Six Injections of Modified Adjuvanted PQ Grass Is Effective and Well-Tolerated in a Pivotal Phase III Trial

Abstract

Background: PQ Grass 27600 SU (PQ Grass) cumulative dose is a pre-seasonal, six-injection, aluminium-free, modified subcutaneous immunotherapy product under development for the treatment of allergic rhinitis (AR). A pivotal Phase III randomised double-blind, placebo-controlled clinical trial was performed to evaluate the efficacy and safety of PQ Grass in subjects with seasonal AR.

Methods: An adaptive group sequential trial PQGrass306 (G306) with one pre-defined interim analysis was designed, using 2 parallel groups applying a 1:1 active versus placebo randomisation of patients aged 18-65. The primary efficacy endpoint was the EAACI (European Academy of Allergy and Clinical Immunology) Combined Symptom and Medication Score (EAACI-CSMS_0-6) averaged over the peak grass pollen season (GPS).

Results: 858 subjects were screened and 555 subjects were randomised. Based on the results of the pre-defined interim analysis, the trial was stopped for success showing superiority in favour of PQ Grass. The primary endpoint EAACI-CSMS_0-6 (peak GPS) demonstrated a highly significant and clinically meaningful point difference of PQ Grass over placebo of -0.27 points (95% CI: -0.42 to -0.12), corresponding to a relative difference of -20.3% (p = 0.0005). Highly consistent and beneficial results were obtained for PQ Grass for all key secondary endpoints. Significant induction of blocking IgG4 and IgA antibody subclasses occurred. PQ Grass was well tolerated, and no unexpected safety signals occurred.

Conclusions: This pivotal Phase III trial demonstrated a significant and clinically meaningful effect on the primary endpoint as well as highly consistent secondary endpoint results and a supportive safety profile.

Keywords: allergic rhinoconjunctivitis; grass pollen allergy; pivotal Phase III clinical trial; short‐course treatment; subcutaneous immunotherapy.

FIGURE 1

(A) Clinical trial design. After the screening period (Period 1) the subjects were randomised 1:1 to receive either 6 sequential injections (V2–V7) of active treatment (PQ Grass: 900, 2700, and 6000 SU weekly, and 6000, 6000, and 6000 SU 4‐weekly) to achieve a cumulative nominal dose of 27600 SU or 6 sequential injections of placebo prior to the onset of the annual GPS (Period 2). The trial duration per annual GPS was 9–13 months each, from the start of Screening to the last safety follow‐up call. The average duration of treatment per annual GPS was 11–18 weeks each. V8–V11 were scheduled pre‐, onset of, during, and end of GPS. V8 was conducted ~3–5 weeks after V7 and ~2 weeks ±7 days prior the start of GPS. Two follow‐up calls were performed in Period 4 at 12 and 24 weeks after the last injection. GPS. grass pollen season; SU, standardised units; V, visit. (B) Subject disposition flow diagram (CONSORT diagram). In total, 858 subjects were screened and there were 303 screen failures. Overall, 555 subjects were randomised, 278 to PQ Grass group and 277 to placebo group. One subject randomised to Placebo group received PQ Grass treatment throughout the trial and was assigned to the PQ Grass group for the safety analysis. A total of 48 (8.6%) subjects prematurely discontinued treatment. Within the PQ Grass group, 28 (10.1%) subjects prematurely discontinued treatment. The most common reasons for premature discontinuation of treatment were “unknown” (total 12 [2.2%] subjects; comprising PQ Grass 9 [3.2%] subjects and placebo 3 [1.1%] subjects) and “withdrawal by subject” (total 10 [1.8%] subjects; comprising PQ Grass 6 [2.2%] subjects and placebo 4 [1.4%] subjects). Only 9 (1.6%) subjects prematurely discontinued due to an AE (PQ Grass 4 [1.4%] subjects and placebo 5 [1.8%] subjects) and no subject discontinued due to lack of efficacy. In total, 27 (4.9%) subjects discontinued the trial; the main reason for subjects discontinuing the trial was “withdrawal by subject”, which accounted for 12 (2.2%) subjects (PQ Grass 6 [2.2%] subjects and placebo 6 [2.2%] subjects).

FIGURE 2

(A) Progression of the EAACI‐CSMS_0–6 relatively to the start of the entire 2023 GPS per treatment group along with mean daily pollen exposure. The blue line represents the mean daily EAACI‐CSMS_0–6 (Combined Symptom and Medication Score) of the placebo group, whereas the red line represents the mean daily EAACI‐CSMS_0–6 of the PQ Grass group during the grass pollen season (GPS). The mean daily grass pollen count [grains/m³] (dashed grey line and area highlighted in grey) forms the basis of the definition of the peak GPS (light blue box). The mean daily EAACI‐CSMS_0–6 is constantly lower during the GPS in the PQ Grass group than in the placebo group. (B) Graphical representation of the primary and key clinical secondary endpoints presented as mean relative differences, 95% confidence intervals and corresponding p‐values. This overview summarises the outcome of primary and key secondary endpoints of the clinical trial. The percentage difference of mean EAACI‐CSMS_0–6, mean dSS (daily symptom score), and mean dMS (daily medication score) during peak and entire GPS are shown with corresponding confidence intervals and p‐values comparing PQ Grass and placebo group. In addition, the improvement in mean RQLQ[S] during the peak GPS in the PQ Grass group compared to placebo group is depicted.

FIGURE 3

Serum biomarker efficacy analysis (secondary and exploratory end points). Level of serum grass‐pollen specific IgG4 (all subject population), defined as key secondary endpoint, and IgA1, IgA2 and inhibitory capacity of serum blocking antibodies (IgE‐FAB) (subgroup of subjects, n = 30) as defined as exploratory endpoints were measured in both treatment groups at baseline, post‐treatment before the start of GPS (V7) and during GPS (V10). Grass‐pollen sIgG4 was measured for all treatment subjects in PQ Grass (n = 278; orange) and placebo (n = 277; blue) groups. Grass‐pollen sIgA1, sIgA2 and IgE‐FAB were measured in a sub‐group of subjects (n = 30): PQ Grass (n = 14; orange) and placebo (n = 16; blue). (A) Serum grass sIgG4 was significantly increased in PQ Grass compared to placebo (p < 0.00001) at V7 and remained significantly elevated during GPS at V10 (p < 0.00001). (B) An induction of specific IgA1 level was observed at V7 (p = 0.0006) and V10 (p = 0.0181) compared to baseline. No induction of sIgA1 was observed in the placebo group. Level of serum grass sIgA1 was found significantly higher in the PQ Grass compared to placebo group at V7 (p < 0.01) and V10 (p < 0.001). (C) Significant increase was detected in grass sIgA2 at V7 (p = 0.0026) and V10 (p = 0.0324) compared to baseline in the PQ Grass group. sIgA2 in the placebo group was unchanged compared to baseline. Grass sIgA2 in the PQ Grass group was significantly higher compared to placebo at V7 (p < 0.05) and V10 (p < 0.001). (D) Serum from the PQ Grass group subjects was able to inhibit cooperative allergen‐IgE complexes binding to B cells at V7 and V10 (p < 0.001) vs. baseline. PQ Grass group demonstrated significant decrease in the level of allergen‐IgE complexes at post‐treatment V7 (p < 0.001) and V10 (p < 0.05) compared to placebo. Data are presented as mean ± SEM. Serum sIgG4 (all subject population) was evaluated using a linear mixed model with multiple imputation for missing values on a by‐subject level, 95% CI. Mann–Whitney U test was used to evaluate significance level for sIgA1, sIgA2 and IgE‐FAB in a sub‐group of subjects (n = 30). ⁺ p < 0.05, ⁺⁺ p < 0.01 and ⁺⁺⁺ p < 0.001 denotes statistical significance vs. placebo.