Roche's Lebrikizumab Shows Potential For Biomarker Targeting In Asthma

Phase II data published in NEJM show that biomarker-assisted therapies could be valuable in targeting the variabilities of the disease.

Roche Holding Inc.'s novel anti-interleukin 13 antibody lebrikizumab may have a key to unlocking the mystery of asthma in a biomarker that selects for IL-13, a regulator suspected of subverting the effects of inhaled corticosteroids on the disease.

Positive results from a Phase II proof-of-concept trial in adults whose asthma was inadequately controlled on glucocorticoids were published Aug. 3 in the New England Journal of Medicine.

Roche announced plans to advance the antibody into Phase III in its July 21 earnings report.

The trial, dubbed MILLY, was conducted by the Swiss pharma's Genentech division. It randomized 219 asthmatic adults to receive either the drug or placebo, but it also prespecified subgroups based on type 2 helper T-cell status and serum periostin level - a marker for activity of IL-13, a cytokine of Th2 cells that affects airway inflammation and mucus production.

At week 12, the mean increase in forced expiratory volume (the primary efficacy endpoint) was significant, with patients overall scoring 5.5 percentage points higher in the treatment group than for placebo (9.8% versus 4.3%) and 8.2 points (14% versus 5.8%) among patients in the high-periostin subgroup, lead author John Matthews, Genentech, reported. Patients receiving lebrikizumab in the low-periostin subgroup also did better than placebo, with an increase of 1.6 points (5.1% versus 3.5%).

Relative changes in FEV were evident after one week of treatment and were sustained throught the study, "indicating that inhibition of [IL-13] had a relatively quick effect on measures of airflow," the article notes.

The results "suggest that the prespecified marker, serum periostin, could potentially be used to identify patients with asthma who may have an increased response to lebrikizumab" and "suggest the potential importance of biomarkers in identifying patients who will have a response to specific therapies for asthma," the authors asserted.

At 24 weeks, a secondary endpoint, the difference between the study arms in the high periostin groups was not as wide, at 4.2 points, while the low periostin group had very similar results. Overall, patients taking lebrikizumab had a mean 8.4 percentage point gain in FEV, compared to 5.2 points for placebo.

There was a non-significant trend toward lower rates of severe exacerbations, requiring hospitalization or glucocorticoid therapy, among patients who took lebrikizumab, the authors reported.

Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% versus 5.4%), though the frequency of both adverse events and severe AEs was similar in the two groups, as was the number of discontinuations (13 for the drug and 12 for placebo).

A Phase II dosing trial, named MOLLY, completed enrollment in the third quarter of 2010, and Roche will present data from both trials at the European Respiratory Society's annual congress Sept. 24-28 in Amsterdam.

Roche set a goal in 2008 to become a leader in respiratory diseases, building on its experience with anti-inflammatory drugs (Also see "Roche Pushes Respiratory Agenda In Early Inflammatory Pipeline" - Pink Sheet, 24 Jun, 2008.). Other drugs currently aimed at asthma in the Roche pipeline are RG7185, a small-molecule CRTH2 antagonist in Phase I, and RG7449, an anti-M1 prime antibody in Phase II.

Altair Therapeutics, which was spun off of Isis Pharmaceuticals Inc. in 2007 with a license to develop ISIS 369645, an inhaled IL-4/Il-13 cytokine inhibitor for asthma, shut down in February of this year after the drug failed (Also see "Isis Spin-Off Altair Will Develop Antisense Asthma Candidate 369645" - Pink Sheet, 17 Oct, 2007.).

-Shirley Haley ([email protected])