BioWorld Today Contributing Writer

New Phase IIb results showed that Biogen Idec Inc.'s multiple sclerosis (MS) candidate, daclizumab high-yield process (DAC HYP), reduced the annualized relapse rate significantly compared to placebo and reduced disability progression by as much as 57 percent. Those results make DAC HYP potentially competitive with Tysabri (natalizumab), Lemtrada (alemtuzumab) and Gilenya (fingolimod). However, safety signals from the trial, including two deaths, may limit market potential for the drug.

Investors showed a scant reaction to the news: Biogen Idec's stock (NASDAQ:BIIB) gained $1.43, to close at $89.43 on Tuesday.

The SELECT randomized, double-blind, placebo-controlled trial design calls for around 600 test subjects with relapsing-remitting MS to receive once-monthly DAC HYP (150 mg, 300 mg) or placebo. Its primary endpoint is reduction in annualized relapse rate at one year.

Biogen Idec's top-line results showed that 150 mg DAC HYP, injected subcutaneously once every four weeks, significantly reduced the annualized relapse rate by 54 percent. In the 300-mg group, there was a 50 percent reduction in the relapse rate.

The trial results also track improvements in secondary endpoints. There was a statistically significant reduction in the number of new gadolinium-enhancing (Gd+) lesions between the eighth and 24th week of the study (69 percent vs. 78 percent), a reduction in new or newly enlarging T2 hyperintense lesions at one year (70 percent vs. 79 percent), a reduction in the proportion of patients relapsing (55 percent vs. 51 percent) and a trend toward improvement in the quality of life.

The SELECT trial had a tertiary endpoint that it explored as well. It demonstrated a reduction in risk of sustained disability progression, according to the expanded disability status scale (EDSS) at one year by 57 percent at the 150-mg dose level, and by 43 percent at the 300-mg dose level, compared to placebo.

Registration trials in MS typically look at two-year endpoints, according to Doug Williams, executive vice president of research and development at Biogen Idec. "The fact that we're seeing these results at one year is encouraging," Williams told BioWorld Today. "That's particularly true with the impact we saw on EDSS outcome." That result will require confirmation with another study.

Less encouraging were the safety results from the trial. There was a 2 percent incidence of serious infections, compared to 0 percent in the placebo arm, and a 1 percent rate of serious cutaneous events vs. 0 percent for placebo. Four percent of DAC HYP-treated patients had liver function test abnormalities greater than five times the upper limit of normal, compared to less than 1 percent for the placebo group.

There was one death in the SELECT trial resulting from an abscess in the psoas muscle. The SELECTION extension study has also recorded a death from autoimmune hepatitis. A contributory role for DAC HYP in those deaths could not be ruled out.

Williams said that results for serious infections and cutaneous events were "not a surprise" and were consistent with results they had seen in previous trials, including the Phase II CHOICE trial.

Analyst response was generally positive, but with reservations regarding the safety profile.

Deutsche Bank's Robyn Karnauskas lined up DAC HYP against Tysabri, finding that DAC HYP was not as effective as Tysabri for reducing relapses, but was better at reducing disability. She suggested that DNA testing could help find patients who would benefit most from the therapy. "We believe JCV-positive patients will opt for Dac due to convenience, stronger EDSS data and reduced risk of PML," Karnauskas wrote. "However, JCV negatives will opt for Tysabri due to strong relapse rate reduction."

Leerink Swann's Joshua Schimmer wrote, "It's premature to anticipate where in the MS treatment paradigm Daclizumab HYP may fit; as a potent, s.c. 1/month drug it offers clear advantages, but the risk of serious infections in the first Phase III trial could relegate it to a niche role in competing with SNY's (OP) Lemtrada for a small piece of the market."

Schimmer estimated $400 million to $500 million in peak sales for DAC HYP, taking a piece each from Lemtrada, Tysabri and Gilenya.

Mark Schoenebaum, of ISI Group, commented, "In our opinion, the safety profile of dac (which modulates T-cells) will not become entirely clear until the drug has been marketed for two to three years – thus, the sales ramp might be slower than some anticipate."

Piper Jaffray analyst Ian Somaiya expressed some optimism that the trial deaths may not be related to DAC HYP. "The serious cutaneous events (1 percent vs. 0 percent in placebo) are a concern given one patient death. However, we have learned that the patient death was attributed to ischemic colitis (obstruction of blood to intestine) and not to the rash."

DAC HYP's once-monthly subcutaneous injection dosing is expected to be an advantage. Patients can dose themselves at home, as opposed to visiting a doctor's office for an I.V. infusion of Tysabri, for example.

The Weston, Mass.-based company is currently enrolling for a Phase III registration trial (DECIDE) comparing DAC HYP to interferon beta-1 over two or three years of therapy.