Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study

Abstract

RATIONALE: Dietary avoidance is currently recommended for peanut allergies. We evaluated sustained effects of treating peanut allergy with oral immunotherapy (OIT) in the first phase 2 randomized-controlled longterm study in adults and children. METHODS: In a double-blind, placebo-controlled, randomized study, 120 peanut-allergic participants (7-53 years old) received up to 4 g of peanut protein or placebo daily for 3 years. Participants received placebo (N525) or peanut protein (N595) over 104 weeks; 60 then discontinued (peanut-0) while 35 received 300 mg daily (peanut-300). Double-blind, placebo-controlled food challenges (DBPCFCs) to 4 g peanut protein were conducted at baseline, week 104, and every 13 weeks thereafter for one year. RESULTS: The primary endpoint was reached at week 117 after 3 months of discontinuation (testing sustained unresponsiveness): 21/60 (35%) peanut-0 participants passed the challenge with no reaction versus 1/25 (4%) placebo (primary endpoint, P50.002). Time to failure was significantly longer in peanut-300 vs. peanut-0 vs. placebo arms (P<0.0001). The percentage of participants passing DBPCFCs in peanut-300 declined significantly (weeks 104 vs. 156; 83% vs. 37%, P<0.001). Adverse allergic reactions decreased over time in all arms. Peanut-specific IgG 4 /IgE levels were higher (P<0.001), and Ara h 2-specific IgE (P<0.001) and basophil activation responses (P50.037) were lower, at baseline in those achieving sustained unresponsiveness at week 117. CONCLUSIONS: Peanut OIT desensitizes most peanut-allergic individuals to 4 g peanut protein but discontinuation, or even a reduction to 300 mg daily, increases the likelihood of regaining clinical reactivity to peanut. Baseline blood tests correlate with week 117 treatment outcomes.

Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

“…In patients with AR undergoing SLIT, basophil activation decreased with clinical efficacy 285 . Similar decreases occurred in patients undergoing peanut immunotherapy 271 . However, in grass pollen SLIT, basophil activation did not correlate with clinical efficacy (Table 3).…”

“…Recent data support skewing toward IgG2 and IgG4 subclasses after SLIT for temperate grass pollen 193 . The IgG4/IgE ratio may monitor AIT progress and outcome, but has demonstrated conflicting utility 269–271 . Flow cytometry‐based assay (IgE‐FAB) and a solid‐phase assay enzyme‐linked immunosorbent‐facilitated antigen binding (ELIFAB) assay can determine IgE‐inhibitory activity.…”

Increased diversity of gut microbiota during active oral immunotherapy in peanut‐allergic adults

“…Thus, the week 52 timepoint represents the end of the up-dosing phase of active OIT (Table 1) Although OIT induces prolonged desensitization in some FA patients, a large portion of FA patients regain their reaction to the food once treatment is discontinued. 5 We have identified specific taxa that were differentially abundant before and after 52 weeks of active OIT, which raises the question of whether the microbiome could be associated with the development of desensitization. In future studies, it will be of interest to identify any structural gut microbial alterations associated with long-term desensitization, particularly without regular intake of the offending foods.…”

“…In this pilot study, we sought to characterize the gut microbiome from a cohort of peanut-allergic patients who participated in our double-blind, randomized, placebocontrolled, phase 2 peanut OIT study and who successfully desensitized . 5 We retrospectively investigated stool samples collected from seven participants who received peanut flour as OIT, sampled before and after 52 weeks of OIT (Table 1). Two additional participants who received oat flour as placebo were included for comparisons (Table S1 and Figure S1).…”

Perturbations to Homeostasis in Experimental Models Revealed Innate Pathways Driving Food Allergy

“…Due to the small number of interventions tried in human food allergy, evaluation of predictive validity is limited, but oral immunotherapy provides a key example. Oral immunotherapy in both mice and humans can increase the threshold of reactivity (i.e., desensitization) to food allergens, although this desensitized state is, just as it is in the majority of humans, unsustained ( 68 , 97 ). This limited assessment of predictive validity will be greatly improved come the initiation of clinical trials testing novel biotherapeutics (e.g., anti-IL-4Rα).…”