Efficacy and safety of the SQ tree sublingual immunotherapy tablet in children and adolescents (5 through 17 years of age) with moderate to severe allergic rhinitis and/or conjunctivitis induced by pollen from birch and trees belonging to the birch homologous group

Despite differences among countries, the incidence and prevalence of allergic
rhinitis and asthma are increasing worldwide. AR/C affects between 10 to 30% of
all adults and up to 40% of children (Pawankar et al. 2011). Sensitisation
rates to 1 or more common allergens among school children are estimated to be
40%-50% (Pawankar et al. 2011). Tree pollen allergy is common across central
and northern Europe and North America and is commonly caused by pollen from the
birch and related trees, also commonly referred to as the birch homologous
group (hereafter referred to as *birch group*). This group currently includes
birch, alder, hornbeam, hazel, beech and oak (Lorenz et al. 2009), although
more species may be included when additional data on cross-reactivity and
allergen homology becomes available (Heath et al. 2015). AIT guidelines
recommend treating allergic patients with AIT using a representative allergen
within a homologous allergen group (Cox et al. 2011; EMEA 2008).
The trees in the birch group are characterised by having Bet v 1 homologous
allergens with a high level of structural sequence identity, leading to
extensive cross-reactivity at the immune response level. Thus, people who are
sensitised to pollen from one of the trees often also experience symptoms in
response to pollen from other members of the birch group. Sensitisation to Bet
v 1 has been estimated up to 24% in adults (Burbach et al. 2009; Chan-Yeung et
al. 2010), and between 14-16% in children (Schmitz et al. 2013; Stemeseder et
al. 2017). The broad cross-reactivity and sequential pollen seasons of birch
related allergens prolong the period of allergic symptoms for people with
allergy to birch. In previous clinical trials conducted by ALK in Europe and
North America with the SQ tree SLIT-tablet, more than 90% of participants with
AR/C induced by birch pollen were also sensitised to alder and hazel
(Biedermann et al. 2019a). Furthermore, Jantunen et al. showed that 95% of
patients diagnosed with birch pollen allergy presented with allergic symptoms
during the alder season (Jantunen et al. 2012). Cross-reactivity of birch
pollen allergens also extends to plant food allergens, resulting in the pollen
food syndrome (Biedermann et al. 2019b).
Treatment options for AR/C include allergen avoidance, symptomatic medications
such as antihistamines and corticosteroids, and AIT (Bousquet et al. 2008).
Avoidance of pollen is difficult to achieve in a normal daily life, and
symptom-relieving medication is widely used, however it does not offer causal
treatment of the allergic disease and up to 44% of patients on optimal
symptom-relieving medication report poor or only partial symptom control
(Valovirta et al. 2008). AIT is the only available treatment modality that can
modify the natural course of the allergic disease by induction of tolerance
(Bousquet et al. 2008). The use of pollen extract for AIT is well-known, both
in SCIT formulations (Blumberga et al. 2011; Bousquet et al. 1998a; Lang &
Hawranek 2006; Winther et al. 2000a; Winther et al. 2000b) and as SLIT-tablets
or drops (Demoly et al. 2016; Durham et al. 2012).

To compare the efficacy of the SQ tree SLIT-tablet to placebo in the treatment
of moderate to severe allergic rhinitis and/or conjunctivitis induced by pollen
from birch and trees belonging to the birch homologous group in children and
adolescents (5 through 17 years of age) based on the average allergic
rhinoconjunctivitis daily total combined score# (average TCS) during the birch
pollen season (BPS)

Key secondary objectives:
To compare the efficacy of the SQ tree SLIT-tablet to placebo based on:
• The average TCS during the tree pollen season (TPS)
• The average allergic rhinoconjunctivitis daily symptom score (average DSS)
during the BPS and TPS
• The average allergic rhinoconjunctivitis daily medication score (average DMS)
during the BPS and TPS
Secondary objectives:
• To compare the safety and tolerability of the SQ tree SLIT-tablet to placebo
• To compare the efficacy of the SQ tree SLIT-tablet to placebo using
additional endpoints based on daily allergic rhinoconjunctivitis symptoms and
rescue medication use
• To compare the efficacy of the SQ tree SLIT-tablet to placebo based on
assessments of quality of life
• To compare the efficacy of the SQ tree SLIT-tablet to placebo based on
patient treatment satisfaction
• To compare the effect of the SQ tree SLIT-tablet to placebo on immunological
parameters to birch, alder, hazel and oak pollen

A phase III, randomised, parallel-group, double-blind, placebo-controlled,
multi-regional trial in children and adolescents with AR/C (with or without
asthma) induced by pollen from birch. The trial consists of 3 periods: a
screening period, a treatment period, which includes pre-seasonal and co
seasonal treatment, and a follow-up period. There may be multiple cohorts
recruited over consecutive seasons to complete the enrolment goal.
The screening visit can take place up to approximately 6 months prior to
randomisation. Eligible subjects will be randomised (1:1) to the SQ tree SLIT
tablet or placebo. The randomisation will be stratified by geographical
location and by age group.
Once randomised, subjects should receive at least 12 weeks pre-seasonal
treatment prior to the TPS. Treatment will continue until 1 week after the end
of the TPS for all subjects, corresponding to up to approximately 12 months of
treatment.
For subjects recruited in the first season (cohort 1) also allergic to grass
pollen, treatment will be extended until 1 week after the end of the grass
pollen season (GPS), corresponding to up to approximately 13 months of
treatment.
Open-label rescue medication for allergic rhinoconjunctivitis will be provided
during the TPS and GPS. Open-label asthma medication will be provided to
subjects with asthma during the TPS and GPS.
A follow-up phone visit will be conducted 1 week after the End-of-treatment
visit.
At least 6 in-clinic visits and 4 telephone contacts are planned for each
subject. The TPS includes hazel, alder, birch and oak pollen seasons.
A data monitoring committee will be established for the trial.

SQ tree SLIT tablet (dose: 12 SQ-Bet) or placebo. Each randomised subject will
receive IMP daily for a maximum of approximately 13 months.

The following side effects are very common (this means that it might happen in
about 1 out of 10 people):
• Itching or irritating feeling in the throat
• Swelling of the mouth
• Prickling feeling or numbness in the mouth or tongue
• Itching in the mouth and ears
The following side effects are common (this means that it might happen in about
1 out of 100 people):
• Runny nose
• Pain in mouth and throat
• Prickling feeling in or loss of feeling in the throat
• Pain when swallowing or difficulty in swallowing
• Feeling of something stuck in the throat
• Pain or burning feeling of the tongue
• Loss of feeling in the mouth
• Swelling of the lips, tongue or throat
• Itchy lips
• Cough, dry throat or changes in the way you speak
• Mouth discomfort
• Changes to taste
• Itching and/or swelling in the mouth and throat after eating certain raw
vegetables, fruits, or nuts (oral allergy syndrome)
• Blisters in the mouth or an area of the mouth that is swollen, red and
painful (inflammation)
• Pain in the stomach
• Diarrhea
• Heartburn (a burning feeling in the throat)
• Swollen red bumps on the skin which can itch, burn or sting (hives) and
itching of the skin
• Chest discomfort
• Nausea (feeling sick and like you might vomit)
• Shortness of breath (difficulty breathing)
• Eye symptoms (e.g. itching, swelling, redness, watery eyes)
Uncommon side effects (this means that it might happen in about 1 out of 1000
people)
• Tightness or swelling of the throat
• Blisters on the lip
• An area of the tongue that is swollen, red and painful (inflammation)
• Mouth ulcers
• Irritation of the oesophagus (the tube connecting your mouth to your stomach)
• Sudden swelling of face, mouth or throat
Other side effects (no information available for how often this occurs)
• Serious allergic reaction
• Allergic inflammation of the oesophagus (eosinophilic oesophagitis)