Almost 3% of individuals with asthma treated with biologics may develop anti-drug antibodies (ADA) and higher incidence may be associated with subcutaneous delivery and longer dosing intervals, according to a review and meta-analysis published in The Journal of Allergy and Clinical Immunology: In Practice.
Biologic therapies are more likely to be immunogenic than earlier treatment small molecule drugs, which may lead to the development of ADA. These antibodies may increase the incidence of adverse events and impact drug effectiveness. Investigators sought to characterize the incidence of ADA and its effect on clinical outcomes and adverse events. The primary endpoints were the incidence and prevalence of ADA. Secondary endpoints included the effect of ADA on efficacy or safety outcomes.
The researchers conducted a review and meta-analyses that included nonrandomized studies, open-label extension studies, and randomized controlled trials involving patients with asthma treated with biologics. In a search of CENTRAL, Embase, and PubMed databases and ClinicalTrials.gov from January 2000 to July 2022, the reviewers found 46 studies that met eligibility criteria. Of those studies, 3 were excluded from the meta-analyses and 7 were excluded from the sensitivity analysis.
Study participants ranged from 6 to 82 years of age, with 4 studies conducted exclusively in children. There was a predominance of female participants, and the majority of participants were White. Baseline mean blood eosinophil counts ranged from 242 to 762 cells/µL, mean total IgE ranged from 179 to 727 IU/mL, and mean pre-bronchodilator forced expiratory volume in the first second (FEV1) ranged from 1.48 to 3.36 liters.
Overall, in 31 studies (n=12,379) the researchers found ADA incidence over the course of follow-up was 2.91% (95% CI, 1.60-4.55). Benralizumab showed the highest incidence (8.35%; risk ratio, 4.9; 95% CI, 2.69-8.92) vs placebo. Incidence rates for other biologics were: dupilumab, 7.61%; reslizumab, 4.39%; mepolizumab, 3.63%; tezepelumab, 1.12%; and omalizumab, 0.0%.
[T]his review and meta-analysis found that less than 3% of individuals enrolled in the trials of the biologics currently approved for asthma treatment developed ADAs over the course of follow-up, and that lower dose, the subcutaneous route, and longer dosing intervals may be associated with higher ADA development.
The incidence of neutralizing antibodies (NAb) was 0.00% to 10.74% for all biologics and highest for benralizumab (7.12%) among the 18 studies (n=9654) used for analyses. Treatment with benralizumab every 8 weeks vs every 4 weeks revealed a higher though nonsignificant incidence of NAb (8.17% vs 5.81%, respectively; P =.399) and ADA prevalence (14.20% vs 11.62%, respectively; P =.184).
Investigators analyzed 26 studies (n=11,271) for prevalence of ADA at baseline across all biologics (1.59%; 95% CI, 0.80-2.61). Pooled prevalence of ADA during follow-up was 4.66%.
A total of 13 studies reported the effect of ADA on efficacy and 23 studies reported effects related to safety; most reports were qualitative and lacking in specific numbers.
Study limitations include differences in methods, timing, medications, and comorbidities between studies; overly sensitive assays in benralizumab studies; missing data on baseline standard-of-care drugs; use of mostly qualitative reports for safety and efficacy; and lack of information on immunogenicity of ADA therapies.
Investigators concluded that “[T]his review and meta-analysis found that less than 3% of individuals enrolled in the trials of the biologics currently approved for asthma treatment developed ADAs over the course of follow-up, and that lower dose, the subcutaneous route, and longer dosing intervals may be associated with higher ADA development.”