CINQAIR Solution for injection Ref.[10775] Active ingredients: Reslizumab

In clinical studies with CINQAIR 3 mg/kg, reductions in blood eosinophil counts were observed following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. Mean eosinophil counts were 696 cells/mcL (n=245) and 624 cells/mcL (n=244) at baseline, and were 55 cells/mcL (92% reduction, n=212) and 496 cells/mcL (21% reduction, n=212) at the Week 52 visit for the CINQAIR and placebo treatment groups, respectively. Early eosinophil reduction was apparent in a subset of patients who had blood eosinophil counts assessed at days 2-3: 220 cells/mcL and 610/mcL for CINQAIR (n=35) and placebo (n=32), respectively. Eosinophils returned towards baseline in those CINQAIR-treated patients who completed a 90-day follow-up assessment (n=35, 480 cells/mcL), approximately 120 days after the last dose of CINQAIR.

Reductions of blood eosinophils were related to reslizumab serum levels, i.e., greater reductions of blood eosinophils were observed in subjects with higher reslizumab serum concentrations.

Treatment-emergent anti-reslizumab antibodies did not interfere with the blood eosinophil reduction effect by reslizumab.

The pharmacokinetics (PK) of reslizumab were characterized in healthy adults (n=130), in patients with asthma (n=438), and in other patient populations (n=236). The PK characteristics of reslizumab were similar across these populations. Inter-individual variability in peak and overall exposure was approximately 20-30%.

Peak serum concentrations were typically observed at the end of the infusion. Serum reslizumab concentrations generally declined from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1.5 to 1.9-fold.

Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies.

Distribution

Reslizumab has a volume of distribution of approximately 5 liters, suggesting minimal distribution to the extravascular tissues.

Metabolism

Similar to other monoclonal antibodies, reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, it is not expected to go through a target-mediated clearance.

Elimination

Reslizumab clearance was approximately 7 mL/hour. Reslizumab has a half-life of about 24 days.

Specific Populations

Age, Race, and Gender

Population PK analyses demonstrated that there was no significant effect of age, race, or gender on the PK of reslizumab.

Hepatic Impairment

No clinical studies were conducted to assess the effect of hepatic impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal liver function tests (total bilirubin less than or equal to the ULN and aspartate aminotransferase [AST] less than or equal to the ULN) and mildly increased liver function tests (total bilirubin above the ULN and less than or equal to 1.5-times the ULN or AST greater than ULN and total bilirubin less than or equal to the ULN).

Renal Impairment

No clinical studies have been conducted to assess the effect of renal impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal renal function (estimated glomerular filtration rate [eGFR] greater than or equal to 90 mL/min/1.73 m2), mild renal impairment (eGFR 60-89 mL/min/1.73 m2), and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2).

Drug Interactions

In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity.

No formal clinical drug interaction studies have been conducted with reslizumab. Population PK analyses indicate that concomitant use of either leukotriene antagonists or corticosteroids does not affect the PK of reslizumab.

In a 6-month bioassay, reslizumab was administered intravenously once every 2 weeks for 26 consecutive weeks (14 total doses) to Tg.rasH2 mice at doses up to 516 mg/kg/dose. There was no evidence of carcinogenicity.

Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as reslizumab is unknown.

In a fertility study, administration of reslizumab to parental mice at doses up to 50 mg/kg (approximately 6 times the MRHD on an AUC basis) had no effects on male or female mating or fertility.

The asthma development program for CINQAIR 3 mg/kg (administered once every 4 weeks) included 4 randomized, double-blind, placebo-controlled studies (Studies I-IV) 16 to 52 weeks in duration involving 981 patients 12 years of age and older. While patients aged 12 to 17 years were included in these trials, CINQAIR is not approved for use in this age group [see Use in Specific Populations (8.4)]. All subjects continued their background asthma therapy throughout the duration of the studies.

Studies I and II

Studies I and II were 52-week studies in 953 patients with asthma who were required to have a blood eosinophil count of at least 400/mcL (within 3 to 4 weeks of dosing), and at least 1 asthma exacerbation requiring systemic corticosteroid use over the past 12 months. The majority of patients (82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to 10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients were on OCS at baseline. CINQAIR 3 mg/kg administered once every 4 weeks for a total of 13 doses was evaluated compared with placebo.

Study III

Study III was a 16-week study in 315 patients who were required to have a blood eosinophil count of at least 400/mcL at screening (within 3 to 4 weeks of dosing). Maintenance OCS were not allowed. CINQAIR 3 mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. While 2 doses of CINQAIR were studied, CINQAIR 3 mg/kg is the only recommended dose [see Dosage and Administration (2.1)].

Study IV

Study IV was a 16-week study in 496 patients unselected for baseline blood eosinophil levels (approximately 80% of patients had a screening [within 3 to 4 weeks of dosing] blood eosinophil count of less than 400/mcL). Maintenance OCS were not allowed. CINQAIR 3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo.

The demographics and baseline characteristics of these 4 studies is provided in Table 1.

Table 1. Demographics and Baseline Characteristics of Patients in Asthma Studies:

^* Baseline for lung function and eosinophil count is the day of randomization.
FEV₁=forced expiratory volume in 1 second; SABA=short-acting beta agonist.

All patients had to be on inhaled corticosteroid (ICS) background therapy and could have been receiving any combination of background therapies (ICS with or without another controller [non-ICS and/or OCS]).

Exacerbations

The primary endpoint for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. An asthma exacerbation was defined as a worsening of asthma that required at least 1 of the following medical interventions:

1. Either the use of a systemic corticosteroid, or ≥ 2-fold an increase in the use of ICS for 3 or more days, and/or
2. Asthma-related emergency treatment including at least 1 of the following: an unscheduled visit to their healthcare professional for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or an asthma-related hospitalization.

The medical intervention had to be corroborated with at least 1 of the following: 1) a decrease in forced expiratory volume in 1 second (FEV₁) by 20% or more from baseline, 2) a decrease in peak expiratory flow rate (PEFR) by 30% or more from baseline on 2 consecutive days, or 3) worsening of symptoms or other clinical signs per physician evaluation of the event.

In Studies I and II, patients receiving CINQAIR 3 mg/kg administered once every 4 weeks had significant reductions in the rate of all asthma exacerbations compared to placebo (Table 2). Exacerbations requiring the use of a systemic corticosteroid (e.g., OCS) as well as exacerbations resulting in hospitalization or an emergency room visit were each reduced with CINQAIR 3 mg/kg.

Table 2. Frequency of Asthma Exacerbations during the 52-Week Treatment Period in Patients with Severe Asthma with an Eosinophilic Phenotype (Studies I and II):

^* Randomized patients

The proportion of patients who did not experience an asthma exacerbation during the 52-week treatment period was higher in the CINQAIR 3 mg/kg group (62% and 75%) compared with the placebo group (46% and 55%), in Studies I and II, respectively. The time to first asthma exacerbation was significantly longer for the groups receiving CINQAIR 3 mg/kg compared with placebo in both Studies I and II. A representative figure from Study I is shown below (Figure 1). Study II showed similar results.

Figure 1. Time to First Asthma Exacerbation by Treatment Group in Patients with Severe Asthma with an Eosinophilic Phenotype (Study I):

Lung Function

The effect of CINQAIR 3 mg/kg administered once every 4 weeks on FEV₁ over time relative to placebo was assessed in all 4 studies (Table 3). FEV₁ was the primary endpoint in the 16-week lung function studies: Study III (Figure 2) and Study IV.

Study III also studied a lower dose, CINQAIR 0.3 mg/kg, that produced significant but numerically smaller changes in FEV₁ and blood eosinophil reduction compared with the 3 mg/kg dose. While 2 doses of CINQAIR were studied, CINQAIR 3 mg/kg is the only recommended dose [see Dosage and Administration (2.1)].

Study IV was the only study to test CINQAIR 3 mg/kg in asthma patients unselected for blood eosinophils (measured 3 to 4 weeks prior to dosing); association of treatment effect (i.e., difference between CINQAIR and placebo in the change in FEV₁ at Week 16) and baseline blood eosinophils was not observed.

Table 3. Mean Change (95% CI) from Baseline in FEV₁ in mL Over 16 Weeks (Difference from CINQAIR and Placebo) in Patients with Severe Asthma with an Eosinophilic Phenotype:

^* Study IV studied asthma patients unselected for blood eosinophils

Improvements in FEV₁ were observed at 4 weeks following the first dose of CINQAIR for Studies I and II and maintained through Week 52.

Figure 2. Mean Change from Baseline in FEV₁ in Patients with Severe Asthma with an Eosinophilic Phenotype (Study III):

The Asthma Control Questionnaire-7 (ACQ-7) and Asthma Quality of Life Questionnaire (AQLQ) were both assessed in Studies I, II, and III. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold over 16 weeks.

• For ACQ-7, the responder rate for those randomized to CINQAIR vs. placebo was 69% vs. 65% for Study I, 70% vs. 58% for Study II, and 64% vs. 58% for Study III.
• For AQLQ, the responder rate for those randomized to CINQAIR vs. placebo was 66% vs. 58% for Study I, 67% vs. 55% for Study II, and 64% vs. 48% for Study III.