EXDENSUR Solution for injection Ref.[116117] Active ingredients: Depemokimab

In placebo-controlled studies involving adult and pediatric patients aged 12 years and older with asthma, a 100 mg dose of EXDENSUR administered SC every 6 months for 52 weeks reduced blood eosinophils to a geometric mean count of 57 cells/mcL (95% CI: 51, 63) at Week 52. This corresponded to a geometric mean reduction of 79% (95% CI: 75.8, 81.8) compared to placebo. This magnitude of blood eosinophil reduction was observed within 2 weeks of treatment (at the first assessment) and was maintained throughout the treatment period.

The pharmacokinetics of depemokimab-ulaa were approximately dose-proportional in patients with asthma following SC administration over a dose range of 0.1-times the recommended dose to 3-times the recommended dose. After SC administration of 100 mg of EXDENSUR every 6 months in patients with severe asthma, the mean (SD) model-based estimated trough concentration of depemokimab-ulaa at Week 26 was approximately 1.30 (0.44) mcg/mL. The mean (SD) model-based estimated average steady-state plasma concentration over a single dosing interval was 6.16 (1.62) mcg/mL.

Absorption

Depemokimab-ulaa median T_max was approximately 14 days. There was no accumulation following repeat SC administration once every 6 months.

Distribution

The estimated typical apparent volume of distribution is 6.3 L.

Elimination

The estimated mean (SD) elimination half-life was 48 (4.7) days following SC administration of EXDENSUR.

The estimated typical apparent clearance was 0.092 L/day.

Metabolism

Depemokimab-ulaa is a monoclonal antibody which is expected to be metabolized into small peptides and amino acids by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of depemokimab-ulaa were observed based on age (12 to 93 years), sex, race (73% White, 7% Black, 19% Asian), body weight (34.6 to 161 kg), renal impairment (eGFR ≥90 mL/min/1.73 m² [normal, N=548]; eGFR 60 to <90 mL/min/1.73 m² [mild, N=380]; eGFR 30 to <60 mL/min/1.73 m² [moderate, N=31], and eGFR ≤30 mL/min/1.73 m² [severe, N=2]), or baseline hepatic function biomarkers (alanine aminotransferase [ALT; 5 to 153 IU/L], aspartate aminotransferase [AST; 9 to 115 IU/L], and bilirubin [1.7 to 42 micromol/L]).

Pediatric Patients

There are limited pharmacokinetic data available in the pediatric population. The pharmacokinetics of depemokimab-ulaa in pediatric patients aged 12 to 17 years were consistent with adults. The pharmacokinetics of depemokimab-ulaa have not been studied in pediatric patients aged less than 12 years.

Drug Interaction Studies

No drug interaction studies have been conducted.

No genotoxicity or carcinogenicity studies have been conducted.

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys receiving SC dosages up to 100 mg/kg depemokimab-ulaa for 6 months. Mating and reproductive performance were unaffected in male and female CD-1 mice receiving an analogous antibody, which inhibits the activity of murine IL-5.

The efficacy of EXDENSUR for the add-on maintenance treatment of severe asthma characterized by an eosinophilic phenotype was evaluated in 2 replicate, randomized (2:1 to EXDENSUR or placebo), double-blind, parallel-group, placebo-controlled, multicenter clinical trials (SWIFT-1 [NCT04719832] and SWIFT-2 [NCT04718103]) of 52 weeks duration. The trials enrolled adult and pediatric patients aged 12 years and older with asthma characterized by an eosinophilic phenotype, defined as a blood eosinophil count ≥150 cells/mcL at screening or ≥300 cells/mcL documented in the year prior to study entry. Patients were required to have 2 or more asthma exacerbations requiring treatment with systemic corticosteroids (SCS) in the prior year while on background asthma therapy consisting of a medium- to high-dose ICS plus at least one additional asthma controller with or without maintenance oral corticosteroids (OCS). Patients were also required to have reduced lung function at baseline (pre-bronchodilator forced expiratory volume in 1 second [FEV₁] <80% predicted normal in adults; FEV₁ <90% or FEV₁ to forced vital capacity ratio <0.8 in pediatric patients aged 12 years and older). Patients were enrolled without requiring a minimum baseline Asthma Control Questionnaire-5 (ACQ-5) score. In these trials, EXDENSUR 100 mg was administered SC once every 6 months for a total of 2 doses in addition to background asthma therapy. The efficacy population consisted of 762 patients who received at least 1 dose of EXDENSUR 100 mg or placebo in SWIFT-1 (N=382) and SWIFT-2 (N=380).

The demographics and baseline characteristics of the efficacy population in SWIFT-1 and SWIFT-2 are provided in Table 2.

Table 2. Demographics and Baseline Characteristics of Adult and Pediatric Patients Aged 12 Years and Older with Severe Asthma in SWIFT-1 and SWIFT-2:

FEV₁ = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; IgE = immunoglobulin E; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; mcL = microliter; N = number of patients in the efficacy population; n = number of patients in the respective group; OCS = oral corticosteroid; SD = standard deviation; U = units.
^a Medium ICS dose = 440 mcg fluticasone propionate (FP) daily or equivalent; High ICS dose >440 mcg FP daily or equivalent.

Exacerbations

The primary efficacy endpoint for SWIFT-1 and SWIFT-2 was the annualized rate of clinically significant exacerbations over the 52-week treatment period. A clinically significant exacerbation was defined as worsening of asthma requiring use of SCS such as intravenous (IV) or oral steroids for at least 3 days or a single intramuscular (IM) corticosteroid dose and/or hospitalization and/or Emergency Department visit. For patients on maintenance SCS, at least double the existing maintenance dose for at least 3 days was required. All patients experiencing an exacerbation were treated with SCS.

In SWIFT-1 and SWIFT-2, the annualized rate of asthma exacerbations was significantly lower in patients receiving EXDENSUR compared to placebo (Table 3). During the 52-week treatment period, fewer patients experienced exacerbations in the EXDENSUR group (32% and 32%) compared to the placebo group (46% and 50%) in SWIFT-1 and SWIFT-2, respectively.

Table 3. Annualized Rate of Clinically Significant Asthma Exacerbations Over 52 Weeks in SWIFT-1 and SWIFT-2:

P-value|\2<> <0.001|\2<> <0.001|

N = number of patients in the efficacy population.
Note: Results obtained from a negative binomial model with an offset term for years in study and fixed effects for treatment group, asthma exacerbation history, baseline ICS dose, geographical region, and baseline pre-bronchodilator % predicted FEV₁.

The percentage of patients with exacerbations requiring hospitalization and/or Emergency Department visit was numerically lower for patients treated with EXDENSUR (1% and 4%) compared with placebo (8% and 10%) in SWIFT-1 and SWIFT-2, respectively.

In SWIFT-1 and SWIFT-2, the time to first clinically significant exacerbation was longer for EXDENSUR compared to placebo (Figures 3 and 4).

Figure 3. Kaplan Meier Curve for Time to First Clinically Significant Exacerbation (SWIFT-1):

Shaded areas represent 95% confidence intervals.

Figure 4. Kaplan Meier Curve for Time to First Clinically Significant Exacerbation (SWIFT-2):

Shaded areas represent 95% confidence intervals.

Lung Function

In SWIFT-1 and SWIFT-2, the mean change from baseline in pre-bronchodilator FEV₁ for EXDENSUR was 160 mL and 240 mL, respectively, compared to 160 mL and 184 mL for placebo. The treatment difference in SWIFT-1 and SWIFT-2 relative to placebo was -1 mL (95% CI: -89, 88) and 56 mL (95% CI: -43, 154), respectively.

Patient-Reported Outcome

In SWIFT-1 and SWIFT-2, the proportion of ACQ-5 responders (clinically meaningful improvement defined as a decrease in score of 0.5 or more) at Week 52 was 54% for EXDENSUR in both studies compared to 55% and 53%, respectively, for placebo.