Sublingual immunotherapy safely, effectively induces peanut allergy remission in toddlers
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- 78.9% of the per-protocol group ingested the full 4,443 mg of peanut protein at month 36.
- Although all of the children experienced reactions, none required epinephrine.
Sublingual immunotherapy was safe and effective in inducing desensitization and remission of peanut allergy in children aged 1 to 4 years, according to a study published in The Journal of Allergy and Clinical Immunology.
Approximately half of these children demonstrated remission 3 months after therapy had ceased as well, Edwin H. Kim, MD, MS, associate professor of medicine at University of North Carolina School of Medicine and division chief of UNC Pediatric Allergy and Immunology, and colleagues wrote.
Oral vs. sublingual immunotherapy
In a prior study published in 2013, Vickery and colleagues reported an association between lower peanut IgE and stronger desensitization as well as a chance for sustained unresponsiveness for 1 month after peanut oral immunotherapy, Kim told Healio.
Knowing that young children who were recently diagnosed tended to have lower peanut IgE, Kim continued, Vickery and colleagues showed in another study published in 2016 that treated toddlers with peanut allergy aged 9 to 36 months had the strongest desensitization to date as well as the highest likelihood of 1 month of sustained unresponsiveness.
“We were curious if this was an effect reserved for OIT or if it could also be true for [sublingual immunotherapy (SLIT)], especially since we anticipated that SLIT is far safer and likely easier to do than OIT,” Kim said.
The two primary advantages that SLIT has over OIT are its safety and ease of administration, Kim said.
“For safety, we know that with OIT, across most studies, about 20% of kids can’t finish treatment due to side effects,” Kim said.
“Allergic reactions are common, much more common than with simple avoidance, and it is expected that a proportion of kids will end up with reactions significant enough to require epinephrine over the course of treatment,” he continued.
The most common side effect with SLIT is itching in the mouth, which goes away on its own after several minutes, Kim said, adding that skin, gastrointestinal and respiratory symptoms are possible but very uncommon with SLIT.
“Although not a perfect measure of safety, even over treatment courses as long as 3 years, no symptoms were significant enough to trigger parents to use epinephrine,” Kim said.
Kim also called OIT very difficult to do because it requires 10 or 11 clinic visits in the first 6 months to build up to the treatment dose. Also, the powder must be mixed with food each time it is dosed.
“Patients need to be sedentary around the time of dosing and dose on a full stomach as these may increase the risk of an allergic reaction,” Kim said. “Patients also frequently have taste, smell and texture aversion to the peanut flour.”
However, SLIT requires four or five visits over 6 months.
“It is pulled straight from the fridge and applied under the tongue and held for 2 minutes,” Kim said. “Then the patient can go about their day.”
There do not appear to be problems with dosing during exercise or on an empty stomach either, Kim continued, and reactions requiring unscheduled clinic visits are uncommon.
Study design, results
Kim and colleagues conducted a randomized, placebo-controlled study that included 50 patients (mean age, 2.4 years; 44% girls; 88% white), of whom 25 received SLIT for peanut and 25 received placebo in the intention-to-treat (ITT) population. Patients received one pump of 1:100 diluted peanut, equating to 2.5 µg peanut protein, or placebo, held under the tongue for 2 minutes before being swallowed. Patients who tolerated this dose in clinic proceeded to administer the dose at home once daily, with four monthly in-clinic escalations until reaching a 4 mg maintenance dose.
At baseline, median cumulative tolerated doses (CTDs) included 143 mg (interquartile range [IQR], 43-143) for the SLIT group and 43 (IQR, 43-143) for the placebo group.
The per-protocol (PP) population included 19 (76%) of the SLIT group and 17 (68%) of the placebo group who completed a double-blind placebo-controlled food challenge (DBPCFC) at 36 months. Also, 16 (64%) patients in the SLIT group and four (16%) in the placebo group completed a DBPCFC at 39 months.
Desensitization — defined as a significant difference in CTD during the 36-month DBPCFC — served as the study’s primary endpoint.
Fifteen patients in the SLIT group (60% of ITT and 78.9% of PP) and none of the patients in the placebo group ingested the full 4,443 mg dose of peanut protein during the 36-month DBPCFC without any dose-limiting symptoms (P < .0001).
Similarly, 12 patients in the SLIT group (48% of ITT and 63% of PP) passed the 39-month DBPCFC, demonstrating remission, the researchers said, compared with none of the patients in the placebo group (P = .0005).
Median CTDs increased from 143 mg to 4,443 mg (P < .0001) for the SLIT group and from 43 mg to 143 mg (P = .024) for the placebo group, both from baseline to month 36. Also, all the SLIT patients experienced increases, but only 13 of the placebo patients experienced increases, with four placebo patients experiencing decreases.
The patients who experienced desensitization had significantly lower peanut-specific IgE (P = .002) and age at enrollment (P = .014) at baseline than the patients who did not as well. Similarly, the patients who experienced remission also had significantly lower peanut sIgE at baseline (P = .013).
Median peanut skin prick test wheal sizes in the SLIT group also had significant decreases from baseline to month 12 (P = .0012), month 24 (P = .0003) and month 36 (P < .0001), but the placebo group did not see any significant changes. At month 36, median peanut SPT results included 3.3 mm for the SLIT group and 12 mm for the placebo group (P < .0001).
Although the decreases in median peanut sIgE for the SLIT group did not reach statistical significance, median peanut-specific IgG4 significantly increased from baseline to month 12 (P = .03), 24 (P = .003) and 36 (P = .004).
The placebo group showed significantly higher peanut sIgE at month 36 (P = .043) and no significant changes in peanut-specific IgG4 or in the ratio of their peanut-specific IgG4 to their IgE.
At month 36, the SLIT group showed significantly lower median peanut sIgE (1 kUA/L vs. 71.8 kUA/L; P = .002) and significantly higher median peanut-specific IgG4/IgE ratios (804.5 vs. 10.6; P = .013) compared with the placebo group.
The researchers found a negative correlation between baseline age and month-36 desensitization DBPCFC outcomes, with a 965 mg DBPCFC decrease for each year of increasing age (r2 = 0.29; P = .018).
Desensitization rates in the SLIT group included 75% of the ITT group and 100% of the PP group among children aged 1 to 2 years, 50% of the ITT group and 75% of the PP group in children aged 2 to 3 years, and 43% of the ITT group and 50% of the PP group among children aged 3 to 4 years.
Remission rates included 58% of the ITT group and 78% of the PP group among children aged 1 to 2 years, 33% of the ITT group and 50% of the PP group in the children aged 2 to 3 years, and 43% for the ITT group and 50% of the PP group for children aged 3 to 4 years.
More patients in the SLIT group experienced missed doses (7.9% vs. 5.6%; P < .0001), with all the participants in both groups reporting at least one adverse event possibly due to the study drug.
For example, 80% of the SLIT group and 28% of the placebo group experienced oropharyngeal itching (P = .0005). But none of the symptoms required treatment with epinephrine, the researchers wrote, with no significant differences between the groups in percentages of patients treated with antihistamines and albuterol for dosing reactions.
Additionally, 5% of the SLIT doses and 1.6% of the placebo doses were followed by symptoms, with multisystem reactions after four SLIT doses and nine placebo doses. The SLIT reactions included two cases of oral itch and belly pain, one case of nasal congestion and belly pain, and one case of rhinorrhea, throat clearing and cough.
Seven of the SLIT participants and 10 of the placebo participants discontinued their participation in the study, but the researchers did not believe that any of these discontinuations were due to dosing safety.
Conclusions, next steps
Based on these results, the researchers concluded that peanut SLIT safely and successfully induced desensitization in most children aged 1 to 4 years with peanut allergy.
“The levels of desensitization, both milligram and percent achieving this level, are the highest that have been reported with SLIT,” Kim said.
“The kids take 4 mg daily, and they end up safely eating over 4,443 mg of peanut at the end of treatment. In addition, after stopping for 3 months, more than half of the kids still have that high level of protection that we are considering a form of remission,” he continued.
Children eat actual peanuts with OIT, usually in large amounts, Kim said, so protection in amounts of thousands of milligrams is not unexpected.
“With SLIT, the dosing is a liquid form and a very small amount, and to achieve these levels is quite exciting,” Kim said.
The FDA has not approved any SLIT products yet, Kim said, although some clinics are looking into providing versions of SLIT with available extracts.
“Clinical trials could also be an avenue, as a couple of companies are developing versions of SLIT to present to the FDA, including a dissolving tablet as well as a toothpaste formulation,” he said.
The researchers also said that larger trials are necessary to validate their findings, and their next step is to expand their work to other foods because many children are allergic to multiple foods in addition to peanut.
“We anticipate that other foods could be similarly treated, but it will be important to find the right dose of treatment and confirm that the safety in other foods is equally reassuring,” Kim said.
In the lab, Kim said that he and his colleagues are continuing to investigate the exact immune changes that are happening in the mouth so they can find ways to strengthen and optimize the treatment.
“This could lead to different versions of the treatment or possibly additives that might prepare the immune system to better respond to the treatment,” Kim said.
References:
- Vickery BP, et al. J Allergy Clin Immunol. 2013;doi:10.1016/j.jaci.2013.11.007.
- Vickery BP, et al. J Allergy Clin Immunol. 2016;doi:10.1016/j.jaci.2016.05.027.
For more information:
Edwin H. Kim, MD, MS, can be reached at edwinkim@email.unc.edu.
Perspective
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The findings here are quite impressive and very promising. The focus here regards a young age group. The same group of authors recently published an open trial of this therapy in an older age group (mean age, 7 years), also with impressive but not quite as dramatic results as in this randomized and placebo-controlled study.
The results here also far surpassed a study we performed with this therapy in children and adults (median age, 15 years) where the increase in the amount of peanut that could be consumed and the persistence of the effect were a fraction of that seen here.
Even in the present study, the youngest children had the best outcomes. Reassuringly, all of the peanut SLIT studies across the age ranges have a very good safety profile in common.
Although comparing the different studies that used different SLIT dosing regimens and outcome measures is unfair, the trend is apparent, and it raises the point that younger age appears more treatable, as also suggested in studies of OIT that use higher doses than SLIT, such as the IMPACT study.
The authors discuss there being a more “pliable” immune system for the youngest children, which is certainly possible, but the younger participants in these studies generally have lower peanut IgE levels than older children and adults who are studied with these therapies. However, they are often given the same doses across ages and weights — that is, the small SLIT dose on a per-weight basis is higher for smaller children. And, perhaps, people at any age with milder immune responses are more treatable.
Whatever the underlying reason, the results here are very compelling for peanut SLIT in this age group.
A caveat here is the small size of the study. Also, although the study was randomized, it is notable that the placebo group at baseline had substantially higher peanut IgE levels (median, 19.5 kUA/L vs. 4.3 kUA/L) and a lower baseline reaction dose (median, 43 mg vs. 143 mg) than the group that was treated.
The authors point out that the strong significance levels for the outcomes across multiple analyses support the positive treatment effect, but it seems possible that the dramatic differences were influenced by this unlucky randomization. Despite this caveat, the results are compelling and clearly provide an impetus to explore this therapy in larger studies.
References:
Burks AW, et al. J Allergy Clin Immunol. 2015;doi:10.1016/j.jaci.2014.12.1917.
Jones SM, et al. Lancet. 2022;doi:10.1016/S0140-6736(21)02390-4.
Kim EH, et al. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.01.036.
Perspective
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Here, Kim and colleagues describe a randomized controlled trial of peanut SLIT in young children aged 1 to 4 years. This study provides important information about SLIT, but also about food allergen immunotherapy for younger children.
This protocol utilized a gradual dose escalation until the 4 mg maintenance dose was reached. This study found that 60% of the peanut SLIT ITT group could tolerate 4,443 mg at month 36. That is a dose much larger than the maintenance dose and equivalent to approximately 15 peanuts. Perhaps most exciting is that 48% passed the challenge after 3 months of avoidance.
This finding is in line with other recent studies that have shown increased likelihood of remission among younger children than what has previously been found in older populations. These studies suggest that there may be a critical window of opportunity when immunotherapy may lead to more long-term immunologic change.
As seen in prior studies, peanut SLIT appeared to be well tolerated without the GI side effects that are commonly seen with OIT. There was also excellent compliance with approximately 92% of doses administered.
This study showed the peanut SLIT may be a safe and efficacious treatment option. Additional SLIT studies are needed in a larger and more diverse patient population to see if the findings would be replicated.
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