EXDENSUR Solution for injection Ref.[116332] Active ingredients: Depemokimab

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airways diseases
ATC code: R03DX12

Mechanism of action

Depemokimab targets human IL-5 with a binding affinity of 10.5 pM, thereby blocking the binding to the IL-5 receptor alpha expressed on the cell surface with picomolar potency (IC₅₀ 4 pM) in vitro. Depemokimab contains a triple amino acid substitution (YTE) in the fragment crystallisable (Fc) region which increases binding to the neonatal Fc receptor and thereby extends the half-life when compared to the IgG1 wildtype.

IL-5 is a pleiotropic cytokine with established impact on eosinophils and other immune and structural cells. In severe asthma, inhibition of IL-5 has demonstrated an improvement in epithelial integrity, mucus plugging and reduction in tissue remodelling. However, the mechanism of action has not been definitively established.

Pharmacodynamic effects

In a clinical pharmacology study with mild-to-moderate asthma patients, a single 100 mg subcutaneous dose of depemokimab produced a rapid reduction in blood eosinophil count. Blood eosinophils were reduced by 54% compared to placebo 24 hours after dosing, which was the first post-dose assessment.

In the asthma and CRSwNP phase 3 studies, these reductions were sustained over the treatment period and blood eosinophil count reductions at week 52 were 79% and 85% compared to placebo, respectively.

Immunogenicity

In patients who received at least one 100 mg dose of depemokimab administered subcutaneously every 6 months, 9% (44/499) of patients with asthma (SWIFT-1 and SWIFT-2) and 8% (21/272) of patients with CRSwNP (ANCHOR-1 and ANCHOR-2) were positive for anti-depemokimab antibodies (ADA) during the 52-week studies.

The percentage of patients who were positive for ADA was 9% (55/622) in a 52-week open-label extension asthma study (AGILE; n=395 with data collected for 104 weeks).

Across the placebo-controlled studies for asthma and CRSwNP indications, and the 52-week open label extension asthma study (AGILE), <1% of the patients (n=7) were positive for neutralising antibodies.

Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, pharmacodynamics, efficacy or safety was observed; however, data are still limited.

Clinical efficacy and safety

Asthma

The efficacy of depemokimab was evaluated in 2 replicate, randomised (2:1 ratio, depemokimab to placebo), double-blind, placebo-controlled, parallel-group, multi-centre clinical studies of 52-weeks treatment duration (SWIFT-1 and SWIFT-2). The two studies enrolled patients aged 12 years and older with asthma with type 2 inflammation characterised by an eosinophilic phenotype. In these studies, depemokimab 100 mg was administered subcutaneously once every 6 months for a total of 2 doses in addition to standard of care (SoC) therapy. Patients were required to have 2 or more asthma exacerbations requiring treatment with systemic corticosteroids (SCS) in the last 12 months, while on medium- to high-dose ICS (≥440 mcg fluticasone propionate or equivalent) plus at least one additional asthma controller. Patients were also required to have a blood eosinophil count of >150 cells/mcL at screening or >300 cells/mcL documented in the year prior to study entry and reduced lung function at baseline (pre-bronchodilator forced expiratory volume in 1 second [FEV₁] <80% predicted normal in adults and [FEV₁] <90% or FEV₁:FVC ratio <0.8 in adolescents). Patients were enrolled without requiring a minimum baseline Asthma Control Questionnaire-5 (ACQ-5) score. Depemokimab was administered as add-on to background asthma treatment which continued throughout the duration of the studies. The Full Analysis Set (FAS) population consisted of 762 patients who were randomised and received at least one dose of depemokimab or placebo in the two studies (382 in SWIFT-1 and 380 in SWIFT-2).

The demographics and baseline characteristics of the patients in these 2 studies are provided in Table 2.

Table 2. Demographics and baseline characteristics (FAS population):

FAS = Full Analysis Set, FEV₁ = Forced Expiratory Volume in 1 second, IgE = immunoglobulin E, SGRQ = St. George's Respiratory Questionnaire, ACQ-5 = Asthma Control Questionnaire, ICS = inhaled corticosteroid, OCS = oral corticosteroid
^a Medium-dose ICS = 440 mcg FP daily or equivalent; High-dose ICS >440 mcg FP daily or equivalent

Exacerbations

The primary efficacy endpoint for SWIFT-1 and SWIFT-2 was the annualised 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 (intravenous or oral steroids for at least 3 days or a single intramuscular corticosteroid dose) and/or hospitalisation 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. The majority of patients (95% and 92% for SWIFT-1 and SWIFT-2, respectively) completed the studies.

In SWIFT-1 and SWIFT-2, the annualised rate of asthma exacerbations was significantly lower in patients receiving depemokimab compared to placebo (Table 3). The percentage of patients with exacerbations requiring hospitalisation and/or emergency department visit was lower for patients treated with depemokimab (1% and 4%) compared with placebo (8% and 10%) in SWIFT-1 and SWIFT-2, respectively.

Table 3. Results of primary exacerbation endpoint (FAS population):

FAS = Full Analysis Set

Secondary endpoints

Additional efficacy assessments included health-related quality of life measured with St. George's Respiratory Questionnaire (SGRQ), asthma control measured with Asthma Control Questionnaire (ACQ-5) and lung function (pre-bronchodilator FEV₁). Table 4 provides the results of these secondary endpoints for the FAS population of SWIFT-1 and SWIFT-2.

Table 4. Results of secondary endpoints (FAS population):

FAS = Full Analysis Set, LS = Least Squares, FEV₁ = Forced Expiratory Volume in 1 second
^a Number of patients with analysable data at the timepoint
^b Adjusted treatment difference (depemokimab vs. placebo)

Open-label extension study in asthma (AGILE)

Patients who completed either the SWIFT-1 or SWIFT-2 study were able to enrol in an open-label extension study (AGILE) where they all received up to two doses of depemokimab over an additional 52 weeks. The analysis of AGILE (n=629) showed an annualised exacerbation rate of 0.56 (95% CI: 0.49, 0.65).

Chronic rhinosinusitis with nasal polyps (CRSwNP)

The efficacy of depemokimab in adult patients with CRSwNP was evaluated in 2 replicate, randomised, double-blind, placebo-controlled, parallel-group, multicentre clinical studies of 52-weeks duration (ANCHOR-1 and ANCHOR-2). These studies evaluated the efficacy of 100 mg of depemokimab administered subcutaneously once every 6 months for a total of 2 doses in addition to standard of care (SoC) therapy. Patients had been treated with systemic corticosteroids (SCS) anytime within the past 2 years; and/or had a medical contraindication/intolerance to SCS; and/or had a documented history of prior surgery for nasal polyps (NP) prior to screening. Randomised patients were required to have an endoscopic bilateral NP score of at least 5 out of a maximum score of 8 with a minimum score of 2 in each nasal cavity and a mean nasal obstruction Verbal Response Scale (VRS) score of 2 or greater at baseline. Other than nasal obstruction, there were no other entry requirements for symptoms or for quality of life at randomisation. A total of 528 patients (271 in ANCHOR-1 and 257 in ANCHOR-2) were included in the Full Analysis Set (FAS) population.

The demographics and baseline characteristics of the patients in these two studies are provided in Table 5 below:

Table 5. Demographics and baseline characteristics (FAS population):

FAS = Full Analysis Set, CRSwNP = chronic rhinosinusitis with nasal polyps, SCS = systemic corticosteroid, NP = nasal polyp, AERD = aspirin-exacerbated respiratory disease, VRS = Verbal Response Scale, SNOT-22=Sino-Nasal Outcome Test
^a Higher scores indicate greater disease severity.
^b As graded by independent blinded assessors.
^c NP score is the sum of scores from both nostrils (0-8 scale) where each nostril was graded (0=no polyps; 1=small polyps in the middle meatus not reaching below the inferior border of the middle concha; 2=polyps reaching below the lower border of the middle turbinate; 3=large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha; 4=large polyps causing almost complete congestion/obstruction of the inferior meatus).
^d Collected daily by patients on a 0 to 3 scale where 0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe symptoms.
^e SNOT-22 is a health-related quality of life assessment tool and includes 22 items in 6 domains of symptoms and impact associated with CRSwNP (nasal, non-nasal, ear/facial, sleep, fatigue, emotional consequences). Higher scores indicate worse health related quality of life.

Total endoscopic nasal polyp score and nasal obstruction VRS score

The co-primary efficacy endpoints in each study were change from baseline in total endoscopic NP score (0-8 scale) at Week 52 as graded by central blinded readers and change from baseline in mean nasal obstruction VRS score (0-3 scale [0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe symptoms]) over Weeks 49 to 52 as self-reported by patients using a daily diary. The results for the co-primary endpoints in the ANCHOR-1 and ANCHOR-2 studies are presented in Table 6.

Table 6. Results of co-primary endpoints (FAS population):

FAS = Full Analysis Set, NP = nasal polyp, LS = Least Squares, VRS = Verbal Response Scale
^a Patients who had nasal surgery or used other maintenance treatment impacting type 2 inflammation (including biologics indicated for CRSwNP, chronic use of systemic corticosteroids and intranasal corticosteroids) prior to the timepoint of interest were assigned the worst possible value of the relevant score for all assessments following surgery or initiation of other maintenance treatment impacting type 2 inflammation.
^b Based on Mixed Model Repeat Measures (MMRM) analyses with covariates of treatment, baseline score, log(e) baseline blood eosinophil count, region, previous surgery for nasal polyps, visit and interaction terms for visit by baseline and visit by treatment.
^c Number of patients with analysable data at the timepoint
^d Adjusted treatment difference (depemokimab vs. placebo)
^e The upper limit of the 95% CI represents a rounded number of -0.003.

In analyses from the individual studies ANCHOR-1 and ANCHOR-2, a treatment difference in favour of depemokimab was observed by Week 12 (first timepoint assessed) for the total endoscopic NP score and by Weeks 1-4 (first timepoint assessed) for the nasal obstruction VRS mean score that was maintained up to Week 52 (Figures 1 and 2).

Figure 1. LS mean change from baseline (95% CI) in total endoscopic NP score up to Week 52 from ANCHOR-1 and ANCHOR-2 studies (FAS population):

LS = Least Squares; NP = nasal polyp; FAS = Full Analysis Set

Figure 2. LS mean change from baseline (95% CI) in nasal obstruction VRS mean score up to Weeks 49-52 from ANCHOR-1 and ANCHOR-2 studies (FAS population):

LS = Least Squares; VRS = Verbal Response Scale; FAS = Full Analysis Set

Nasal surgery, systemic corticosteroid use, initiation of other maintenance treatment impacting type 2 inflammation for CRSwNP

Across the two ANCHOR studies, the key secondary endpoint of the proportion of patients who required nasal surgery (actual or planned) or initiated other maintenance treatment impacting type 2 inflammation (including biologics indicated for CRSwNP, chronic use of systemic corticosteroids and intranasal corticosteroids) was 16% (44/272) in the depemokimab group and 22% (56/256) in the placebo group (27% risk reduction; HR: 0.735; 95% CI: 0.495, 1.092, Figure 3). The proportion of patients who had nasal surgery or initiated other maintenance treatment impacting type 2 inflammation for CRSwNP was 12% (33/272) in the depemokimab group, compared with 17% (43/256) in the placebo group, representing a 29% risk reduction (HR: 0.713; 95% CI: 0.453, 1.124).

Figure 3. Kaplan Meier curve for time to first nasal polyps surgery (actual or planned) or initiation of other maintenance treatment impacting type 2 inflammation¹ for CRSwNP up to Week 52 (pooled FAS population):

CRSwNP = chronic rhinosinusitis with nasal polyps; FAS = Full Analysis Set
¹ Other maintenance treatment impacting type 2 inflammation includes biologics indicated for CRSwNP, chronic use of systemic corticosteroids and intranasal corticosteroids.

Across the two ANCHOR studies, the proportion of patients that required at least 1 course of SCS for CRSwNP or other maintenance treatment impacting type 2 inflammation for CRSwNP or nasal surgery was 26% (72/272) in the depemokimab group compared with 36% (92/256) in the placebo group (OR: 0.58, 95% CI: 0.40, 0.86).

Paediatric population

Asthma

In the SWIFT-1 and SWIFT-2 studies, there were 30 adolescents (12 to 17 years old), of which 15 received placebo and 15 received depemokimab 100 mg subcutaneously. In a combined analysis of these studies, a 43% reduction in clinically significant exacerbations was observed in adolescents following depemokimab treatment compared to placebo (rate ratio 0.57; 95% CI: 0.15, 2.13).

Chronic rhinosinusitis with nasal polyps (CRSwNP)

There are no clinical data available in children and adolescents aged less than 18 years old.

The European Medicines Agency has waived the obligation to submit the results of studies with EXDENSUR in all subsets of the paediatric population in asthma and CRSwNP (see section 4.2 for information on paediatric use).