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.