Ligelizumab May Improve Response in Chronic Urticaria

Diana Phillips

October 03, 2019

In the fight against chronic hives, the humanized anti-IgE monoclonal antibody ligelizumab may pack a more powerful punch than omalizumab (Xolar, Genentech), the previous top contender for trapping IgE antibodies for patients with chronic spontaneous urticaria (CSU).

A small international trial compared the efficacy and safety of the two drugs relative to placebo in patients with CSU whose condition had not responded to standard-of-care therapy, including H1 antihistamines, report Marcus Maurer, MD, of the Department of Dermatology and Allergy, Charité–Universitätsmedizin Berlin, Germany, and colleagues.

The researchers found that ligelizumab, which was tested at two different doses, was associated with complete symptom control in a higher percentage of patients compared with omalizumab or placebo. The findings were published online today in the New England Journal of Medicine.

Currently, multiple international guidelines recommend omalizumab as an add-on third-line therapy for patients whose condition does not respond to second-generation H1 antihistamines at locally approved doses, which is considered first-line treatment, or to escalation up to four times the approved dose, which is off-label second-line treatment, the authors note.

Although add-on therapy with omalizumab has proven effective for many patients, not everyone's condition responds. Previous research has shown that ligelizumab binds to IgE with greater affinity than omalizumab and thus may have a stronger treatment effect, they explain.

To compare the drugs, the researchers conducted a multicenter, double-blind, placebo-controlled, clinical trial (phase 2b) that involved 382 patients whose CSU was refractory to antihistamines and, in some cases, to leukotriene receptor antagonists. The patients were randomly assigned to receive either subcutaneous injections of omalizumab (300 mg), ligelizumab (24 mg, 72 mg, or 240 mg), or placebo every 4 weeks for 20 weeks. In addition, one group of patients received a single 120-mg dose of ligelizumab at week 0 followed by placebo every 4 weeks to test duration of effect.

The primary endpoint was demonstration of a dose-response relationship for achieving a complete response at week 12, which was defined as a weekly hives-severity score of 0. "The dose–response curve showed a steep dose-response relationship with a plateau starting close to the 72-mg dose of ligelizumab," Maurer and colleagues report. They note that no further improvement in response was associated with the 240-mg dose.

Secondary endpoints included rates of complete response of hives at weeks 12 and 20 with ligelizumab doses of 24 mg, 72 mg, and 240 mg compared with 300 mg of omalizumab and placebo; the comparative mean changes from baseline in the weekly hives-severity score, the weekly itch-severity score, the weekly urticaria activity score, and the weekly angioedema activity score; and the comparative safety of ligelizumab relative to 300 mg of omalizumab and placebo during the 20-week treatment period and 24 weeks of follow-up.

A secondary endpoint was complete control of hives at week 12. This was achieved by 30%, 51%, and 42% of the patients treated with 24 mg, 72 mg, and 240 mg of ligelizumab, respectively. In contrast, only 26% of the patients in the omalizumab group and no patients in the placebo group achieved this outcome.

In addition to a higher response rate, ligelizumab appeared to work quickly. "[R]esponses according to changes from baseline in the weekly hives-severity score, itch-severity score, and urticaria activity score were observed as early as week 4 after receipt of the 72-mg, 120-mg, and 240-mg doses of ligelizumab, thus indicating an onset of action within this time frame for ligelizumab," the authors write.

Time to relapse after treatment discontinuation was longer with ligelizumab. On average, relapse occurred 10 weeks after the last injection, compared with 4 weeks after the last injection of omalizumab.

The percentage of patients in the the single-dose group who had a complete response was similar to that observed with the 72-mg and 240-mg doses. The effect lasted 8 weeks, which suggests that ligelizumab may need to be administered be less frequently than omalizumab, the authors report.

Side effects for both biologic drugs were generally similar, although more adverse events, including mild or moderate injection-site reactions and mild injection-site erythema, were observed in patients who received the 72-mg and 240-mg doses of ligelizumab than in the other groups, the authors write.

Serious adverse events were reported in 7%, 2%, and 2% of the patients treated with 24 mg, 72 mg, and 240 mg of ligelizumab, respectively, as well as in 4% of the patients treated with omalizumab and 9% of those who received placebo. No patients died or developed anaphylaxis during the trial.

The authors note that the response rate in the omalizumab group at week 12, as determined on the basis of the weekly urticaria activity score, was lower than in previous studies (34% to 44%). They hypothesize that this might be because more patients in this trial had CSU that contained an autoimmune type IIb component.

Although the findings are favorable for ligelizumab, both in terms of a clear dose-response relationship for achieving complete hives response and for rapid and sustained symptom control, "[l]arger and longer trials are needed to establish the clinical efficacy of ligelizumab in patients with chronic spontaneous urticaria and its comparative profile with that of omalizumab," the authors write.

David M. Center, MD, from the Boston University Clinical and Translational Science Institute and the Boston Medical Center, agrees. "Although ligelizumab appears to be a better IgE trap than omalizumab, many questions remain," he writes in an accompanying commentary. A better understanding of which patients are most likely to benefit from the newer agent is needed, and it's not yet clear how the available treatment should best be sequenced.

"These questions await greater clinical experience with the drug and larger trials," Center writes. "However, an anti-IgE therapy that induces remission in more patients with a longer interval between administration of the drug is much appreciated and should gain clinical popularity. We all await better understanding about the causes of chronic spontaneous urticaria as we search for good predictive markers for responses to therapy."

The research was supported by Novartis Pharma. Several authors report financial relationships with Novartis. A full list of disclosures can be found on the journal website. Center has disclosed no relevant financial relationships.

N Engl J Med. Published online October 3, 2019. Abstract, Editorial

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