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Clinical Trials

Date: 2018-05-28

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the Congress of the European Academy of Allergy , Asthma, and Immunology (EAACI) 2018

Company: Aimmune Therapeutics (USA - CA) previously Allergen Research Corporation (ARC)

Product: AR101

Action mechanism:

  • immunotherapy product. AR101 is part of Aimmune Therapeutics’ approach to treating food allergies using its characterized oral desensitization immunotherapy, or CODIT™, system. The CODIT system leverages extensive independent scientific research on oral immunotherapy, or OIT, demonstrating that food allergy patients can be desensitized to exposure to food allergens by being administered well-defined, gradually increasing doses of the allergen over a period of months. Aimmune Therapeutics’ CODIT system is designed to precisely control the amount of allergen administered and follow a systematic dosing regimen that begins with very low doses of the allergen. Once a patient attains desensitization to a clinically meaningful level of food allergen, the patient continues to take a daily maintenance dose of the CODIT system product in order to maintain such desensitization.

Disease: peanut allergy

Therapeutic area: Allergic diseases

Country: Canada, Denmark, Germany, Ireland, Italy, Netherlands, Spain, Sweden, UK, USA

Trial details:

  • The purpose of the Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults (PALISADE)  is to demonstrate the efficacy and safety of AR101 through reduction in clinical reactivity to peanut allergen in peanut-allergic children and adults. A total of 554 peanut-allergic patients, ages 4-49, were randomized to receive either AR101 or placebo for approximately six months of up-dosing followed by six months of maintenance therapy. (NCT02635776)

Latest news:

  • • On May 28, 2018, Aimmune Therapeutics reported additional results from its pivotal Phase 3 PALISADE trial of AR101 for the treatment of peanut allergy at the Congress of the European Academy of Allergy , Asthma, and Immunology (EAACI) 2018 in Munich . Aimmune previously announced that the trial met its primary and secondary efficacy endpoints in the pre-specified primary analysis of the 4-17 age cohort (See below). Additional analyses including adults treated in the study were presented at EAACI.
  • PALISADE enrolled a total of 554 patients ages 4-55 (90% ages 4-17). After approximately one year of treatment (up-dosing and maintenance), clinical reactivity to peanut protein was assessed in an exit double-blind, placebo-controlled food challenge (DBPCFC). The trial met its primary endpoint as 67% of AR101 patients ages 4–17 tolerated at least a 600-mg dose of peanut protein in the exit DBPCFC, compared to 4% of placebo patients (p<0.00001). The lower-bound of the 95% confidence interval (CI) of the difference between treatment arms at the primary endpoint was 53%, greatly exceeding the pre-specified threshold of 15% (p<0.00001).
  • Based on these results, Aimmune plans to submit a Biologics License Application (BLA) for AR101 to the FDA by the end of 2018, followed by a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) in the first half of 2019. In the United States , AR101 has FDA Fast Track Designation, as well as FDA Breakthrough Therapy Designation for peanut-allergic patients ages 4–17.
  • New analyses presented at EAACI of the 4-55 age intent-to-treat population showed a statistically significant difference of 60% between the proportion of patients in the AR101 group (65%) and placebo group (5%) who tolerated the 600-mg dose of peanut protein in the exit DBPCFC (p<0.00001; 95% CI: 50, 69). In an exploratory analysis of AR101 patients who completed the trial, efficacy was similar across all ages, refined into three groups. In the exit DBPCFC, 85% of children (ages 4-11), 83% of adolescents (ages 12-17), and 85% of adults (ages 18-55) tolerated the 600-mg dose of peanut protein. Though the number of adults in the study was small, the treatment difference in this population showed a strong trend on an intent-to-treat basis (p=0.07). The safety profile in adults was similar to that observed in the pediatric and adolescent populations previously reported.
  • In a separate late-breaking presentation, Prof. Kirsten Beyer , of University Hospital Charité, Berlin , and principal investigator for PALISADE in Germany , presented new immunological findings from the trial3. Exposure to AR101 was strongly associated with immunologic changes consistent with the immunotherapeutic efficacy, specifically increased peanut-specific IgG4 and decreased peanut skin-prick test wheal size.
  • New data from the laboratory of Dr. Erik Wambre of the Benaroya Research Institute from a small subset of patients from PALISADE showed that treatment with AR101 was linked to a statistically significant decrease in peanut-specific TH2A cells compared to patients treated with placebo after up-dosing and at the end of the trial2. These findings and similar results from Aimmune’s ARC001 Phase 2 trial suggest that the clinical responses observed with AR101 treatment are associated with fundamental modulation of T cell subsets that drive the allergic response.
  • • On March 4, 2018, Aimmune Therapeutics announced that the results of its pivotal Phase 3 PALISADE trial of AR101 for the treatment of peanut allergy were presented at the 2018 American Academy of Allergy , Asthma & Immunology–World Allergy Organization Joint Congress in Orlando.
  • PALISADE enrolled a total of 554 patients ages 4-49. After approximately one year of treatment, patients completed an exit DBPCFC. In the trial’s primary analysis of ages 4–17, patients were highly atopic and highly sensitive to peanut. The median tolerated dose of peanut protein in the entry DBPCFC was 10 mg, the equivalent of approximately 1/30 of a peanut, and, at baseline, 43% of patients had a peanut-specific IgE level >100 kU/L. Furthermore, more than half of the study participants had been diagnosed with asthma, nearly two thirds had multiple food allergies, and almost three quarters reported a history of anaphylaxis.
  • In the primary analysis of ages 4–17, 296 patients (79.6%) from the AR101 arm completed the trial, compared to 116 patients (93.5%) from the placebo arm.
  • Intent-to-Treat Efficacy: Percent of Patients Who Tolerated Each Dose in Exit DBPCFC1
    300 mg 600 mg 1000 mg
    AR101 (n=372) 76.6% 67.2% 50.3%
    Placebo (n=124) 8.1% 4.0% 2.4%
    95% CI difference (58.6–78.5%) (53.0–73.3%) (38.0–57.7%)
    p-value p<0.00001 p<0.00001 p<0.00001
    1 Ages 4–17 years Completer Efficacy: Percent of Patients Who Tolerated Each Dose in Exit DBPCFC1
    300 mg 600 mg 1000 mg
    AR101 (n=296) 96.3% 84.5% 63.2%
    Placebo (n=116) 8.6% 4.3% 2.6%
    95% CI difference (78.0–97.3%) (69.7–90.6%) (49.9–71.3%)
    p-value p<0.00001 p<0.00001 p<0.00001
    1 Ages 4–17 years At an Aimmune-sponsored event the same day as the late-breaking oral presentation, an exploratory analysis showed that patients with baseline psIgE less than or equal to 100 kU/L tended to have more favorable outcomes than those with baseline psIgE above 100 kU/L. The lower peanut-specific IgE group had a higher overall completer rate, a higher response rate at the 1000-mg endpoint, fewer GI-related withdrawals, and no severe treatment-related adverse events.
  • There were no deaths or suspected, unexpected serious adverse reactions (SUSARs) in the trial, and the incidence of serious adverse events (SAEs) was low, as 1.1% of AR101 patients experienced SAEs that were possibly related to treatment. One AR101 patient (0.2%) experienced a severe SAE of anaphylaxis and withdrew from the trial; this patient had high peanut-specific IgE (>100 kU/L) at the start of the trial. There were no cases of anaphylactic shock observed in the trial.
  • Most AR101 patients (85.5%) did not experience any investigator-reported systemic hypersensitivity reactions (SHRs) during the trial. Among those (14.5%) who did, nearly all (98.2%) had mild or moderate reactions.
  • Aimmune expects to submit a Biologics License Application (BLA) for AR101 with the FDA by the end of 2018, followed by a Marketing Authorisation Application (MAA) with the European Medicines Agency (EMA) in the first half of 2019. In the United States , AR101 has FDA Fast Track Designation, as well as FDA Breakthrough Therapy Designation for peanut-allergic patients ages 4–17.
  • • On February 20, 2018, Aimmune Therapeutics announced that its pivotal Phase 3 PALISADE efficacy trial of AR101 met the primary endpoint. PALISADE enrolled 499 patients ages 4–17, 496 of whom received treatment. After approximately one year of treatment, patients completed an exit double-blind, placebo-controlled food challenge (DBPCFC). In the primary analysis of 496 patients ages 4–17, 67.2% of AR101 patients tolerated a single highest dose of at least 600 mg of peanut protein (1043 mg cumulative) with no more than mild symptoms in the exit DBPCFC, compared to 4.0% of placebo patients. The corresponding difference in response rates was 63.2% (p<0.00001, 95% CI=53.0–73.3%), and, at 53%, the lower bound of the 95% confidence interval greatly exceeded the pre-specified success criterion, which was 15%. Additionally, 50.3% of AR101 patients tolerated a single highest dose of 1000 mg of peanut protein (2043 mg cumulative), compared to 2.4% of placebo patients (p<0.00001). In order to minimize the risk of assessment bias, the primary endpoint evaluations were conducted by independent, blinded assessors, who were not involved in patients’ ongoing care in the trial and who were blinded to treatment assignment and the sequence of the DBPCFCs.
Intent-to-Treat Efficacy: Percent of Patients Tolerating Each Dose in Exit DBPCFC1
300 mg 600 mg 1000 mg
AR101 (n=372) 76.6% 67.2% 50.3%
Placebo (n=124) 8.1% 4.0% 2.4%
95% CI difference (58.6–78.5%) (53.0–73.3%) (38.0–57.7%)
p-value p<0.00001 p<0.00001 p<0.00001
1 Ages 4–17
  • Of patients ages 4–17, 296 patients (79.6%) from the AR101 arm completed the trial, compared to 116 patients (93.5%) from the placebo arm. Of these AR101 completers, 96.3% tolerated a single highest dose of at least 300 mg (443 mg cumulative) of peanut protein in the exit DBPCFC, 84.5% tolerated at least 600 mg (1043 mg cumulative), and 63.2% tolerated 1000 mg (2043 mg cumulative). Additionally, AR101 significantly reduced symptom severity at each exit DBPCFC dose level, compared to placebo.
Completer Efficacy: Percent of Patients Tolerating Each Dose in Exit DBPCFC1
300 mg 600 mg 1000 mg
AR101 (n=296) 96.3% 84.5% 63.2%
Placebo (n=116) 8.6% 4.3% 2.6%
95% CI difference (78.0–97.3%) (69.7–90.6%) (49.9–71.3%)
p-value p<0.00001 p<0.00001 p<0.00001
1 Ages 4–17
  • PALISADE enrolled a highly allergic patient population, and enrollment was balanced for baseline disease characteristics between the two treatment arms. Patients in the primary analysis group of ages 4–17 tolerated no more than 30 mg of peanut protein in the entry DBPCFC; additionally, 72.2% had a past medical history of anaphylaxis, 53.0% had a present or previous diagnosis of asthma, and 65.5% reported multiple food allergies.In the trial’s primary analysis group of ages 4-17, 496 patients from both arms (372 AR101 and 124 placebo) were evaluable for safety. In both arms, the incidence of serious adverse events (SAEs) was low. A total of 10 patients experienced SAEs, none of which were considered life-threatening: nine of these patients were in the AR101 arm (2.4%) and one was in the placebo arm (0.8%). Of the nine AR101 patients who experienced a SAE, five patients experienced mild or moderate SAEs. The other four AR101 patients experienced severe SAEs, which, for two of these patients, were not related to treatment (a concussion and a viral asthmatic exacerbation). Of the two patients who experienced severe SAEs related to treatment, both of whom had elevated baseline peanut-specific IgE levels greater than 100 kU/L, one experienced anaphylaxis, and the other experienced wheezing on the first day of treatment. Both of these patients discontinued from the study.In ages 4–17, 20.4% of AR101 patients and 6.5% of placebo patients discontinued the trial. In the AR101 arm, 12.4% of patients discontinued due to investigator-reported adverse events, including 6.7% due to gastrointestinal adverse events and 2.7% due to systemic allergic hypersensitivity reactions. In the placebo arm, 2.4% of patients discontinued due to investigator-reported adverse events.
Discontinuations in the AR101 Group1
AR101 (n=372)
% n
Total discontinuations regardless of causality 20.4% 76
Discontinuations not related to adverse events 8.0% 30
Discontinuations related to adverse events 12.4% 46
• Gastrointestinal2 6.7% 25
• Systemic hypersensitivity reactions3 2.7% 10
• Respiratory system 1.1% 4
• Cutaneous 0.8% 3
• Other4 1.1% 4
1 Ages 4-17 2 Includes one case of biopsy-confirmed eosinophilic esophagitis; no additional cases were identified in the study 3 Of these, seven were investigator-identified anaphylaxis events (one severe) 4 Includes one discontinuation for each: acute viral illness, eye pruritus, headache, and an unknown factor
  • One patient (an 11-year-old boy), with a baseline peanut-specific IgE level of 352 kU/L) was discontinued from the study after being found to have biopsy-confirmed, moderate eosinophilic esophagitis during the study. By the time the patient left the study, the symptoms had resolved. No additional cases of eosinophilic esophagitis were identified in the study.Hypersensitivity reactions are an expected and common side effect of oral immunotherapy. In PALISADE patients ages 4–17, 14.5% of AR101 patients experienced systemic hypersensitivity reactions, and for 98.2% of those patients, the reactions were mild or moderate. In comparison, 3.2% of placebo patients experienced systemic hypersensitivity reactions, and for all of those patients, the reactions were mild or moderate.Across all ages, there were no deaths or suspected, unexpected serious adverse reactions (SUSARs) in the trial.PALISADE included 55 adult patients ages 18–49 who were randomized into the study, with 41 patients in the AR101 arm and 14 patients in the placebo arm. In the AR101 arm, 21 patients discontinued treatment, eight due to adverse events. In an exploratory analysis of this age group, 85% of AR101 patients who completed the study tolerated at least 600 mg of peanut protein in the exit DBPCFC, compared to 15% of placebo patients who completed the study.
  • • On January 8, 2018, Aimmune Therapeutics announced that the company plans to report topline results in February from its pivotal Phase 3 PALISADE trial of AR101 for peanut allergy, following the completion of the 554-subject trial in late 2017. To support regulatory filings, Aimmune also plans a data readout from the PALISADE follow-on trial, ARC004, in the third quarter of 2018.
  • • On June 20, 2017, Aimmune Therapeutics reported findings from pre-randomization, preliminary clinical data collected from the European screening population of the PALISADE trial in AR101 program. The data were presented at the 2017 European Academy of Allergy and Clinical Immunology (EAACI) Congress in Helsinki. Aimmune presented a preliminary dataset of 166 patients in Europe who underwent a screening double-blind, placebo-controlled food challenge (DBPCFC) to determine eligibility for the PALISADE trial (57% ages 4–11, 28% ages 12–17, and 15% ages 18–55; 59% male). The DBPCFC allowed a progression of doses of peanut protein up to a dose of 100 mg (1 mg, 3 mg, 10 mg, 30 mg, and 100 mg). Patients who reacted with dose-limiting symptoms at or before the 100-mg dose (“reactors”) were eligible for randomization into the trial. Observations from preliminary evaluable baseline characteristics results from these patients included the following:
  • - Sixty-two percent of the subjects screened were reactors, who experienced dose-limiting symptoms in the DBPCFC at or before the 100-mg dose (median = 30 mg dose, meaning a cumulative amount of 44 mg peanut protein); 38% were “non-reactors” who consumed all doses in the DBPCFC with no dose-limiting symptoms
  • - Reactors had a statistically significant larger peanut skin-prick test (SPT) wheal diameters, a higher peanut-specific IgE (psIgE) and higher Ara h 2–specific IgE than non-reactors. Ara h 2–specific IgE demonstrated greatest sensitivity and specificity for discriminating between reactors and non-reactors, based on receiver operating characteristic (ROC) curve analysis of the data
  • - SPT, peanut-specific IgE and Ara h 2 were not associated with the severity of reactions during the screening DBPCFC
  • • On June 12, 2017, Aimmune Therapeutics announced that, in the ongoing Phase 3 PALISADE trial of AR101, more than 97 percent of patients currently on study have completed up-dosing. Based on observations of aggregated data to date, Aimmune expects that the percentage of patients completing the entire study (up-dosing and maintenance) will be well ahead of the powering calculations behind the study design. With the vast majority of patients now successfully through up-dosing in PALISADE, Aimmune estimates that final study visits will be completed around year-end 2017, and that topline data will be available in the first quarter of 2018.
  • • On March 6, 2017, Aimmune Therapeutics announced clinical data presented at the 2017 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Atlanta. A late-breaking abstract presented baseline characteristics from 583 peanut-allergic patients who were screened to determine eligibility for the Phase 3 PALISADE trial in North America. Among the inclusion criteria, a double-blind, placebo-controlled food challenge (DBPCFC) administered at screening allowed a progression of doses of peanut protein up to a dose of 100 mg (1 mg, 3 mg, 10 mg, 30 mg, and 100 mg). Subjects who reacted with dose-limiting symptoms at or before the 100 mg dose (“reactors”) were eligible for randomization into the trial. This unique dataset of screening DBPCFCs is the largest ever collected on peanut-allergic patients in the clinical trial context and yielded the following observations and insights:
  • - 457 patients (78%) were reactors, who experienced dose-limiting symptoms in the DBPCFC at or before the 100 mg dose (median = 44 mg cumulative amount of peanut protein); 116 subjects (20%) were “non-reactors” who consumed all 144 mg in the DBPCFC with only mild symptoms or no symptoms at all; 10 subjects (2%) reacted to placebo
  • Reactors demonstrated higher baseline peanut-specific IgE (psIgE) and Ara h2-specific IgE levels and larger peanut skin prick test (SPT) wheal diameters than non-reactors, and psIgE appeared to provide the greatest utility to discriminate between reactors and non-reactors
  • The median psIgE in reactors was 70.2 kUA/L, compared with 5.3 kUA/L in non-reactors (a threshold psIgE of 19.25 kUA/L showed the greatest sensitivity and specificity for predicting reactors)
  • Sensitivity to peanut and severity of symptoms during screening DBPCFCs were not closely linked, and neither was associated with baseline immune parameters or age
  • Also at the AAAAI meeting, Blake Rust, Ph.D., and Erik Wambre, Ph.D., of the Benaroya Research Institute at Virginia Mason (BRI) presented data on peanut-specific effector and regulatory T cells in a blinded subset of samples from patients screened for PALISADE. Key findings from this work include:
  • - Percent of activated CD4+ effector T cells were significantly higher after individuals underwent the DBPCFC as compared to their pre-challenge levels
  • - At baseline, peanut-allergic individuals exhibit higher frequency of peanut-specific effector T cells relative to DBPCFC non-reactors. Peanut-allergic individuals exhibit low frequencies of peanut-specific regulatory T cells at baseline, but higher than those seen in DBPCFC non-reactors
  • - Within the group of patients who reacted to the DBPCFC, two distinct immunophenotypes were observed as defined by mutually exclusive CRTH2 and CCR6 expression.
  • • On February 16, 2017, Aimmune Therapeutics provides an update on ongoing AR101 phase 3 program for peanut allergy based on FDA feedback. The primary efficacy analysis in the ongoing Phase 3 PALISADE trial will now be conducted on ages 4-17 years, which aligns with the Breakthrough Therapy Designation population, based on the company’s discussions with the FDA. The company expects to conduct separate analyses for older patients in PALISADE. Additionally, based on FDA feedback, the company anticipates that the safety database for a potential Biologics License Application (BLA) will include data from at least 600 patients treated with AR101.
  • The PALISADE trial enrolled 554 patients, 90 percent of whom were between ages 4-17. This age group, which represents a high-unmet need for peanut allergy therapy, is the largest segment of the 6 million peanut allergic patients in the United States and Europe.
  • • On November 28, 2016, Aimmune Therapeutics announced that it has completed global enrollment of its Phase 3 PALISADE trial of AR101 for the treatment of peanut allergy, with the total randomized to the trial expected to be approximately 540 patients. Aimmune expects topline data from PALISADE in the fourth quarter of 2017, followed by regulatory submissions for marketing approval of AR101 in 2018 in both the United States and Europe. The company announced completion of North American enrollment in PALISADE in September, ahead of schedule and above target enrollment.
 

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