ITULAZAX 12SQ-BET Oral lyophilisate Ref.[50425] Active ingredients:

Pharmacotherapeutic group: Allergen extracts, tree pollen
ATC code: V01AA05

Mechanism of action

ITULAZAX is an allergen extract for immunotherapy of tree (birch homologous group) pollen-induced allergic rhinitis and/or conjunctivitis. Allergy immunotherapy with allergen products is the repeated administration of allergens to allergic individuals with the purpose of modifying the immunological response to the allergen.

The pharmacodynamic effects of allergy immunotherapy are exerted on the immune system, but the exact mechanism of action underlying clinical efficacy is not fully understood. However, several studies have shown that the immunological response to allergy immunotherapy is characterised by an induction of allergen specific IgG4. Allergen specific IgG4 competes with IgE for the binding to allergens, and thereby reduces activation of immune cells. The reduction of IgE binding to birch allergen has been confirmed for subjects treated with ITULAZAX and this was accompanied by induction of a treatment induced systemic IgG4 response specific for birch. Extensive IgE cross-reactivity was observed towards the birch homologous trees before treatment initiation, thus indicating allergic sensitisation to the trees in this group, and a comparable level of IgG4 cross-reactivity towards the birch homologous trees was observed after treatment with ITULAZAX. The increase in IgG4 levels is observed after approximately 1 month of treatment and maintained throughout the treatment period.

Treatment with ITULAZAX also results in a rise in serum levels of apple (Mal d 1) specific IgG4.

Clinical efficacy and safety

The efficacy and safety of ITULAZAX in the treatment of subjects with birch pollen-induced allergic rhinitis and/or conjunctivitis with or without asthma (controlled/partly controlled) has been demonstrated in 2 double-blind, randomised, placebo-controlled clinical trials (1 phase II and 1 phase III). Overall, ITULAZAX was well tolerated in birch pollen allergic subjects with no major safety concerns detected. ITULAZAX leads to improvements in disease control and quality of life reflected by symptom relief and reduced need for allergy pharmacotherapy/symptom relieving medication. Efficacy results from the 2 trials are described below.

Phase II (TT-03)

The phase II trial was a randomised, double-blind, placebo-controlled trial conducted in an allergen exposure chamber with doses of 2, 7 and 12 SQ-Bet (ITULAZAX) in 219 adults with birch pollen-induced rhinoconjunctivitis. The ITULAZAX group receiving 12 SQ-Bet included 54 subjects and the placebo group included 56 subjects. Subjects were exposed to birch pollen before treatment initiation and after 8, 16 and 24 weeks of treatment, and to oak pollen before treatment initiation and after 24 weeks of treatment. The primary endpoint was the average total symptom score during the week 24 birch challenge session. Total symptom score was calculated as the sum of the total nasal symptom score and the total ocular score.

Treatment with ITULAZAX resulted in a reduction in total symptom score during birch pollen exposure compared to placebo after 16 weeks of treatment, which was sustained until end-of-trial after 24 weeks of treatment (Table 1). Treatment with ITULAZAX also resulted in a reduction in total symptom score during oak pollen exposure after 24 weeks of treatment (Table 1). The results suggest that the clinical efficacy of ITULAZAX is similar during birch and oak pollen exposure.

Table 1, Analyses related to symptom scores during birch and oak sessions (TT-03):

N = Number of subjects in analysis set, modified FAS = all subjects with observations, *p-value is for the test of an absolute difference of 0.

The response variable in the analysis was: the square root of the average TSS (results were back-transformed to original scale). The analysis was based on an LME model with treatment, visit (8, 16 and 24 weeks) and their two-factor interaction as fixed class effects, the average TSS at baseline as a fixed regression variable and chamber cohort and subject as random class variables.

TSS= total symptom score. CL = confidence limits.

Phase III (TT-04)

The phase III trial was a randomised, double-blind, placebo-controlled, multinational trial in 634 adults and adolescents (age 12-65) with birch pollen induced allergic rhinitis and/or conjunctivitis. Subjects received ITULAZAX (12 SQ-Bet) or placebo for approximately 16 weeks prior to start of the tree pollen season and continued throughout the season with an average treatment duration of 32 weeks.

The primary endpoint was the average total combined score (TCS) of rhinoconjunctivitis symptoms and medication use during the birch pollen season (BPS).

The pre-defined key secondary endpoints were the TCS during the tree pollen season (TPS), which was defined by the combined alder, hazel and birch pollen seasons, and the average rhinoconjunctivitis daily symptom score (DSS) during the BPS and TPS. Pre-defined secondary endpoints included the daily medication score (DMS) during the BPS and TPS.

Treatment with ITULAZAX resulted in a statistically significant treatment effect during both the BPS and the TPS. Subjects on ITULAZAX experienced reductions in symptoms and medication scores compared to placebo for an average of 50 days (average duration of the TPS) (Table 2).

Table 2. Analyses related to symptom and medication scores during pollen seasons (TT-04):

N = number of subjects with observations, CL = confidence limits, TCS = total combined score, BPS = birch pollen season, TPS = tree pollen season, FASBPS = subjects in full analysis set with observations during the BPS, DSS = daily symptom score, DMS = daily medication score, *p-value is for the test of an absolute difference of 0.

DSS was the sum of 4 rhinitis and 2 conjunctivitis symptoms (range 0-18).

DMS was the sum of rescue medication provided by the sponsor (range 0-20).

TPS: Defined as days included in any of the hazel, alder and birch pollen seasons.

BPS: The start date was defined as the first day of 3 consecutive days with birch pollen counts ≥30 grains/m³ and the stop date was defined as the last day in the last occurrence of 3 consecutive days with birch pollen count ≥30 grains/m³.

Alder and hazel seasons: The start date was defined as the first day of 3 consecutive days with pollen counts ≥10 grains/m³ and the stop date was defined as the last day in the last occurrence of 3 consecutive days with pollen count ≥10 grains/m³.

Additional secondary endpoints supported the overall treatment effect of ITULAZAX. Subjects treated with ITULAZAX reported more days with minimal allergic rhinoconjunctivitis symptoms compared to placebo subjects (mild days) and fewer days with severe rhinoconjunctivitis symptoms during the BPS (Table 3). Rhinitis quality of life as measured by RQLQ was also improved for subjects in the ITULAZAX group compared to placebo during the BPS (Table 4). Similar results were obtained for mild/severe days and RQLQ during the TPS. The results indicated an overall improved well-being for subjects treated with ITULAZAX.

Table 3. Analyses of estimated proportion of mild and severe days during the BPS (FASBPS) (TT-04):

BPS = birch pollen season, FASBPS = subjects in full analysis set with observations during the BPS, N = number of subjects with observations, CL = confidence limits, OR = odds-ratio.

OR: calculated as placebo/active.

Mild day: day without intake of antihistamines or olopatadine eye drops and no individual symptom scores higher than 1 (mild).

Severe day: day with DSS≥6 and at least 2 moderate or 1 severe symptom.

Table 4. Analysis of seasonal overall RQLQ during the BPS (FASBPS) (TT-04):

RQLQ = rhinoconjunctivitis quality of life, BPS = birch pollen season, FASBPS = subjects in full analysis set with observations during the BPS, N = number of subjects with observations, CL = confidence limits.

Paediatric population

The efficacy of ITULAZAX in adolescents with birch pollen induced allergic rhinitis and/or conjunctivitis was also investigated in the TT-04 trial (n=25 ITULAZAX, n=32 placebo). Treatment with ITULAZAX resulted in a 31% relative reduction (absolute reduction 1.94) in TCS compared to placebo during the birch pollen season for the adolescent subgroup, but data are limited. The safety of ITULAZAX in adolescents with birch pollen induced allergic rhinitis and/or conjunctivitis was investigated in the TT-02 (phase II) and the TT-04 trial. A descriptive comparison of pooled safety data indicated that tolerability for ITULAZAX is similar in adults and adolescents, but data on adolescents are limited.

The European Medicines Agency has waived the obligation to submit the results of studies with ITULAZAX in children under the age of 5 years in birch pollen-induced allergic rhinitis/rhinoconjunctivitis (treatment of allergic rhinitis/rhino-conjunctivitis).

The European Medicines Agency has deferred the obligation to submit the results of studies with ITULAZAX in children 5 years or older in birch pollen-induced allergic rhinitis/rhinoconjunctivitis (treatment of allergic rhinitis/rhino-conjunctivitis) (see section 4.2 for information on paediatric use).