CINQAERO Concentrate for solution for infusion Ref.[8992] Active ingredients: Reslizumab

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases
ATC code: R03DX08

Mechanism of action

Reslizumab is a humanised monoclonal antibody (IgG4, κ) against the human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5 and interferes with IL-5 binding to its cell-surface receptor. IL-5 is a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. Reslizumab binds human IL-5 with picomolar affinity blocking its biological function; consequently survival and activity of eosinophils are reduced.

Pharmacodynamic effects

Effect on sputum eosinophils

The effect of reslizumab in patients with asthma and elevated sputum eosinophil counts (at least 3%) was evaluated in a 15-week, phase 2, randomised, double-blind, placebo-controlled clinical study with reslizumab 3 mg/kg. Sputum eosinophils were measured in a subset of 38 adult patients at the end of therapy. In this study, the percentage of sputum eosinophils was reduced from a mean baseline value of 17.4% (standard deviation: 15.9%) by 82% at end of therapy in the reslizumab group.

Effect on blood eosinophils

In clinical Studies I and II with reslizumab 3 mg/kg, decreases in blood eosinophil counts were seen following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. In pooled data, mean eosinophil counts were 655 µL^-1 (n=476) and 654 µL^-1 (n=477) for the placebo and reslizumab treatment groups at baseline and were 514 µL^-1 (n=405) and 61 µL^-1 (n=407) at week 52. Eosinophils began to return towards baseline in those reslizumab patients completing a 90-day follow-up assessment (394 µL^-1, n=36). Decreases in blood eosinophils were related to reslizumab levels.

The reduction in blood eosinophil counts by reslizumab in anti-reslizumab antibody-positive patients was not different from patients who were anti-reslizumab antibody-negative.

Clinical efficacy and safety

Overview of clinical efficacy

The efficacy of reslizumab in eosinophilic asthma (blood eosinophils ≥400 µL^-1) was evaluated in three randomised, double-blind, placebo-controlled studies (Studies I to III) from 16 to 52 weeks' duration involving 1268 patients with moderate to severe asthma inadequately controlled on mediumto high-dose inhaled corticosteroids (ICS) (at least 440 μg of fluticasone propionate daily or equivalent) with or without other controllers; prior stable allergen immunotherapy was allowed.

Studies I and II were 52-week, randomised, placebo-controlled studies in patients who had at least one asthma exacerbation requiring systemic corticosteroid use over the past twelve months. Maintenance OCS (up to 10 mg per day prednisone equivalent) were allowed. The patients received either 13 doses of placebo or reslizumab 3 mg/kg administered once every 4 weeks.

Study III was a 16-week, randomised, placebo-controlled study. There was no prior asthma exacerbation requirement for this study. Maintenance OCS was not allowed. The patients received either four doses of placebo or reslizumab 0.3 mg/kg or 3 mg/kg administered once every 4 weeks.

Table 3 presents the demographics and baseline characteristics of Studies I, II and III.

Table 3. Demographics and baseline characteristics of asthma studies I – III:

^a FEV₁=forced expiratory volume in 1 second
^b NA=not available c The GINA classification is based on the Global Initiative for Asthma (GINA) definition:
GINA step 4 patients received medium- to high-dose ICS plus another controller.
GINA step 5 patients received in addition, as an add-on, maintenance OCS.
^d The percentage of patients with refractory asthma (based on the American Thoracic Society [ATS]/European Respiratory Society [ERS] 2000 workshop definition for refractory asthma) from Studies I and II was analysed post hoc.

Studies I and II

The primary efficacy measure for both Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. In both studies, an asthma exacerbation was defined as a worsening of asthma that required the following medical intervention:

1. use of systemic corticosteroids or an increase in the use of ICS treatment for 3 or more days, and/or
2. asthma-related emergency treatment including at least one of the following: an unscheduled visit to their healthcare professional for nebuliser treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or asthma-related hospitalisation.

Overall population

In Studies I and II, patients receiving reslizumab 3 mg/kg had significant reductions in asthma exacerbations (50% and 59%, respectively) compared to placebo (see Table 4). The overall reduction was 54%.

Table 4. Frequency of asthma exacerbations during the 52-week treatment period – Studies I and II, integrated data (Studies I and II) for the overall population and subgroup GINA 4 and 5:

^a Rate adjusted for stratification factors (baseline usage of OCS and geographical region).
^b CI = Confidence interval

In the subset of patients requiring courses of OCS treatment for management of their asthma exacerbation, reslizumab was shown to reduce the frequency of asthma exacerbations by 56% (p<0.0001) and 60% (p<0.0001) in Study I and Study II, respectively. A reduction in asthma exacerbations resulting in hospitalisation or an emergency room visit was observed with reslizumab 3 mg/kg that was not statistically significant (34% [p=0.2572] and 31% [p=0.4020] in Study I and Study II, respectively).

The proportion of patients who did not experience an asthma exacerbation during the 52-week treatment period was higher in the reslizumab 3 mg/kg group (62% and 75%) compared with the placebo group (46% and 55%), in Studies I and II, respectively.

Patients with severe eosinophilic asthma

In Studies I and II, severe eosinophilic asthma is defined as any patients falling into GINA steps 4 and 5 (medium- to high-dose ICS [≥ 440 µg fluticasone propionate] plus another controller, with or without maintenance OCS) with a blood eosinophil count of ≥400 µL-1 at start of treatment. A cohort of 763 patients within Studies I and II met this criterion; the primary efficacy outcome is presented in Table 4. In integrated Studies I and II, patients receiving reslizumab 3 mg/kg had significant reductions in asthma exacerbations (56% for subgroup GINA 4 and 5) compared to placebo.

The effect of reslizumab 3 mg/kg administered once every 4 weeks on secondary endpoints, including FEV₁, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ) and Asthma Symptom Utility Index (ASUI), further supports the efficacy of reslizumab 3 mg/kg compared to placebo. Improvements were observed as early as 4 weeks following the first dose of reslizumab (AQLQ at 16 weeks) and sustained through week 52.

Results for FEV₁, ACQ and AQLQ are shown in Table 5 below for the overall population, and subgroup GINA 4 and 5.

Table 5. Treatment difference in mean change from baseline for selected secondary efficacy variables – Integrated data (Studies I and II) for the overall population and subgroup GINA 4 and 5:

^a The values represent the treatment difference between placebo and reslizumab 3 mg/kg based on adjusted means over the specified time period for each treatment group, except for the change to week 16 for AQLQ, which was the first timepoint where AQLQ was assessed.
^b CI = Confidence interval.

Patients with severe refractory eosinophilic asthma

Reslizumab produced significant reductions in asthma exacerbations relative to placebo in the refractory population (59%) and non-refractory population (49%). Results were supported by the secondary efficacy endpoints and were in line with the overall population.

Study III

The primary endpoint was the change from baseline over 16 weeks in FEV₁. In Study III, patients receiving reslizumab 3 mg/kg had significantly larger increases in FEV₁ from baseline compared to placebo (treatment difference: 160 mL, p=0.0018). Improvements were noted in FEV₁ at 4 weeks following the first dose of reslizumab.

Immunogenicity

In phase 3 placebo-controlled studies with a duration of 16 to 52 weeks, low-titre, frequently transient anti-reslizumab antibodies were detected in 53 out of 983 asthma patients (5%) receiving reslizumab at 3 mg/kg. In an open-label phase 3 extension study, low-titre, frequently transient anti-reslizumab antibodies were detected in 49 out of 1,014 asthma patients (5%) who received 3 mg/kg reslizumab for up to 36 months. Systemic exposure to reslizumab appears to be unaffected by anti-reslizumab antibodies. The antibodies had no impact on clinical pharmacodynamics, efficacy or safety.

Ethnicity

Population pharmacokinetic analyses indicated that the pharmacokinetics of reslizumab is not significantly different between ethnic groups (white, black and Asian). There are limited safety data in non-white ethnic populations.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with CINQAERO in one or more subsets of the paediatric population in asthma (see section 4.2 for information on paediatric use).

39 paediatric asthma patients from 12 to 17 years were randomised to reslizumab 0.3 mg/kg, reslizumab 3 mg/kg or placebo as part of two 52-week exacerbation studies (Studies I and II) and one 16-week lung function study (Study III). In Studies I and II only, patients were required to have at least one asthma exacerbation requiring systemic corticosteroid use in the year prior to study entry. Asthma exacerbations were evaluated only in the exacerbation studies (Studies I and II: reslizumab 3 mg/kg [n=14] and placebo [n=11]). No treatment effect on asthma exacerbations was observed for this age group (asthma exacerbation rate ratio [reslizumab/placebo] of 2.09). Given the small sample size and baseline imbalances resulting from subgroup analysis, no conclusion can be drawn regarding asthma efficacy in the paediatric population.