MILAN – The therapeutic value of inhibiting the activity of IgE in patients with chronic spontaneous urticaria (CSU) was reinforced by two large phase 3 trials with ligelizumab, a drug characterized as a new generation anti-IgE monoclonal antibody.
Both doses of ligelizumab evaluated met the primary endpoint of superiority to placebo for a complete response at 16 weeks of therapy, reported Marcus Maurer, MD, director of the Urticaria Center for Reference and Excellence at the Charité Hospital, Berlin.
The data from the two identically designed trials, PEARL 1 and PEARL 2, were presented at the annual congress of the European Academy of Dermatology and Venereology. The two ligelizumab experimental arms (72 mg or 120 mg administered subcutaneously every 4 weeks) and the active comparative arm of omalizumab (300 mg administered subcutaneously every 4 weeks) demonstrated similar efficacy, all three of which were highly superior to placebo.
The data show that “another anti-IgE therapy – ligelizumab – is effective in CSU,” Maurer said.
“While the benefit was not different from omalizumab, ligelizumab showed remarkable results in disease activity and by demonstrating just how many patients achieved what we want them to achieve, which is to have no more signs and symptoms,” he added.
Majority of Participants With Severe Urticaria
All of the patients entered into the two trials had severe (about 65%) or moderate (about 35%) symptoms at baseline. The results of the two trials were almost identical. In the randomization arms, a weekly Urticaria Activity Score (UAS7) of 0, which was the primary endpoint, was achieved at week 16 by 31.0% of those receiving 72-mg ligelizumab, 38.3% of those receiving 120-mg ligelizumab, and 34.1% of those receiving omalizumab (Xolair). The placebo response was 5.7%.
The UAS7 score is drawn from two components, wheals and itch. The range is 0 (no symptoms) to 42 (most severe). At baseline, the average patients’ scores were about 30, which correlates with a substantial symptom burden, according to Maurer.
The mean reduction in the UAS7 score in PEARL 2, which differed from PEARL 1 by no more than 0.4 points for any treatment group, was 19.2 points in the 72-mg ligelizumab group, 19.3 points in the 120-mg ligelizumab group, 19.6 points in the omalizumab group, and 9.2 points in the placebo group. There were no significant differences between any active treatment arm.
Complete symptom relief, meaning a UAS7 score of 0, was selected as the primary endpoint, because Maurer said that this is the goal of treatment. Although he admitted that a UAS7 score of 0 is analogous to a PASI score in psoriasis of 100 (complete clearing), he said, “Chronic urticaria is a debilitating disease, and we want to eliminate the symptoms. Gone is gone.”
Combined, the two phase 3 trials represent “the biggest chronic urticaria program ever,” according to Maurer. The 1,034 patients enrolled in PEARL 1 and the 1,023 enrolled in PEARL 2 were randomized in a 3:3:3:1 ratio with placebo representing the smaller group.
The planned follow-up is 52 weeks, but the placebo group will be switched to 120 mg ligelizumab every 4 weeks at the end of 24 weeks. The switch is required because “you cannot maintain patients with this disease on placebo over a long period,” Maurer said.
Ligelizumab Associated With Low Discontinuation Rate
Adverse events overall and stratified by severity have been similar across treatment arms, including placebo. The possible exception was a lower rate of moderate events (16.5%) in the placebo arm relative to the 72-mg ligelizumab arm (19.8%), the 120-mg ligelizumab arm (21.6%), and the omalizumab arm (22.3%). Discontinuations because of an adverse event were under 4% in every treatment arm.
Although Maurer did not present outcomes at 52 weeks, he did note that “only 15% of those who enrolled in these trials have discontinued treatment.” He considered this remarkable in that the study was conducted in the midst of the COVID-19 pandemic, and it appears that at least some of those left the trial did so because of concern for clinic visits.
Despite the similar benefit provided by ligelizumab and omalizumab, Maurer said that subgroup analyses will be coming. The possibility that some patients benefit more from one than the another cannot yet be ruled out. There are also, as of yet, no data to determine whether at least some patients respond to one after an inadequate response to the other.
Still, given the efficacy and the safety of ligelizumab, Maurer indicated that the drug is likely to find a role in routine management of CSU if approved.
“We only have two options for chronic spontaneous urticaria. There are antihistamines, which do not usually work, and omalizumab,” he said. “It is very important we develop more treatment options.”
Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, agreed.
“More therapeutic options, especially for disease states that have a small armament – even if equivalent in efficacy to established therapies – is always a win for patients as it almost always increases access to treatment,” Friedman said in an interview.
“Furthermore, the heterogeneous nature of inflammatory skin diseases is often not captured in even phase 3 studies. Therefore, having additional options could offer relief where previous therapies have failed,” he added.
Maurer reports financial relationships with more than 10 pharmaceutical companies, including Novartis, which is developing ligelizumab. Friedman has a financial relationship with more than 20 pharmaceutical companies but has no current financial association with Novartis and was not involved in the PEARL 1 and 2 trials.
This story originally appeared on MDedge.com, part of the Medscape Professional Network.
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