Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis

Abstract

Background: Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.

Objective: To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).

Methods: This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed.

Results: Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness.

Conclusion: In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients.

Clinical trial registration: ClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).

Keywords: ADA; NAb; anti-drug antibody; atopic dermatitis; dupilumab; immunogenicity; neutralizing antibody.

Figure 1

Individual titer over time by maximum titer category in ADA-positive patients in the adult OLE. Baseline records from parent studies were used to derive maximum titer category and ADA status. The titer was imputed as 10 for ADA-negative results for the purpose of this figure. ADA, anti-drug antibody; n, number of participants with titer category; OLE, open-label extension; qw, once weekly.

Figure 2

Individual concentrations of functional dupilumab in serum by nominal time and maximum ADA titer category.^a (A) Pooled SOLO 1 and 2: dupilumab 300 mg q2w. (B) ADOL: dupilumab 200/300 mg q2w. (C) PEDS: dupilumab 200 mg q2w + TCS (≥30 kg)/300 mg q4w + TCS (<30 kg). Concentrations below the LLOQ (horizontal dashed line) were set to LLOQ/2. Concentration results are jittered by maximum titer category on the X-axis for better data presentation. ADA, anti-drug antibody; LLOQ, lower limit of quantitation; q2w, every 2 weeks; q4w, every 4 weeks; TCS, topical corticosteroid(s). ^aLow = ADA titer <1,000; moderate = ADA titer ≥1,000 to ≤10,000; high = ADA titer >10,000.

Figure 3

Efficacy (percent change in EASI from baseline) by nominal time and maximum ADA titer category.^a (A) Pooled SOLO 1 and 2: dupilumab 300 mg q2w. (B) ADOL: dupilumab 200/300 mg q2w. (C) PEDS: dupilumab 200 mg q2w + TCS (≥30 kg)/300 mg q4w + TCS (≤30 kg). Results are jittered by maximum titer category on the X-axis for better data presentation. ADA, anti-dupilumab antibody; EASI, Eczema Area and Severity Index; q2w, every 2 weeks; q4w, every 4 weeks; TCS, topical corticosteroid(s). ^aLow = ADA titer <1,000; moderate = ADA titer ≥1,000 to ≤10,000; high = ADA titer >10,000.