Background & Aims Gluten ingestion leads to small intestinal mucosal injury in patients with celiac disease, necessitating strict life-long exclusion of dietary gluten. Despite adherence to a ...gluten-free diet, many patients remain symptomatic and still have small intestinal inflammation. In this case, nondietary therapies are needed. We investigated the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial. Methods We established the optimal daily dose of gluten to be used in a 6-week challenge study. Then, in the intervention study, adults with biopsy-proven celiac disease were randomly assigned to groups given ALV003 (n = 20) or placebo (n = 21) together with the daily gluten challenge. Duodenal biopsies were collected at baseline and after gluten challenge. The ratio of villus height to crypt depth and densities of intraepithelial lymphocytes were the primary end points. Results A daily dose of 2 g gluten was selected for the intervention study. Sixteen patients given ALV003 and 18 given placebo were eligible for efficacy evaluation. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height to crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P = .0007; density of CD3+ intraepithelial lymphocytes changed from 61 to 91 cells/mm after challenge; P = .0003). However, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3+ intraepithelial lymphocyte counts differed significantly from baseline to week 6 ( P = .0133 and P = .0123, respectively). There were no statistically significant differences in symptoms between groups. Conclusions Based on a phase 2 trial, the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten. Clinicaltrial.gov , Numbers: NCT00959114 and NCT01255696.
Background
The benefit of daily administration of Peanut (Arachis hypogaea) Allergen Powder‐dnfp (PTAH)—formerly AR101—has been established in clinical trials, but limited data past the first year of ...treatment are available. This longitudinal analysis aimed to explore the impact of continued PTAH therapeutic maintenance dosing (300 mg/day) on efficacy, safety/tolerability, and food allergy‐related quality of life.
Methods
We present a subset analysis of PALISADE‐ARC004 participants (aged 4–17 years) who received 300 mg PTAH daily for a total of ~1.5 (Group A, n = 110) or ~2 years (Group B, n = 32). Safety assessments included monitoring the incidence of adverse events (AEs), accidental exposures to food allergens, and adrenaline use. Efficacy was assessed by double‐blind, placebo‐controlled food challenge (DBPCFC); skin prick testing; peanut‐specific antibody assays; and Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) scores.
Results
Continued maintenance with PTAH increased participants’ ability to tolerate peanut protein: 48.1% of completers in Group A (n = 50/104) and 80.8% in Group B (n = 21/26) tolerated 2000 mg peanut protein at exit DBPCFC without dose‐limiting symptoms. Immune biomarkers showed a pattern consistent with treatment‐induced desensitization. Among PTAH‐continuing participants, the overall and treatment‐related exposure‐adjusted AE rate decreased throughout the intervention period in both groups. Clinically meaningful improvements in FAQLQ and FAIM scores over time suggest a potential link between increased desensitization as determined by the DBPCFC and improved quality of life.
Conclusions
These results demonstrate that daily PTAH treatment for peanut allergy beyond 1 year leads to an improved safety/tolerability profile and continued clinical and immunological response.
Daily administration of Peanut (Arachis hypogaea) Allergen Powder‐dnfp (formerly AR101) beyond the 1‐year PALISADE trial (total treatment of ~1.5 or ~2 years) increased participants’ ability to tolerate peanut protein. This was paralleled by a pattern of immunomodulation consistent with desensitization and an improved safety/tolerability profile. Treatment beyond 1 year was associated with clinically meaningful improvements in self‐reported and caregiver‐reported food allergy‐related quality of life.
Abbreviations: AE, adverse event; ARC004, PALISADE Follow‐on Study; DBPCFC, double‐blind placebo‐controlled food challenge; FAIM, Food Allergy Independent Measure; FAQLQ, Food Allergy Quality of Life Questionnaire; MWD, mean wheal diameter; PALISADE, Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults; PTAH, Peanut (Arachis hypogaea) Allergen Powder‐dnfp; QoL, quality of life; SPT, skin prick test.
Immunotherapy is promising as an efficacious treatment for food allergy. Other food allergy treatments are also under development. However, adverse allergic events during treatment, as well as during ...oral food challenges, are common and reporting is not standardized.
A more nuanced grading scale is needed to create a comprehensive and universal system to categorize adverse events and their severity for food allergy clinical trials.
Starting with the 2012 Consortium for Food Allergy Research (CoFAR) Grading Scale and the World Allergy Organization Grading System, we developed the CoFAR Grading Scale for Systemic Allergic Reactions, Version 3.0, in collaboration with industry partners with expert opinion.
The revised CoFAR Grading Scale for Systemic Allergic Reactions has 5 levels of increasing severity, ranging from generalized urticaria, localized angioedema, rhinitis, and abdominal pain (grade 1) to death (grade 5). Systemic reactions are further categorized within each grade by relevant organ system. Mild, single-system reactions are differentiated from mild, multisystem reactions. Lower respiratory tract symptoms are graded on the basis of response to therapy; those that are refractory to standard treatment (eg, requiring >3 doses of intramuscular epinephrine, continuous intravenous epinephrine infusion, and continuous albuterol nebulization) and respiratory compromise requiring mechanical ventilation are classified as grade 4, life-threatening reactions.
Universal and consistent use of the revised CoFAR Grading Scale beyond the CoFAR centers would allow for better data aggregation and safety comparisons in clinical trials for food allergy.
Eliciting doses (EDs) (eg, ED01 or ED05 values, which are the amounts of allergen expected to cause objective symptoms in 1% and 5% of the population with an allergy, respectively) are increasingly ...being used to inform allergen labeling and clinical management. These values are generated from food challenge, but the frequency of anaphylaxis in response to these low levels of allergen exposure and their reproducibility are unknown.
Our aim was to determine (1) the rate of anaphylaxis in response to low-level peanut exposure and (2) the reproducibility of reaction thresholds (and anaphylaxis) at food challenge.
We conducted a systematic review and individual participant data meta-analysis of studies that reported at least 50 individuals with peanut allergy reacting to peanut at double-blind, placebo-controlled food challenge (DBPCFC) and were published between January 2010 and September 2020. Risk of bias was assessed by using National Institute for Clinical Excellence methodologic checklists.
A total of 19 studies were included (covering a total of 3151 participants, 534 of whom subsequently underwent further peanut challenge). At individual participant data meta-analysis, 4.5% (95% CI, 1.9% to 10.1%) of individuals reacted to 5 mg or less of peanut protein with anaphylaxis (moderate heterogeneity I2 = 57%). Intraindividual thresholds varied by up to 3 logs, although this variation was limited to a half-log change in 71.2% (95% CI, 56.2% to 82.6%) of individuals. In all, 2.4% (95% CI, 1.1% to 5.0%) of patients initially tolerated 5 mg of peanut protein but then reacted to this dose at subsequent challenge (low heterogeneity I2 = 16%); none developed anaphylaxis.
Around 5% of individuals reacting to an ED01 or ED05 level of exposure to peanut might develop anaphylaxis in response to that dose. This equates to 1 and 6 anaphylaxis events per 2500 patients exposed to an ED01 or ED05 dose, respectively, in the broader population of individuals with peanut allergy.
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Background & Aims Gluten ingestion leads to symptoms and small intestinal mucosal injury in patients with celiac disease. The only option is the strict lifelong exclusion of dietary gluten, which is ...difficult to accomplish. Many patients following a gluten-free diet continue to have symptoms and have small intestinal mucosal injury. Nondietary therapies are needed. We performed a phase 2 study of the ability of latiglutenase, an orally administered mixture of 2 recombinant gluten-targeting proteases, to reduce mucosal morphometric measures in biopsy specimens from patients with celiac disease. Methods We performed a double-blind, placebo-controlled, dose-ranging study to assess the efficacy and safety of latiglutenase in 494 patients with celiac disease (with moderate or severe symptoms) in North America and Europe, from August 2013 until December 2014. Participants reported following a gluten-free diet for at least 1 year before the study began. Patients with documented moderate or severe symptoms and villous atrophy (villous height:crypt depth ratio of ≤2.0) were assigned randomly to groups given placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. Subjects completed the Celiac Disease Symptom Diary each day for 28 days and underwent an upper gastrointestinal endoscopy with duodenal biopsy of the distal duodenum at baseline and at weeks 12 and 24. The primary end point was a change in the villous height:crypt depth ratio. Secondary end points included numbers of intraepithelial lymphocytes, serology test results (for levels of antibodies against tissue transglutaminase-2 and deamidated gliadin peptide), symptom frequencies, and safety. Results In a modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in villous height:crypt depth ratio, numbers of intraepithelial lymphocytes, or serologic markers of celiac disease. All groups had significant improvements in histologic and symptom scores. Conclusions In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.
Abstract Background Celiac disease is a chronic inflammatory condition with wide ranging effects on individual’s lives caused by a combination of symptoms and the burden of adhering to a gluten-free ...diet (GFD). Objectives To further understand patients’ experience of celiac disease, the impact it has on health-related quality of life (HRQOL), and to develop a conceptual model describing this impact. Methods Adults with celiac disease on a GFD reporting symptoms within the previous 3 months were included; patients with refractory celiac disease and confounding medical conditions were excluded. A semistructured discussion guide was developed exploring celiac disease symptoms and impact on patients’ HRQOL. An experienced interviewer conducted in-depth interviews. The data set was coded and analyzed using thematic analysis to identify concepts, themes, and the inter-relationships between them. Data saturation was monitored and concepts identified formed the basis of the conceptual model. Results Twenty-one participants were recruited, and 32 distinct gluten-related symptoms were reported and data saturation was reached. Analysis identified several themes impacting patients’ HRQOL: fears and anxiety, day-to-day management of celiac disease, physical functioning, sleep, daily activities, social activities, emotional functioning, and relationships. The conceptual model highlights the main areas of impact and the relationships between concepts. Conclusions Both symptoms and maintaining a GFD have a substantial impact on patient functioning and HRQOL in adults with celiac disease. The conceptual model derived from these data may help to design future patient-reported outcomes as well as interventions to improve the quality of life in an individual with celiac disease.
Background
The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to ...peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut‐allergic individuals undergoing oral desensitization immunotherapy with AR101.
Methods
Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T‐cell reactivity to peanut.
Results
The absence of clinical reactivity to the entry double‐blinded placebo‐controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T‐cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut‐reactive TH2A cells were observed in many but not all peanut‐allergic patients and their level in peripheral blood correlates with T‐cell reactivity to peanut and with serum peanut‐specific IgE and IgG4 levels. POIT reshaped circulating peanut‐reactive T‐cell responses in a subset‐dependent manner. Changes in basophil and T‐cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut‐reactive Treg cell frequency was observed between groups.
Conclusion
Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut‐reactive T effector cell responses supporting its potential as an immunomodulatory therapy.
CRTH2+ pTeff cells and CCR6+ pTeff cells represent two mutually exclusive, nonoverlapping cellular and molecular entities involved in food‐allergic diseases. Circulating CRTH2+ pTeff cells are mostly restricted to peanut‐allergic individuals who react to the 100 mg DBPCFC compared to those with lower clinical sensitivity to peanut. Changes in basophil and T‐cell responses to peanut closely parallel clinical benefits to POIT and resemble responses in those that did not react to the baseline 100 mg DBPCFC.Abbreviations: BAT‐EC50, concentration of allergen corresponding to 50% of maximal activation of basophils in basophil activation test; CCR6, C‐C motif chemokine receptor 6; CRTH2, chemoattractant receptor‐homologous molecule expressed on Th2 cells; DBPCFC, double‐blinded placebo‐controlled peanut challenge; FOXP3, forkhead box P3; freq, frequency; GATA3, GATA binding protein 3; HPGDS, hematopoietic prostaglandin D synthase; IFNG, interferon gamma; IL, interleukin; PALISADE, Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults; POIT, peanut oral immunotherapy; PPARG, peroxisome proliferator activated receptor alpha; pTeff, peanut‐reactive T cell; RORC, RAR related orphan receptor C; ST2, suppression of tumorigenicity 2
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Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions.
This study aimed to determine whether inherent ...qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT).
We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT.
Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6−CRTH2+ and CCR6+CRTH2−). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation.
Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.
Background
Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long ...gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease.
Aims
The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials.
Methods
In study 1 (
N
= 28) the study drug was administered in the fasted state; in study 2 (
N
= 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics).
Results
All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (
N
= 8) and 88 ± 5% (
N
= 8), respectively, of one gram of wheat bread gluten.
Conclusions
ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.
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