced by 70% and 79%, respectively, and the number of relapses was reduced by 55% and 51%, respectively.

All good news for the MS contender, which works by binding the CD25 receptor on abnormally activated T cells. Clinical data show an increase in the number of CD56 bright natural killer cells, which target activated immune cells, with daclizumab.

Daclizumab's efficacy data might even support its use ahead of Tysabri, Deutsche Bank analyst Robyn Karnauskas hypothesized in a research alert. The 57% progression reduction bests Tysabri's 47%, though Tysabri is better at reducing relapses, she said, adding that disability reduction is becoming the more used value.

In fact, Karnauskas suggests daclizumab might become an option for patients who test positive for JC virus, which is thought to be linked to progressive multifocal leukoencephalopathy, the rare but deadly brain disease that has dogged Tysabri. "We believe JCV-positive patients will opt for [daclizumab] due to convenience, stronger EDSS data, and reduced risk of PML," while "JCV-negatives will opt for Tysabri due to strong relapse rate reduction."

In addition to safety data, Karnauskas is looking to Biogen/Abbott to release a subset analysis on CD56 bright NK cells, which could be a biomarker for daclizumab. Patients with higher counts of CD56 bright natural killer cells respond better to daclizumab, she noted, adding that the biomarker could be used to help identify the right patient population.

Biogen had hoped to have information about testing for JCV status added to Tysabri labeling in the last round of PML-related revision (Also see "U.S. Tysabri Labeling Updated With More PML Risk Info But No Reference To JCV Testing" - Pink Sheet, 22 April, 2011.).

The companies said complete SELECT data would be reported in an upcoming scientific forum, possibly as a late-breaker at the October ECTRIMS meeting in Amsterdam.

Cladribine, Merck KGaA's oral contender, also falls into the highly efficacious category, but its NDA was dealt a "complete response" letter by FDA in March because of safety questions. The agency is seeking further study data to better size up the drug's risk-benefit profile and the company is counting on data from three ongoing studies to fill that need (Also see "Merck KGaA Pins Cladribine Hopes On Ongoing Studies After Complete Response Letter" - Pink Sheet, 2 March, 2011.).

-Shirley Haley (s.haley@elsevier.com)

Daclizumab Has Winning Efficacy In MS, But Safety Questions Linger

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