Discussion
These results from a pooled safety analysis of clinical trials with 929 adults and adolescents with allergic rhinitis and/or conjunctivitis induced by birch pollen, revealed no major safety concerns in relation to daily at-home use of the SQ tree SLIT-tablet. Thus, the safety profile supports daily at-home sublingual administration once the first dose is tolerated when administered under medical supervision: Most application-site reactions were local reactions of the mouth, throat, and ear and were generally occurring early in treatment and were transient, and self-resolving. Also, no anaphylactic reactions or IMP-related SAEs were reported for the subjects.
The results confirm previous safety findings with other SQ sublingual immunotherapy tablets. A grass SLIT-tablet showed a similar safety profile dominated by local allergic applications-site reactions primarily in the oral cavity and throat of mild or moderate severity with an early onset and transient and self-resolving AEs16-17. Also, the safety profile of a house dust mite SLIT-tablet revealed transient, mild local allergic reactions representing the most commonly occurring adverse reactions18.
Around 70 percent of individuals with birch pollen allergy develop pollen food syndrome (PFS)1, and in the present study 64% of subjects had PFS. This PFS subpopulation could be expected to be more challenged in relation to their allergic disease, and the safety profile may therefore differ compared with a subpopulation with no PFS19. In the present data, subjects with PFS tended to experience more AEs regardless of treatment than subjects without PFS, especially oral pruritus. Of subjects treated with 12 SQ-Bet, oral pruritus was reported by almost half of the subjects with PFS (45%) and was thus far more frequent than in subjects without PFS (29%). This difference was not seen in relation to severity. This high reporting of oral pruritus is in accordance with what is usually seen in relation to PFS19.
The present data suggest no increased risk of asthma events among all subjects treated with 12 SQ-Bet. In addition, no acute asthma worsening was seen in subjects with a medical history of asthma. This is in line with the general safety profile of sublingual immunotherapy revealing no greater risk for adverse reactions in well controlled asthma7. However, in the studied population, subjects with severe and/or uncontrolled asthma were excluded, and the safety profile of 12 SQ-Bet remains to be investigated in this subpopulation.
Patients with birch pollen allergy may show urticaria or worsening of atopic dermatitis when exposed to birch pollen20-21. In the present pooled safety analysis, only one event of worsening of atopic dermatitis was reported, however we saw more events of urticaria in the group treated with 12 SQ-Bet compared with placebo. Contact urticaria following direct contact to allergen containing SLIT tablets are to be interpreted like PFS developing in the mouth. Only one subject in the active group developed urticaria at sites distant from the local exposure. This may or may not be related to the systemic administration of 12 SQ-Bet, since similar events were reported in the placebo group.
EoE is highly associated with PFS and one study has found that around half of EoE patients had symptomatic PFS.22, 23 In the present study, more than 60% of the subjects had PFS, but the incidence of EoE in populations with PFS has to our knowledge not been investigated.  No cases of EoE were found during treatment, however the length of the studies including 6-9.5 months of treatment might not have been sufficient to detect possible EoE cases.
The studies included in the present pooled safety analysis were all short-term studies conducted during one pollen season. No long-term studies have been conducted with the SQ tree SLIT-tablet, however long-term studies with the grass SLIT-tablet has revealed a favourable safety profile and long-term treatment effect17,24.