Could This Biologic Drug Work in Patients Lacking Its Target?

NEW ORLEANS — Apparently it’s not necessary to have the protein that a monoclonal antibody is designed to bind for it to achieve a clinical benefit, if a study of patients with chronic urticaria can be taken at face value.

At the Cleveland Clinic, the condition was brought under complete control in seven patients after omalizumab (Xolair) was added to their treatment regimen — even though immunoglobulin E (IgE), the biologic agent’s target, was undetectable in these patients, reported Sara Ghannam, MD, an allergy fellow at the institution.

Six other chronic urticaria patients seemingly lacking IgE also received omalizumab, of whom three obtained initial relief followed by recurrence, while it had no effect on the other three, Ghannam said at a poster presentation at the American College of Allergy, Asthma, and Immunology (ACAAI) annual meeting.

Since the 54% success rate was lower than figures of “up to 80%” reported in omalizumab’s clinical trials, her group’s conclusion was that undetectable IgE could serve as a biomarker for lessened responsiveness in chronic urticaria.

But that still leaves the question of why more than half of the sample did seem to respond despite lacking the drug’s nominal target.

It’s true that the study had no placebo control (it came from a records review) and omalizumab was given open-label, and thus a placebo effect cannot be ruled out. But 54% is a hefty placebo effect, and Ghannam wasn’t ready to say that’s what the patients experienced. “There could definitely be a potential placebo component” was as far as she would go.

The study originated in an attempt to determine whether serum IgE testing could help individualize treatment for chronic urticaria, a condition in which patients develop itchy hives with no obvious allergic cause. While the literature suggests that omalizumab is effective in “up to 80% of patients,” Ghannam said, there is still the other 20%. She noted that no biomarker has been found to predict who will respond to omalizumab.

Omalizumab was FDA approved for chronic spontaneous urticaria in 2014; its label does not call for IgE testing before prescribing for this condition, although it’s recommended for establishing dosing when used for its other approved indications.

Ghannam and colleagues went looking in the Cleveland Clinic’s records for patients treated with omalizumab and who had serum IgE testing, explaining that it is not performed routinely before giving the drug.

In all, the researchers identified nearly 1,200 clinic patients who had undergone IgE testing for any reason and who showed undetectable levels. Of these, 13 had been diagnosed with chronic urticaria and received omalizumab for it. All patients were also receiving antihistamines (omalizumab is approved as an add-on treatment) and one patient was also receiving systemic corticosteroids. One patient had a concomitant diagnosis of immune deficiency. Mean omalizumab treatment duration was about 14 months.

They expected to find that patients with absent IgE responded poorly to omalizumab, but the 54% rate of complete control seemed to undercut that finding.

An ACAAI attendee offered his take on biomarkers for chronic urticaria: Jonathan Bernstein, MD, of the University of Cincinnati, said the 54% control rate in the IgE-minus patients was not much higher than the placebo response rates seen in clinical trials, which he said were in the 45% range.

He suggested to Ghannam that signals of autoimmunity might be a more profitable line of inquiry, such as low eosinophil and/or basophil counts, along with basophil activation testing. “I think you’re going to see a composite type of profile” with multiple markers, Bernstein commented.