Efficacy of the investigational drug lebrikizumab is maintained in patients with moderate to severe atopic dermatitis for at least 1 year, according to new results from the phase 3 ADvocate1 and ADvocate2 trials.
“We’re focused on the responders,” said Andrew Blauvelt, MD, MBA, as he presented the positive findings at the European Academy of Dermatology and Venereology (EADV) 2022 Annual Meeting.
Responders were the 291 people whose atopic dermatitis greatly improved after an initial 16 weeks’ treatment with lebrikizumab in both trials and who were then randomly allocated to receive injections every 2 weeks (Q2W, n = 113) or every 4 weeks (Q4W, n = 118), or to receive placebo injections Q2W (n = 60).
“Very interestingly, for me, the Q4W maintenance dosing was just as good as the Q2W maintenance dosing,” said Blauvelt, president of Oregon Medical Research Center in Portland.
“Another highlight of these data is that the patients who went on to placebo, about 50% of the patients maintained good responses, despite no treatment from week 16 to week 52,” he added.
Most patients did not require topical steroids, and “there were no surprises here” in terms of the safety profile. Lebrikizumab, a monoclonal antibody, binds to soluble IL-13 and blocks IL-13 signaling.
“So, the study really shows that specific targeting of IL-13 with lebrikizumab, either Q2W or Q4W, has high maintenance of efficacy and is reasonably tolerated and safe in adolescents and adults with atopic dermatitis,” Blauvelt concluded.
“We know now that IL-13 is a critical cytokine in AD [atopic dermatitis] pathogenesis,” Blauvelt said. “The unique features of this drug I want to highlight is that it has high binding affinity for IL-13,” Blauvelt said.
“It has a slow dissociation off rate, meaning it binds IL-13 tightly, very potently, and stays blocking and stays hold of IL-13 in a strong manner,” he added. The drug has a half-life of 25 days.
These features could be very important for long-term dosing of the drug, he argued.
Lebrikizumab Phase 3 Trials
ADvocate-1 and ADvocate-2 are two of several phase 3 trials evaluating the efficacy and safety of lebrikizumab for the treatment of atopic dermatitis.
These include the completed ADhere study, in which lebrikizumab was used in combination with topical steroids and showed positive results in skin improvement and relief of pruritis.
The ADore study, an open-label trial in adolescents, is yet to report. The ongoing ADjoin study, a long-term extension study, is actively recruiting.
ADvocate1 and ADvocate2 are two identically designed ― multicenter, randomized, double-blind, placebo-controlled, parallel-group ― monotherapy trials that initially pitched two dosing regimens of lebrikizumab (250 mg) against placebo with a double loading dose at baseline and week 2 and then one dose every 2 weeks. The pair of trials enrolled a total of 869 adolescents and adults.
After the 16-week induction period, all patients in the lebrikizumab arm who had responded to treatment were re-randomly assigned to receive lebrikizumab 250 mg every 2 weeks (Q2W) or every 4 weeks (Q4W), or placebo Q2W during a 36-week long-term maintenance treatment period.
This brought the total treatment time to 52 weeks for those whose atopic dermatitis had initially responded to lebrikizumab, explained Blauvelt.
Responders were those who, at 16 weeks, had an Investigator’s Global Assessment score of 0 or 1 (IGA 0/1) with a 2-point improvement or who had a 75% improvement in the Eczema Area and Severity Index score (EASI75) without the need for rescue medication compared to baseline values.
Induction and Maintenance Phase Results
At the end of the 16-week induction period, a greater proportion of patients who had been treated with lebrikizumab than placebo met a primary outcome of IGA 0/1 in each trial (43.1% vs 12.7% in ADvocate-1 and 33.2% vs 10.8% in ADvocate-2).
A similar result was seen for another primary outcome, EASI75 (58.8% vs 16.2% and 52.1% vs 18.1%) and for a secondary outcome, improvement in pruritis using a numerical rating scale (45.9% vs 13.0% and 39.8% vs 11.5%).
In the maintenance phase, with respect to responders, Blauvelt reported “very similar results” between the QW2 and Q4W maintenance dosing, “and still a quite high response in [half] the patients who were randomized to placebo at week 16.”
In the ADvocate1 and ADvocate2 trials, respectively, an IGA 0/1 with a ≥2 point improvement was maintained at week 52 in 75.8% and 64.6% of patients treated with the every-2-week lebrikizumab dose, 74.2% and 80.6% of those treated with the every-4-week dose, and 46.5% and 49.8% of those given placebo.
EASI75 was maintained at week 52 in a respective 79.2% and 77.4% of patients treated with the 2-week dose, 79.2% and 84.7% with the 4-week dose, and 61.3% and 72.0% with placebo.
As for maintenance of at least a 4-point improvement in pruritis score, results at 52 weeks were 81.2% and 90.3% for the 2-week dose, 80.4% and 88.1% for the 4-week dose, and 65.4% and 67.6% for placebo.
Although topical corticosteroid treatment was allowed during the maintenance phase, only about 15% of patients needed this, Blauvelt said.
Different Dosing Results Questioned
During the discussion period, one delegate highlighted that the twice-weekly maintenance dosing schedule seemed to “do worse a little bit” than the 4-week dosing, with both “close to placebo,” although “the long-term effect is already very impressive.”
Blauvelt noted that a pooled analysis had been done and that “it’s very clear that being on lebrikizumab works better than not being on lebrikizumab.
“Now, Q2W vs Q4W. We believe that this may be due to the long half-life of the drug possibly. It could be due to the slow disassociation rate, it’s binding tightly,” Blauvelt suggested.
“We also could talk about disease modification, right. So, it opens up the concept of hit hard, hit early for 16 weeks, and then maybe you can modify disease over time,” Blauvelt said.
He added: “That’s highly speculative, of course.”
Short-term Safety Data
The 52-week safety profile of lebrikizumab is consistent with previously published data at 16 weeks, Blauvelt said. The most common adverse events during the studies included atopic dermatitis, nasopharyngitis, conjunctivitis, conjunctivitis allergic, headache, and COVID-19.
“This drug has comparable efficacy with dupilumab and tralokinumab,” said Jashin J. Wu, MD, FAAD, from the Dermatology Research and Education Foundation in Irvine, California, in an interview with Medscape Medical News. He was not involved in the study.
“As it does not have any significant advantages with less long-term safety data, I do not see a place for it in my practice,” Wu said.
Dupilumab (Dupixent) and tralokinumab (Adbry) are monoclonal antibodies that also block IL-13. Both are already licensed for treating atopic dermatitis. Dupilumab was approved by the US Food and Drug Administration in 2017, and tralokinumab was approved in 2021.
The study was funded by Demira, a wholly owned subsidiary of Eli Lilly and Company. Eli Lilly has exclusive rights for the development and commercialization of lebrikizumab in the United States and all countries outside Europe; European rights belong to Almirall, SA, for all dermatology indications, including atopic dermatitis. Blauvelt acts as an investigator and advisor to these companies as well as many other pharmaceutical companies that are involved in developing new dermatologic treatments. Wu has been an investigator, consultant, or speaker for multiple pharmaceutical companies.
European Academy of Dermatology and Venereology (EADV) 2022 Annual Meeting: Late-breaking oral presentation 3456. Presented September 8, 2022.
Sara Freeman is a freelance journalist based in London, England.
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