Lebrikizumab demonstrated dose-dependent improvements across endpoints spanning the range of atopic dermatitis signs and symptoms, including skin lesions and pruritus, when administered once every two or four weeks.

Primary results from Dermira, Inc.'s Phase 2b dose-ranging study of lebrikizumab were presented during the 39^th Annual Fall Clinical Dermatology Conference in Las Vegas, NV. Lebrikizumab is currently being evaluated in a Phase 3 program in adult and adolescent patients with moderate-to-severe atopic dermatitis.

Lebrikizumab is a novel, investigational, monoclonal antibody designed to bind IL-13 with very high affinity, specifically preventing the formation of the IL-13Rα1/IL-4Rα heterodimer complex and subsequent signaling, thereby inhibiting the biological effects of IL-13 in a targeted and efficient fashion. IL-13 is believed to be a central pathogenic mediator that drives multiple aspects of the pathophysiology underlying the range of signs and symptoms of atopic dermatitis by promoting type 2 inflammation and mediating its effects on tissue, resulting in skin barrier dysfunction, itch, skin thickening, and infection.

“These results are encouraging and suggest that lebrikizumab has the potential to advance the standard of care for patients with moderate-to-severe atopic dermatitis by delivering improvements in efficacy, tolerability, and convenience relative to available therapies,” said April W. Armstrong, MD, MPH, professor of dermatology and associate dean of clinical research at the University of Southern California Keck School of Medicine, and an investigator in the lebrikizumab study. “In this study, lebrikizumab administered once every two or four weeks demonstrated robust, broad efficacy with a safety profile consistent with the substantial prior experience with this and other biologics targeting the IL-4/-13 pathway. Among these encouraging results, I am particularly excited about the impact of lebrikizumab on itch, which is one of the most burdensome symptoms for many atopic dermatitis patients.”

The randomized, double-blind, placebo-controlled, parallel-group Phase 2b study was designed to evaluate the safety and efficacy of lebrikizumab as monotherapy compared with placebo and establish a dosing regimen for the Phase 3 program in patients with moderate-to-severe atopic dermatitis. The study enrolled 280 patients ages 18 years and older with moderate-to-severe atopic dermatitis at 57 sites in the US. Three different lebrikizumab treatment dosing arms were evaluated, compared to a placebo arm, with patients randomized in a 3:3:3:2 fashion as follows:

• Group 1: A loading dose of 250 mg of lebrikizumab at baseline (day 0), followed by 125 mg of lebrikizumab every four weeks.
• Group 2: A loading dose of 500 mg of lebrikizumab at baseline (day 0), followed by 250 mg of lebrikizumab every four weeks.
• Group 3: A loading dose of 500 mg of lebrikizumab at baseline (day 0) and week 2, followed by 250 mg of lebrikizumab every two weeks.
• Group 4: Placebo at baseline (day 0) and every two weeks thereafter.

The inclusion criteria for patients enrolled in this study included the presence of chronic atopic dermatitis for at least one year, an Eczema Area and Severity Index (EASI) score of 16 or greater, an Investigator’s Global Assessment (IGA) score of 3 or 4 (on a 5-point scale ranging from 0 to 4) and body surface area (BSA) involvement of at least 10 percent at screening and baseline.

The primary endpoint of the study was the percent change in EASI from baseline to week 16. Secondary endpoints that were evaluated during the 16-week treatment period included: the proportion of patients with a 75 percent improvement from baseline in EASI score (EASI-75); the proportion of patients with a reduction of 2 or more points in IGA score from baseline to a final score of 0 (clear) or 1 (almost clear) (IGA0/1); the proportion of patients achieving EASI-50 and EASI-90; changes in pruritus (itch) and sleep loss scores from baseline, each scored using a numerical rating scale (NRS); and the proportion of patients with an improvement in pruritus NRS score (on an 11-point scale) of at least 4 points from baseline.

Initial topline findings from the Phase 2b study were previously announced in March 2019, showing that across all doses evaluated, lebrikizumab demonstrated dose-dependent and statistically significant improvements in the primary endpoint, the mean percent change in EASI score from baseline to week 16.

The data being presented highlight secondary endpoints assessing measures spanning the range of signs and symptoms of atopic dermatitis, including skin lesions (the proportions of patients achieving EASI-50, EASI-75, EASI-90 and IGA0/1) and pruritus (mean percent change in pruritus NRS score and the proportion of patients achieving an improvement of at least 4 points in pruritus NRS score) over the 16-week treatment period. Key findings include the following:

Skin Lesions

• A response was observed as early as the first on-treatment visit at week 4 for all atopic dermatitis severity scores. Lebrikizumab demonstrated a dose-dependent response across each of the EASI-50, EASI-75, EASI-90 and IGA0/1 endpoints, with marked improvement at both the 250 mg every two weeks (Q2W) and 250 mg every four weeks (Q4W) doses.
• A greater proportion of lebrikizumab- versus placebo-treated patients achieved EASI-50, EASI-75, EASI-90 and IGA0/1 at week 16, with statistically significant improvements seen with lebrikizumab as follows:

Pruritus (Itch)

• Dose-dependent improvements in pruritus, as reported by patients, were observed as early as day 2 and continued through week 16.
  • By week 16, patients receiving lebrikizumab at doses of 125 mg Q4W, 250 mg Q4W and 250 mg Q2W reported mean improvements in pruritus NRS score of 36.9% (p<0.01), 48.6% (p<0.001) and 61.8% (p<0.001), compared to a mean worsening of 6.8% in patients receiving placebo.
  • The proportion of patients reporting an improvement of at least 4 points in pruritus NRS score was highest in the 250 mg Q2W group, reaching 51.9% by week 4 and at week 16, 70.0% (p<0.001 vs. placebo).

As expected, based on prior experience, lebrikizumab was generally well-tolerated, with a safety profile consistent with that observed in prior studies in more than 4,000 patients. Adverse events observed in lebrikizumab-treated patients were primarily mild to moderate in severity and infrequently led to treatment discontinuation. The most common adverse events reported across the lebrikizumab 250mg Q2W, 250mg Q4W and 125mg Q4W dosing arms were upper respiratory tract infection (2.7%, 11.3% and 8.2%, respectively, vs. 5.8% for placebo), nasopharyngitis (12.0%, 2.5% and 5.5%, respectively, vs. 3.8% for placebo), headache (5.3%, 1.3% and 4.1%, respectively, vs. 5.8% for placebo) and injection site pain (5.3%, 3.8% and 0.0%, respectively, vs. 1.9% for placebo). Rates of herpes viral infections (which includes oral herpes, herpes zoster, genital herpes, herpes simplex, and eczema herpeticum) were 2.7%, 5.0% and 2.7%, respectively, vs. 3.8% for placebo) and conjunctivitis (2.7%, 3.8% and 1.4%, respectively, vs. 0.0% for placebo) were low. Across all studies of lebrikizumab conducted to date in atopic dermatitis, conjunctivitis has been reported at low rates similar to those in patients receiving placebo.

“Our goal with lebrikizumab is to develop a best-in-disease therapy for patients with moderate-to-severe atopic dermatitis that not only improves the severity of disease, but that is also safe and convenient,” said Eugene A. Bauer, MD, chief medical officer at Dermira and a dermatologist. “These results support our belief that specifically targeting IL-13 with lebrikizumab has the potential to deliver on all of these objectives and thus help address the substantial unmet medical need in this prevalent, debilitating condition.”

Based on the Phase 2b study results, Dermira recently announcedthe initiation of a Phase 3 clinical development program to further evaluate lebrikizumab in adult and adolescent patients with moderate-to-severe atopic dermatitis.