Epicutaneous immunotherapy using an experimental skin patch safely induced a modest but statistically significant treatment response after 52 weeks in a multicenter, randomized controlled trial.
Younger children were more likely to respond to therapy, the authors note. In addition, the researchers point out that immune changes seen among responders were comparable to those for other types of food immunotherapy.
"This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy," write Stacie M. Jones, MD, a pediatric allergist at Arkansas Children's Hospital and a professor of medicine at the University of Arkansas in Little Rock, and colleagues in an article published online October 26 in the Journal of Allergy and Clinical Immunology.
The phase 2 double-blind, placebo-controlled trial assessing the experimental Viaskin Peanut patch (DBV Technologies) was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health and conducted by the NIAID-funded Consortium of Food Allergy Research (CoFAR).
Researchers at five US centers randomly assigned 74 participants aged 4 to 25 years to one of the following daily regimens: the patch at 250 μg (n = 25) or 100 μg (n = 24) peanut protein, or a placebo patch (n = 25). Every 24 hours, the liquid protein extract patch was applied at one of six rotating sites on the upper arm (age >11 years) or between the shoulder blades (age 4 - 11 years).
The majority of participants were male, and the median age was 8.2 years. Baseline demographic characteristics, comorbid atopic diseases, and immunologic measurements were comparable across groups. Median baseline peanut skin prick test response was 12.8 mm, and median peanut immunoglobulin (Ig) E level was 78.2 kUA/L, whereas the median successfully consumed dose was 44 mg peanut protein.
The study's primary end point was a two-criteria treatment success outcome, defined as a participant's ability to meet a 5044-mg oral protein challenge or to tolerate at least a 10-fold increase in consumed dose from baseline to 1 year.
At week 52, 3 (12%) placebo-treated participants, 11 (46%) 100-μg participants, and 12 (48%) 250-μg participants achieved the primary outcome (P = .005 and P = .003, respectively). There was no significant difference between the two active treatment groups (P = .48).
In terms of dose tolerance, median changes in successfully consumed doses were 0, 43, and 130 mg protein in the placebo, 100-μg, and 250-μg groups, respectively (placebo vs 100 μg, P = .014; placebo vs 250 μg, P = .003). "The dosing responses translated to an increase of about a seventh of a peanut for 43 mg and about half a peanut for 130 mg. We consider a peanut to be about 300 mg," Dr Jones told Medscape Medical News.
When stratified by age, the researchers found that most responses occurred among the youngest participants, ages 4 to 11 years, vs those aged 12 years and older. Among younger participants, treatment success was seen in 10 (58.8%) of the participants in the 100-μg group, 11 (61.1%) in the 250-μg group, and 1 (5.6%) in the placebo group. In comparison, among those aged 12 years and older, success was seen in one participant in each treatment group (14.3% each) and two in the placebo group (28.6%).
"The clinical benefit seen in younger children highlights the promise of this innovative approach to treating peanut allergy," said Daniel Rotrosen, MD, director of NIAID's Division of Allergy, Immunology and Transplantation, in a NIAID news release. "Epicutaneous immunotherapy aims to engage the immune system in the skin to train the body to tolerate small amounts of allergen, whereas other recent advances have relied on an oral route that appears difficult for approximately 10 to 15 percent of children and adults to tolerate."
As for adverse events, overall, 14.4% of placebo doses and 79.8% of the two active doses induced reactions, predominantly local and mild, grade 2 or lower reactions (P = .003). Levels of peanut-specific IgG4 levels and IgG4/IgE ratios increased in peanut epicutaneous immunotherapy recipients, and trends emerged for downregulated basophil activation and peanut-specific T-helper cell 2 (TH2) cytokines.
"The most significant and encouraging immunological response was the elevation in IgG4 antibodies, which is often viewed as a blocking antibody that rises in other forms of immunotherapy such as injection, as the treatment effect is seen," Dr Jones said. She and her associates also noted that trends in basophil and TH2 responses indicate that cutaneous exposure may modulate the reactivity of these immune cells.
Overall adherence was unusually high. Of an expected total of 26,372 doses, 25,611 (97.1%) were administered: 97.0% of 4- to 11-year-olds and 97.4% of those older than 11 years. Three participants in both the placebo and 100-μg groups withdrew before study's end. There was only a single withdrawal resulting from grade 3/4 local cutaneous reactions. Mostly mild, nonsite reactions occurred in 18.9% of participants overall, and these were responsive to oral antihistamines or topical corticosteroids, with no need for epinephrine.
The authors concede, however, that the primary outcome of the study, which was the first efficacy trial in the United States, might not have been stringent enough, as it set only a minimum 10-fold change from baseline as the challenge threshold. "If we had set the criterion higher, we may have seen less of a treatment response," Dr Jones told Medscape Medical News.
"The ongoing question in these studies is that we have to figure out what the right threshold is in terms of determining an adequate response," said J. Andrew Bird, MD, director of the Food Allergy Center at the Children's Medical Center and associate professor of pediatric and internal medicine at University of Texas Southwestern Medical Center, both in Dallas, Texas, in an interview with Medscape Medical News. "If someone has reacted, for example, to 100 mg of protein at the challenge and after a year of therapy only reacts at 1000 mg, or about three peanuts, that's very meaningful for a family. But if the increase were from 10 mg to 100 mg, then it's questionable whether that's a significant result for an allergic child."
Dr Bird was a coauthor on a phase 2b trial that evaluated an earlier version of the patch; that study showed a 95% adherence rate and very few adverse reactions. "Overall, it's a simple treatment to use [that] doesn't have a lot of impact on the quality of life and activities of patients compared with other desensitization therapies." He is currently involved in the phase 3 trial testing the skin patch, he said.
Added Stephanie Leonard, MD, director of the Food Allergy Center at Rady Children's Hospital in San Diego, California, "What the study is trying to do is protect children from accidental ingestion of peanut. So going from reacting to a trace amount of peanut to tolerating up to one peanut is something can change your daily life. The point of the study is not to allow kids to eat a peanut butter sandwich every day but to protect them from the unknown, the trace amount you can't see."
The reduction in daily anxiety is "a big deal," Dr Leonard, said, and because the peanut protein stays on the skin treatment surface without entering the bloodstream, the risk for anaphylaxis during treatment is dramatically reduced.
"These data are exciting, but we need to see if there's more benefit long term," Dr Bird said.
Dr Jones agreed that although the initial small improvements at 52 weeks are encouraging, "we will be interested to see if at the end of 2 and a half years, those successes can grow and the effect will be durable and amplified. We don't want to stay at 43 mg and 130 mg." Additional time on therapy should reveal whether epicutaneous immunotherapy confers durable clinically meaningful protection from anaphylaxis to the treatment.
An open-label continuation phase of this study will extend therapy to 130 weeks.
This trial is funded by NIAID, with additional support from the National Center for Advancing Translational Sciences. Dr Jones reports receiving grant support from DBV Technologies, which is developing the Viaskin Peanut patch; FARE; Aimmune Technologies; the National Peanut Board; and the National Institutes of Health/NIAID, and serving as a consultant for Stallergenes. Several coauthors report receiving grant support, serving on the board or consulting for, or owning stock in one or more companies, including DBV Technologies. One coauthor is an employee of and own stocks in Aimmune Therapeutics. One coauthor is an employee of and received stock from DBV Technologies. The rest of the authors have disclosed no relevant financial relationships. Full disclosures can be found in the journal. Dr Bird reports that he is involved in sponsored trials for a variety of interventional food allergy therapeutics. Dr Leonard will be a site investigator for a trial testing the patch, but has no financial stake in DVP Technologies, the patch's maker.
J Allergy Clin Immunol. Published online October 26 2016.
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Cite this: Skin Patch Safe, Modestly Effective for Peanut Allergy - Medscape - Oct 26, 2016.