Across all doses, lebrikizumab showed significant dose-dependent improvement in primary study endpoints for improvements in atopic dermatitis, according to data from phase 2b trials.
In phase 2b, lebrikizumab (Eli Lilly and Company) achieved rapid, dose-dependent improvement across a range of atopic dermatitis (AD) metrics. These findings suggest a central role for interleukin (IL)-13 in the pathophysiology of AD, investigators add.
Lebrikizumab is a novel high-affinity monoclonal antibody targeting IL-13 that selectively blocks the IL-13 receptor α1 (IL-13Rα1) and IL-4Rα heterodimer signaling complex.
“Importantly,” says Emma Guttman-Yassky, M.D., Ph.D., “it leaves intact the endogenous IL-13 regulation through the IL-13 receptor α2.” She is the Clara Kest Professor and Vice Chair of Dermatology at the Icahn School of Medicine at Mount Sinai in New York. She co-authored a February 26 JAMA Dermatology publication of phase 2b results and presented these data during the AAD VMX Virtual Meeting Experience 2020, June 12-14.1,2
The clinical success of dupilumab (Dupixent, Sanofi and Regeneron), an FDA-approved anti-IL-4Rα monoclonal antibody for moderate-to-severe AD, underscores the importance of type 2 immune cytokine activation in AD pathophysiology. However, dupilumab’s inhibition of downstream signaling of both IL-4 and IL-13 make it impossible to discern which cytokine plays a more central role. Based on lebrikizumab phase 2b and other data, Dr. Guttman-Yassky and colleagues suggest that IL-13 may be the essential pathogenic mediator in AD, and that targeting it alone may achieve therapeutic responses.
Investigators randomized a total of 280 patients with moderate-to-severe AD to placebo or one of three lebrikizumab regimens:
Across all doses, lebrikizumab showed significant dose-dependent improvement in the primary endpoint, with mean week 16 reductions in Eczema Area and Severity Index (EASI) scores of 72.1% for the highest dose, 69.2% for the 250 mg every four-week dose, 62.3% for lebrikizumab 125 mg every four weeks and 41.1% for placebo.
Similar to the EASI numbers, 70% of patients at the highest dose experienced pruritus numeric rating scale (NRS) score reductions of at least four points, versus 27.3% on placebo (P<0.001). For all three doses, least-squares mean pruritus NRS reductions from baseline ranged from 35.9% to 60.6%. Conversely, pruritus scores in the placebo arm improved until week six, and then gradually worsened until week 16 (mean increase 4.3%).
For patients on lebrikizumab, improvement in pruritus started early. By day two, a combined 10.5% of patients on both 250 mg doses achieved at least four-point NRS reductions.
“And this continues until day seven, where already 30% of patients at the highest dose have at least four-point improvement in pruritus NRS,” she says.
Similarly, week 16 sleep NRS scores at the highest dose fell more than 60%, versus 20.2% for placebo.
“And all the drug arms show major, statistically significant changes, whereas the change in the placebo arm is not significant at week 16,” Dr. Guttman-Yassky says.
Mean Patient-Oriented Eczema Measure (POEM) scores ranged from a 12.4-point reduction from baseline at the highest drug dose versus a 5.8-point reduction for placebo.
“Even the lowest dose shows a major improvement (-8.9 patients) compared to placebo,” Dr. Guttman-Yassky says.
Mean Dermatology Life Quality Index (DLQI) scores declined by approximately 8 to 10 points among actively treated patients, versus 5.9 points for placebo. Additionally, 39% of patients at the highest dose had week 16 DLQI zero or one, versus 16.7% of placebo-treated patients. Patient global assessment scores followed a similar pattern.
Consistent with previous studies, lebrikizumab was well-tolerated — 2.7% of patients at the highest dose experienced moderate conjunctivitis. Ongoing phase 3 studies will further examine this adverse effect.
“But so far,” says Dr. Guttman-Yassky, “lebrikizumab has achieved a very good safety profile.” Dermira expects topline phase 3 findings in the first half of 2021.
Dr. Guttman has received research funds (grants paid to Mount Sinai) from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boerhinger Ingelheim, Celgene, Dermavant, DS Biopharma, Eli Lilly, Glenmark, Galderma, Innovaderm, Janssen, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, Regeneron, Sienna Biopharma, UCB and Union Therapeutics. She is also a consultant for AbbVie, Almirall, Amgen, Asana Biosciences, AstraZeneca, Boerhinger Ingelheim, Cara Therapeutics, Celgene, Concert, DBV Technologies, Dermira, DS Biopharma, Eli Lilly, EMD Serono, Escalier Biosciences, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Sienna Biopharma and Union Therapeutics.
1. Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial. JAMA Dermatol. 2020;156(4):411–420.
2. Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al. “Lebrikizumab, a high-affinity IL-13 inhibitor, demonstrates rapid and clinically meaningful improvements in quality of life measures in a phase 2b trial of moderate-to-severe atopic dermatitis patients.” American Academy of Dermatology VMX. June 12, 2020.