ADP101 multifood oral immunotherapy for food-allergic patients: Harmony phase 1/2 randomized clinical trial

Abstract

Background: Oral immunotherapy is an established approach to desensitize the immune system in the context of allergic disease; however, the only currently approved product is for peanut allergy. ADP101 is a novel, pharmaceutical-grade, multifood oral immunotherapy in development to simultaneously treat single or multiple food allergies, containing allergenic proteins from 15 foods in equal parts by protein weight.

Objective: The phase 1/2 Harmony trial (NCT04856865) evaluated efficacy and safety of ADP101 in participants with qualifying allergy to 1 to 5 foods in ADP101, defined as dose-limiting symptoms with a ≤100 mg challenge dose during double-blind, placebo-controlled food challenge (DBPCFC).

Methods: Participants were randomized to low-dose (1500 mg/d; 100 mg protein per food) or high-dose (4500 mg/d; 300 mg protein per food) ADP101, or matched placebo, with dose escalation followed by daily maintenance dosing over 40 weeks. The primary endpoint was the proportion of participants tolerating a ≥600 mg challenge dose of a single qualifying food without dose-limiting symptoms at the Week 40 Exit DBPCFC (ie, responders).

Results: In the primary analysis population (61 pediatric participants aged 4-17 years), a greater response rate was observed in both the high-dose ADP101 (55.0%) and low-dose ADP101 (38.1%) groups compared with pooled placebo (20.0%) (nominal P = .048, P = .306, respectively; adjusted for multiple comparisons, P = .097, P = .306, respectively). Desensitization to ≥2 foods was observed in individuals with multiple food allergies, as was desensitization at levels over 600 mg. ADP101-treated participants showed an overall reduction in skin-prick test reactivity, with an increase in maximum tolerated dose across the majority of foods tested. Adverse events were mostly mild or moderate, with no life-threatening events or deaths.

Conclusions: The study did not meet its primary endpoint, but ADP101 demonstrated a favorable safety profile and increased the reactive threshold in DBPCFC in pediatric participants with single or multiple food allergies across multiple endpoints, warranting further clinical investigation.

Keywords: Food allergy; allergy desensitization; clinical trial; multifood allergy; oral immunotherapy; pediatric food allergy.

Fig 1

Harmony trial design and updosing schedule. Updosing was attempted every 2 weeks and permitted through Week 38. Dose (in mg) refers to protein content. mOIT, Multifood OIT; R, randomization.

Fig 2

Participant screening, randomization, and follow-up. Of 105 participants, 32 (31%) did not meet inclusion criteria (17%), had exclusion criteria (4%), or had another reason (10%) to be removed from study; other reasons included withdrawal of consent, time constraints, planned travel, investigator recommendation, SPT reaction not within protocol limits, and SPT-negative control reaction >3 mm. Primary analysis population (N = 61) was the pediatric ITT population. In this group, 47 (77%) of 61 completed treatment, with 40 (66%) planning to continue in the OLE. Treatment discontinuation occurred in 14 (23%) of pediatric participants as a result of patient withdrawal (12%), AEs (7%), and other reasons (5%); other reasons included site closure/declined site transfer. One participant who discontinued treatment continued study participation through the end-of-treatment visit. All other participants who discontinued treatment also discontinued the study. Thirteen (21%) of 61 discontinued study, with primary reason being administration (8%), other (8%), and AE (5%); other reasons included withdrawal of consent because of product taste and/or texture, concerns over number of food challenges and school time missed, noncompliance, and inability to attend study visits. ∗Twelve adult participants were included as a feasibility cohort; cases are described individually in Online Repository at www.jaci-global.org. OLE, Open-label extension.

Fig 3

Response rates for primary and secondary efficacy endpoints (pediatric participants). (A) Primary efficacy endpoint; participants tolerating ≥600 mg of ≥1 qualifying food at Exit DBPCFC. ITT population was defined as all randomized participants. The primary endpoint was not met after adjustment for multiple comparisons. In supplemental ITT analysis, response status was imputed using multiple imputation for participants discontinuing for administrative reasons; all other discontinuations were considered nonresponse. Per-protocol population is defined as all participants from ITT population without major protocol deviations that affect statistical analysis, conducted as a sensitivity analysis of primary efficacy endpoint. (B) Secondary efficacy endpoints. P values are unadjusted unless otherwise stated, determined by Fisher exact test. Adjusted P values were determined by Simes global test with Holm procedure. Error bars depict 95% CI of proportion, estimated by Clopper-Pearson exact method. Dose (in mg) refers to protein content. Adj, Adjusted; CI, confidence interval.

Fig 4

Response rate in participants reaching or not reaching 1500 mg or 4500 mg of study drug (pediatric ITT population). ADP101 dose threshold analysis. Patients randomized to both LD-ADP101 and HD-ADP101 could reach 1500 mg dose (pooled ADP101), whereas only those randomized to HD-ADP101 could reach 4500 mg dose. Reached dose refers to participants who were treated with specified dose and tolerated this for ≥2 weeks. (A) Participants with a ≥600 mg desensitization response to ≥1 qualifying food at exit DBPCFC. (B) Participants with a ≥1000 mg desensitization response to ≥1 qualifying food at exit DBPCFC. (C) Participants with a ≥600 mg desensitization response to ≥2 qualifying foods at exit DBPCFC. (D) Participants with a ≥1000 mg desensitization response to ≥2 qualifying foods at exit DBPCFC. NA, Not applicable.

Fig 5

Participants tolerating higher levels (≥2000 mg) of ≥1 qualifying food (pediatric ITT population). Ad hoc efficacy analysis (not included in statistical analysis plan). Desensitization response defined as tolerating ≥2000 mg or 4000 mg challenge dose without dose-limiting symptoms at Exit DBPCFC. All P values are unadjusted, determined by Fisher exact test. Error bars depict 95% CI of proportion, estimated by Clopper-Pearson exact method. CI, Confidence interval.