DISCUSSION
PPOIT induced desensitization in 75% and 8-week SU in 60% of patients, with SU persisting at 3-years post-treatment in 55% of initial treatment responders. These findings support the previous PPOIT-001 randomized trial10 results, confirming that PPOIT is highly effective at inducing SU and that SU persists long-term in a majority of treatment responders. Importantly, the PPOIT-002 study applied a more robust measure of SU at end-of-treatment than in the PPOIT-001 trial, with the DBPCFC performed at 8-weeks post-treatment (rather than 2-6 weeks post-treatment) and with a higher cumulative dose of peanut protein (4950mg vs. 4000mg) administered during DBPCFC. Assessment criteria for persistent SU were similar in both studies and yielded similar results with 54.5% of treatment responders retaining SU at 3-years post-treatment in the present study (4950mg peanut protein, 8-weeks elimination) and 70% of treatment responders retaining SU at 4-years post-treatment in PPOIT-001 (4000mg peanut protein, 8-weeks elimination).
Peanut OIT is associated with frequent reactions despite restrictive measures and dosing rules9. Gastrointestinal symptoms in particular are common and eosinophilic esophagitis (EoE) has been reported in 2.7% to 5.3% of treated patients15-17. PPOIT treatment in this study did not result in SAEs or EoE. The majority of participants experienced treatment-related AEs, with the majority of these being mild.
Treatment withdrawals may provide a measure of tolerability. Studies of peanut OIT have consistently reported high withdrawal rates due to treatment-related AEs (12%-15%), in particular treatment-related gastrointestinal AEs (6-10% withdrawals)18-20. A large phase-3 study evaluating a 300mg peanut OIT (Palforzia, AR101), reported that 24.5% (102/416) of subjects in the active treatment group withdrew during the treatment phase, with 11.6% withdrawing due to AE19. In the present study, there were no treatment discontinuations due to PPOIT-related AEs or PPOIT-related gastrointestinal AEs despite 6-7-fold higher maintenance dose; however the sample size is small. Studies have shown Lactobacillus rhamnosus can inhibit intestinal epithelial cell inflammatory responses, increase gut barrier function through increased mucus production, and increase secretory IgA production21-23, which provide a plausible pathway for reduced gastrointestinal symptoms and improved tolerability of OIT.
The mechanisms underpinning desensitization and SU remain elusive. Reduction in allergen-specific IgE reflects modulation of the underlying allergic response to allergen and is associated with successful attainment of SU18,24. Studies suggest that longer duration of OIT has greater ability in reducing allergen-specific IgE levels18,25. In this study, 18-months of PPOIT led to significant reduction in circulating peanut and peanut component sIgE levels, and levels continued to decrease over the 3-years post-treatment, suggesting long-lasting redirection of the underlying allergic response.
HRQL reflects patient perceived benefits of treatment that are not necessarily captured by other endpoints. When evaluating food allergy treatments, improvement in patient reported outcomes is relevant to assessment of cost effectiveness, benefit over risk, and clinical meaningfulness of endpoint improvements. A meta-analysis of peanut OIT studies, most of which induced desensitization without SU, found no convincing evidence that peanut OIT can improve HRQL9. In our study, HRQL/FAQL (FAQLQ-PF/FAIM) improved significantly by 12-months post-treatment and improvements were sustained at 3-years post-treatment. The greatest improvement was for the sub-scale assessing food-related anxiety. Our findings here are consistent with previous results from the PPOIT-001 randomized trial and support the notion that SU leads to improved quality of life whereas desensitization may not12.
The major limitations of this study were the small sample size and open-label design. Known weaknesses of open-label studies include being more at risk of bias and overestimation of treatment-related AEs. Strengths of this study are the comprehensive assessments that were taken, including clinical efficacy, immunological measures and HRQL, as well as the long-term assessment at 3-years post-treatment. Retention from end-of-treatment to 3-years post-treatment was high at 81.25% (13/16). Additionally, peanut allergy diagnosis was confirmed by DBPCFC at study entry and a more robust measure of SU (longer duration of elimination and higher cumulative challenge dose) was applied in this study compared to the previous PPOIT-001 study.
To conclude, sustained treatment benefit is a vital factor to consider in any clinical trial. Findings from this single-arm open-label study demonstrated that PPOIT induced desensitization and SU in a high proportion of treated patients, with persistence of SU out to 3-years post-treatment in a majority of initial responders, and sustained HRQL improvements. Persistent SU was associated with lasting reduction in peanut sIgE, providing compelling evidence that PPOIT modulated the underlying allergic response with durable effect. Further studies are needed to clarify whether the addition of probiotic to peanut OIT contributes to efficacy and/or safety outcomes.