FormalPara Key Summary Points

Why carry out this study?

Lebrikizumab is a monoclonal antibody targeting IL-13 that has shown efficacy and safety in patients with moderate-to-severe atopic dermatitis in phase 2/3 trials.

ADopt-VA was carried out to assess the impact of lebrikizumab on immune responses to two non-live vaccines, Tdap (diphtheria/tetanus toxoids/pertussis) and MCV (meningococcal serogroups A, C, Y, and W-135) in adults with moderate-to-severe atopic dermatitis.

What was learned from the study?

Lebrikizumab did not negatively impact immune responses for Tdap or MCV vaccines in adults with moderate-to-severe atopic dermatitis.

Lebrikizumab demonstrated significant improvement in signs and symptoms of atopic dermatitis compared with placebo, consistent with previous studies of lebrikizumab in patients with moderate-to-severe atopic dermatitis, demonstrating that the vaccines did not influence treatment efficacy.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, heterogeneous skin disease that affects 2–7% of the adult population [1,2,3,4]. Approximately 30% of adults with AD have moderate-to-severe disease and many have comorbid asthma and rhinitis. Symptoms of AD negatively impact quality of life and include intense itching, skin pain, and impaired sleep.

Lebrikizumab is a high-affinity monoclonal antibody that selectively inhibits interleukin (IL)-13, the dominant skin cytokine in AD pathogenesis. Lebrikizumab exhibits high binding affinity, slow dissociation rate, and neutralizes IL-13 with high potency, thereby preventing the formation of the IL-4Rα/IL-13Rα1 heterodimer receptor signaling complex. As a result of the potential immunomodulatory effect of blocking IL-13 bioactivity, there is a need to assess immune response to vaccines in patients receiving lebrikizumab.

Here, we report the results of a phase 3, 16-week, randomized, double-blind, placebo-controlled, parallel-group study to assess the impact of lebrikizumab on responses to two non-live vaccines in adult patients with moderate-to-severe AD.

Methods

Patients and Study Design

ADopt-VA (NCT04626297) was a double-blind, placebo-controlled, parallel-group, 16-week, phase 3 randomized study conducted at 81 sites in the USA from 17 November 2020 to 30 September 2022 to assess the impact of lebrikizumab treatment on non-live vaccine immune responses, and efficacy and safety of lebrikizumab compared with placebo for adult patients with moderate-to-severe AD.

Eligible patients included adults from 18 to 55 years of age with moderate-to-severe AD according to the American Academy of Dermatology Consensus Criteria for at least 1 year before screening, with a history of inadequate response to topical treatment or when they are not medically advisable. Patients were required to have an Eczema Area and Severity Index (EASI) of ≥ 16, Investigator’s Global Assessment (IGA) score of ≥ 3 (scale of 0–4), and ≥ 10% body surface area (BSA) of AD involvement at baseline. Additionally, patients must not have received any tetanus-containing vaccine within 5 years of randomization, must never have received a meningococcal conjugate vaccine (MCV), and must have received no more than one dose of a vaccine containing one or more of meningococcal serogroups A, C, W, or Y at least 4 years before randomization.

Eligible patients were randomly assigned in a 1:1 ratio to lebrikizumab or placebo and stratified according to disease severity (IGA score 3 vs. 4). Patients and investigators were blinded to treatment and patients were allocated by a computer-generated random sequence using an interactive web-response system to receive either lebrikizumab as a loading dose of 500 mg administered at baseline and week 2, followed by 250 mg every 2 weeks (Q2W) thereafter, or placebo by subcutaneous injection. At week 12, pre-dose vaccine titers were withdrawn and then one dose of both Tdap (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [Sanofi]) and MCV (Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine [GlaxoSmithKline]) were administered to all patients who were still receiving study treatment.

Low to mid-potency topical corticosteroids (TCS) were permitted for AD symptoms starting at baseline, and topical calcineurin inhibitors were permitted for use on sensitive skin areas. Patients were eligible to receive rescue treatment following clinical worsening of AD symptoms that were intolerable with any locally approved AD treatments at the discretion of the investigator, including high potency TCS, oral corticosteroids, systemic immunosuppressants, or phototherapy. Patients who received systemic rescue treatment were permanently discontinued from study drug but remained in the trial for subsequent assessments.

All patients were required to give informed consent for participation in the study and prior to any study-specific procedures. The protocol was approved by local ethical review boards and was conducted according to International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki.

Objectives

The primary endpoints were the development of a booster response to tetanus toxoid 4 weeks after administration of the Tdap vaccine and a positive antibody response to MCV 4 weeks after administration of the vaccine. Tdap booster response was defined as ≥ fourfold increase in anti-tetanus toxoid immunoglobulin (IgG) antibody concentration if the pre-vaccination level was > 0.10 IU/mL and ≤ 2.7 IU/mL, ≥ twofold increase in anti-tetanus toxoid IgG antibody concentration if the pre-vaccination level was > 2.7 IU/mL, or ≥ fourfold increase in anti-tetanus toxoid IgG antibody concentration and a post-vaccination level ≥ 0.10 IU/mL if the pre-vaccination level was ≤ 0.10 IU/mL. Positive antibody response to MCV was defined as post-vaccination rabbit complement serum bactericidal assay (rSBA) titer ≥ 4 times the lower limit of quantitation (LLOQ) if the pre-vaccination rSBA titer is less than the LLOQ, or post-vaccination rSBA titer ≥ 4 times the pre-vaccination titer if the pre-vaccination rSBA titer is greater than or equal to the LLOQ. Secondary endpoints included the percentage of patients at week 16 who achieved IGA 0,1 with ≥ 2-point improvement from baseline, 75% improvement in EASI (EASI 75), 90% improvement in EASI (EASI 90), ≥ 4-point improvement from baseline in Pruritus Numeric Rating Scale (NRS), percentage change from baseline in EASI score and Pruritus NRS, change from baseline in percent BSA of AD involvement, and change from baseline in Sleep-Loss Scale score. Exploratory endpoints included change from baseline to week 16 in Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, PROMIS Depression, Patient-Oriented Eczema Measure (POEM), and percentage of patients who achieved a ≥ 4-point reduction in Skin Pain NRS score from baseline to week 16.

Patient IGA, EASI, and BSA were assessed at baseline and at weeks 4, 12, and 16. PROMIS Anxiety and PROMIS Depression were assessed at baseline and week 16. POEM was collected weekly via electronic diary and assessed at weeks 1, 2, 4, 6, 8, 10, 12, 14, and 16. Pruritus NRS, Skin Pain NRS, and Sleep-Loss Scale score assessments were recorded daily by the patient using an electronic diary and are reported as weekly mean scores.

Safety was assessed by the monitoring of adverse events, hematologic and urinalysis laboratory evaluations, physical examinations, and vital signs. An external data and safety monitoring board monitored patient safety by conducting formal unblinded reviews of accumulated safety data.

Statistical Analyses

The intent-to-treat (ITT) population was defined as all randomized patients, regardless of whether they took the assigned treatment, received the correct treatment, or otherwise followed study protocol. All efficacy analyses were conducted on a modified ITT (mITT) population that excluded seven patients (from two study sites) from the ITT population because some or all of these patients did not meet the eligibility criterion of moderate-to-severe AD, or there was a lack of source documentation needed to substantiate eligibility for these patients. Safety analyses were conducted on all randomized patients who received at least one dose of study treatment, except for the seven excluded patients (modified safety population). The primary endpoints were assessed using a per-protocol set consisting of all patients in the safety population without any significant protocol deviations (Supplementary Appendix Table S1).

For each primary endpoint, a 90% confidence interval (CI) for the difference in proportions between treatment groups was constructed using the stratified (by baseline IGA severity) Newcombe approach, and missing data was not imputed. For IGA, EASI, Pruritus NRS, Skin Pain NRS, and Sleep-Loss Scale score, Cochran–Mantel–Haenszel (CMH) tests were used to compare treatment groups in categorical endpoints and an analysis of covariance model (ANCOVA) was used to analyze continuous endpoints, after adjusting for stratification factors. Data after rescue therapy usage or treatment discontinuation due to lack of efficacy were set to the baseline value and Markov chain Monte Carlo multiple imputation (MCMC-MI) was used to handle the remaining missing data. For analyses of other categorical endpoints, the CMH test was used, and missing data were imputed using nonresponders imputation (NRI). For analyses of other continuous endpoints, the mixed-effects model for repeated measures or last observation carried forward methods were used to handle missing data. All statistical tests were 2-sided and performed at the 0.05 level of significance. All calculations were performed using SAS statistical software (version 9.4; SAS Institute, Inc).

Results

Patients

A total of 442 patients were screened and 254 (7 patients who were randomized were excluded from the ITT population) were randomly assigned to lebrikizumab (N = 125) or placebo (N = 122) (Fig. 1). Of these patients, 199 (80.6%) completed the 16-week treatment period and 48 (19.4%) discontinued. Reasons for treatment discontinuation included withdrawal by participant (4.8%, n = 6 lebrikizumab; 14.8%, n = 18 placebo), adverse events (2.4%, n = 3 lebrikizumab; 4.1%, n = 5 placebo), lost to follow-up (2.4%, n = 3 lebrikizumab; 4.9%, n = 6 placebo), and protocol deviation (0.8%, n = 1 lebrikizumab; 3.3%, n = 4 placebo).

Fig. 1
figure 1

CONSORT diagram for patient disposition. A total of seven patients (from two study sites) were excluded from the ITT population because some or all of these patients did not meet the eligibility criterion of moderate-to-severe AD, or there was a lack of source documentation needed to substantiate eligibility for these patients

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Patient demographics and disease characteristics were similar across both treatment groups (Table 1). The mean age at baseline was 35.4 years (standard deviation [SD] = 10.9) and 55.1% (n = 136) of patients were female.

Table 1 Baseline demographics and characteristics in the mITT population
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Primary Objectives

At week 16, 73.6% (n = 78/106) of patients in the lebrikizumab group achieved Tdap booster response compared with 73.4% (n = 58/79) of patients in the placebo group (difference with placebo = 0.3%; 90% CI for the difference, lebrikizumab vs. placebo = − 10.2%, 11.2%, Fig. 2). MCV vaccine response was observed in 86.9% of patients in the lebrikizumab group (n = 86/99) and 75.0% (n = 60/80) patients in the placebo group (difference with placebo = 12.2%, 90% CI for the difference, lebrikizumab vs. placebo = 2.5%, 22.0%, Fig. 2).

Fig. 2
figure 2

Sero-responses to the Tdap and MCV of lebrikizumab and placebo-treated patients. Only patients from the per-protocol safety population (safety population without any protocol deviations that could impact precise evaluation of the primary objective) with non-missing values for vaccine responses were included for the analysis

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Secondary and Exploratory Objectives

At week 16, an IGA score of 0 or 1 with ≥ 2-point improvement from baseline was achieved by 40.6% (n = 51) of patients treated with lebrikizumab and 18.9% (n = 23) on placebo (p < 0.001; Table 2, Fig. 3). There was also a greater proportion of patients achieving EASI 75 response at week 16 in the lebrikizumab-treated patients (58.0%, n = 72) compared with placebo (32.7%, n = 40, p < 0.001, Table 2). Patients in the lebrikizumab treatment group had greater improvements compared to placebo in other secondary and exploratory endpoints at week 16: EASI 90 (lebrikizumab = 39.2%, placebo = 18.9%; p < 0.001); EASI percentage change from baseline (lebrikizumab = − 72.5%, placebo = − 47.1%, p < 0.001); pruritus NRS ≥ 4-point improvement from baseline (lebrikizumab = 51.7%, placebo = 33.2%; p = 0.014); pruritus NRS percentage change from baseline (lebrikizumab = − 57.3%, placebo = − 33.0%, p < 0.001); BSA (lebrikizumab = − 27.6%, placebo = − 19.3%, p < 0.001); Sleep-Loss Scale score change from baseline (lebrikizumab = − 55.26, placebo = − 26.56, p = 0.031); PROMIS anxiety change from baseline (lebrikizumab = − 2.89, placebo = − 1.36, p = 0.115); and PROMIS depression change from baseline in (lebrikizumab = − 2.43, placebo = − 0.50, p = 0.022, Table 2). At week 16, lebrikizumab-treated patients (− 9.4 [standard error (SE) 0.78]) had a greater reduction in POEM score compared to placebo-treated patients (− 6.62 [SE 0.83], p = 0.014, Table 2). At week 16, 53.5% (n = 42) of lebrikizumab-treated patients with a skin pain NRS ≥ 4 at baseline achieved a ≥ 4-point reduction in Skin Pain NRS compared to 41% (n = 31, p = 0.100) of placebo-treated patients (Table 2).

Table 2 Secondary and exploratory outcomes in the mITT population at week 16
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Fig. 3
figure 3

Secondary efficacy results. Time course for outcomes of IGA 0,1 response, EASI 75, and Pruritus NRS ≥ 4-point improvement from baseline. IGA Investigator’s Global Assessment, EASI Eczema Area and Severity Index, NRS Numeric Rating Scale. *p < 0.05, **p < 0.01, ***p < 0.001

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Low-moderate potency TCS were used in 17 (13.9%) placebo and 9 (7.2%) lebrikizumab-treated patients, respectively. Only 2 (1.6%) placebo and 2 (1.6%) lebrikizumab-treated patients utilized high potency TCS (Supplementary appendix Table S2). Low-moderate potency TCS use was not considered rescue therapy in this trial.

Safety

Adverse events were reported by 48 (38.4%) of 125 patients who received lebrikizumab and 42 (34.4%) of 122 patients who received placebo (Table 3). Most adverse events were mild or moderate in severity, and discontinuation due to adverse events was low (3.2%, n = 8). The most frequently reported TEAEs were COVID-19 infection, reported by 7 (5.6%) and 5 (4.1%) of patients who received lebrikizumab and placebo, respectively, and atopic dermatitis exacerbation, reported by 6 (4.8%) and 8 (6.6%) of patients who received lebrikizumab and placebo, respectively (Table 3). The proportion of patients who reported an infection related treatment-emergent adverse event (TEAE) was 19.2% (n = 24) in the lebrikizumab group and 10.7% (n = 13) in the placebo group; none of these TEAEs were severe and no opportunistic infections were identified, including herpes infections.

Table 3 Adverse events through week 16 in the modified safety population
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Conjunctivitis occurred among patients treated with lebrikizumab at a higher frequency (4.0%, n = 5) compared to placebo (0%, n = 0). The incidence of injection-site reactions was 2.4% (n = 3) among patients who received lebrikizumab and 1.6% (n = 2) among patients who received placebo (Table 3). AD exacerbation was more common in placebo-treated patients at 6.6% (n = 8) vs. 4.8% (n = 6) for lebrikizumab.

Discussion

Previously, no vaccine response studies have been conducted for lebrikizumab. Because lebrikizumab suppresses IL-13 signaling, a potential immunomodulator effect, there is a need to assess immune response to vaccinations in patients receiving this drug. This study aimed to assess the impact of lebrikizumab on vaccine immune responses to two commonly used vaccines (Tdap and MCV) in adult patients with moderate-to-severe AD. In addition, this study further assessed the efficacy and safety of lebrikizumab in patients with moderate-to-severe AD.

Vaccine sero-responses to both non-live vaccines were not negatively impacted by concomitant lebrikizumab treatment in adult patients with moderate-to-severe AD. The results from this study demonstrate that lebrikizumab does not reduce the humoral immune response to non-live vaccines as it is an immunomodulating and not an immunosuppressive agent. For positive booster response to tetanus toxoid at week 16, the response rate was similar between placebo arm (73.4%) and lebrikizumab arm (73.6%), and for positive booster response to MCV at week 16, the response rate in lebrikizumab arm (86.9%) was higher than the placebo arm (75.0%). Lebrikizumab-treated patients have comparable MCV response rate compared to other studies for dupilumab and tralokinumab [5, 6]. However, the response rate for placebo-treated participants in this study does fall within the lower end of the range of response rates reported in a separate clinical trial evaluating MCV post-vaccination seroconversion in healthy volunteers, indicating that the lower rate seen in the placebo-treated group is within previously reported sero-response rates of 75–85% [7].

Similar to previous reports, lebrikizumab patients achieved greater improvements in skin-based measures of disease such as IGA 0,1 with ≥ 2-point improvement and EASI 75, as well as in itch and other secondary endpoints, and primarily in monotherapy.

The safety profile was consistent with what has been reported previously [8, 9]. Most adverse events were mild or moderate in severity. The overall incidences of serious adverse events and trial discontinuations due to adverse events were low. Conjunctivitis was more commonly reported among patients treated with lebrikizumab compared to placebo; this is consistent with previous studies on lebrikizumab and other biologic agents targeting IL-13/14 like tralokinumab and dupilumab [8,9,10,11]. Injection-site reactions were infrequently reported. Two patients experienced vaccine-related AEs (as determined and reported by the investigators). One patient experienced mild symptoms of fatigue possibly related to the vaccine, the second patient experienced moderate inflammation in their shoulder following both Tdap and MCV vaccine injections. No adverse interactions between the non-live vaccines and lebrikizumab treatment were noted up to week 16. Overall, efficacy and safety were consistent with other lebrikizumab phase 3 studies.

The limitations of the study include the short time frame of 16 weeks, that live vaccines and mRNA vaccines were not studied and hence no conclusions can be drawn regarding their effect on the efficacy and safety of lebrikizumab, and the study population was limited to participants who were 18–55 years old and hence no conclusions can be drawn regarding populations outside of this age bracket.

Conclusions

Treatment with lebrikizumab did not impact response to non-live vaccines Tdap and MCV in this study. Lebrikizumab treatment had a significant degree of efficacy compared to placebo across multiple endpoints.