Safety and Tolerability of Twice-Yearly Depemokimab in Patients with Asthma and Chronic Rhinosinusitis with Nasal Polyps: Pooled Results from SWIFT-1/-2 and ANCHOR-1/-2

Abstract

Introduction

Depemokimab, the first ultra-long-acting respiratory biologic, is under investigation for diseases with underlying type 2 (T2) inflammation. Subcutaneous depemokimab 100 mg was efficacious in patients with T2 asthma characterized by blood eosinophil count and in chronic rhinosinusitis with nasal polyps (CRSwNP) when administered twice-yearly in four Phase III randomized, double-blind, placebo-controlled studies (SWIFT-1/-2 and ANCHOR-1/-2, respectively). This pooled analysis examined the safety and tolerability of subcutaneous depemokimab 100 mg versus placebo in patients with T2 asthma and in CRSwNP.

Methods

Adverse event (AE) frequency, severity, time-to-onset, duration, and relative risk (RR) were evaluated for depemokimab 100 mg and placebo administered subcutaneously every 26 weeks for 52 weeks using pooled SWIFT-1/-2 and ANCHOR-1/-2 data. The impact of immunogenicity on safety was also evaluated.

Results

Overall, 1290 patients from the four studies were included in the safety analysis population (773 [60%] received depemokimab; 517 [40%] received placebo). On-treatment AEs were reported by 73% and 78% of patients in the depemokimab and placebo groups, respectively; the majority were mild or moderate in intensity and transient, with similar durations between treatment groups. Serious AEs (SAEs; 5% and 10%, with depemokimab and placebo, respectively), and discontinuations due to AEs (< 1% and 1%, respectively) were infrequent. No fatal AEs or treatment-related SAEs (per investigator assessment) were reported. RRs (vs. placebo) were similar for all common on-treatment AEs except asthma and back pain, which occurred less frequently in the depemokimab group compared with the placebo group. Antidrug antibodies and neutralizing antibodies occurred infrequently, and no association between antidrug antibody status and depemokimab efficacy was identified.

Conclusions

In these studies, twice-yearly depemokimab 100 mg was generally well tolerated by patients with T2 asthma or CRSwNP over the 52-week treatment period, supporting the safety of the first ultra-long-acting biologic for these diseases.

Clinical trial identifier(s)

NCT04719832/NCT04718103/NCT05274750/NCT05281523.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03457-4.

Plain Language Summary

Depemokimab is a treatment in development for asthma and for chronic rhinosinusitis with nasal polyps (CRSwNP). Once injected under the skin, depemokimab works for a 6-month period, so injections are only needed twice a year. It is the first ultra-long-acting biologic for respiratory diseases. Results from previous clinical trials have shown that depemokimab reduces the number of asthma attacks experienced by patients with a certain type of asthma (SWIFT-1 and SWIFT-2 studies), and reduces symptoms and improves quality of life in patients with CRSwNP (ANCHOR-1 and ANCHOR-2 studies). In this article, we describe the side effects that people experienced in these four studies. We found that the number of people who reported side effects was similar in patients who took twice-yearly depemokimab and in those who took a matching twice-yearly dose of placebo (inactive drug). The most common events over the study period, in both the depemokimab and placebo therapy groups, were colds, COVID-19, and upper respiratory tract infections. The majority of side effects were mild or moderate in intensity and were not long-lasting, with similar durations between treatment groups. This provides evidence of the safety of depemokimab for patients with asthma and CRSwNP.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03457-4.

Key Summary Points

Why carry out this study?

Depemokimab is the first ultra-long-acting respiratory biologic with enhanced interleukin-5 binding affinity, high potency, and an extended half-life, enabling twice-yearly dosing.

The Phase III studies, SWIFT-1/-2 and ANCHOR-1/-2, demonstrated the safety and efficacy of depemokimab in patients with type 2 asthma characterized by blood eosinophil count, and in patients with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP), respectively.

Combining data from these four studies provides increased sample sizes for a more thorough analysis of depemokimab safety, and provides the opportunity to expand on data beyond what has been previously published.

This multi-trial pooled analysis of the SWIFT-1/-2 and ANCHOR-1/-2 population examined the safety and tolerability of subcutaneous depemokimab 100 mg versus placebo in patients with type 2 asthma and CRSwNP.

What was learned from the study?

This pooled analysis demonstrates that twice-yearly depemokimab is generally well tolerated across patients with type 2 asthma and/or CRSwNP.

Low discontinuation rates due to adverse events (AEs) were observed, along with no fatal or treatment-related serious AEs, and no significant safety concerns identified; AEs were generally mild or moderate in intensity and transient, with no differences in AE duration observed between treatment groups.

Results presented here support the twice-yearly dosing schedule of depemokimab and provide evidence for healthcare providers to make informed decisions and tailor treatment decisions appropriately for patients with these diseases.

Digital Features

This article is published with digital features, including a graphical abstract, to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.30720587.

Introduction

Asthma is a common chronic inflammatory disease of the airways, characterized by shortness of breath, cough, and wheeze, and episodes of acute exacerbations requiring treatment with systemic corticosteroids (SCS) [1]. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also an inflammatory airway disease, characterized by persistent symptoms such as nasal obstruction, rhinorrhea, facial pain/pressure, and loss of smell [2]. Both these conditions can substantially impair patient quality of life and exert a large healthcare burden, especially if uncontrolled [2–5]. Common therapies for type 2 (T2) asthma include inhaled bronchodilators, inhaled corticosteroids (ICS), and SCS, while for CRSwNP these include intranasal corticosteroids (INCS), saline douching, SCS, and endoscopic sinus surgery [1, 3]. However, these therapies often prove inadequate, failing to consistently control chronic airway inflammation and asthma exacerbations or prevent the recurrence of nasal polyps after surgery [1, 2]. In addition, they are associated with risks and side effects, for example, SCS carry the risks of adrenal suppression, osteoporosis, and venous thromboembolism [1, 2].

T2 inflammation is known to be a driver of symptoms in the majority of patients with asthma and CRSwNP, with greater inflammation associated with an increased risk of exacerbations in asthma and declining lung function, as well as increased disease severity and a higher risk of nasal polyp recurrence in CRSwNP [2, 6–9]. T2 inflammation itself is mediated by core cytokines such as interleukin(IL)-4, IL-5, and IL-13 [8]. Several precision-targeted biologics have been approved as therapies for T2 inflammatory diseases with varying mechanisms of action, including dupilumab (anti-IL-4 receptor alpha, also blocks IL-13 signaling), omalizumab (anti-immunoglobulin E), tezepelumab (anti-thymic stromal lymphopoietin), benralizumab (anti-IL-5 receptor alpha), reslizumab (anti-IL-5), and mepolizumab (anti-IL-5) [10–18]. IL-5 in particular is well known for its critical role in the maturation, activation, proliferation, migration, and survival of eosinophils, and research has indicated a key role for IL-5 and eosinophilic inflammation in the pathogenesis of airway diseases (including T2 asthma and CRSwNP) [6, 8, 19]. However, it is now appreciated that IL-5 biology is much broader than its association with eosinophils, and that the impact of IL-5 inhibition extends to effect additional immune cells, such as plasma cells and mast cells, as well as impacting on the activity of structural airway cells, including airway smooth muscle cells, bronchial and nasal epithelial cells, and bronchial fibroblasts [19]. This broader biological impact is relevant to the long-term therapeutic impact of anti-IL-5 biologic therapies [20, 21].

Depemokimab is the first ultra-long-acting biologic with enhanced IL-5 binding affinity, high potency, and an extended half-life, enabling the sustained suppression of T2 inflammation with twice-yearly subcutaneous dosing [22, 23]. In the Phase III, randomized, double-blind, placebo-controlled SWIFT-1/-2 studies in patients with T2 asthma characterized by blood eosinophil count, depemokimab 100 mg administered subcutaneously every 26 weeks significantly reduced the annualized rate of exacerbations versus placebo at Week 52 (by 58% [95% confidence interval (CI): 41%, 70%] in SWIFT-1, and 48% [95% CI: 27%, 64%] in SWIFT-2) [23]. Similarly, in the Phase III, randomized, double-blind, placebo-controlled ANCHOR-1/-2 studies, depemokimab 100 mg at the same dosing frequency led to a statistically significant reduction in nasal polyp score and nasal obstruction versus placebo in patients with CRSwNP (treatment difference for nasal polyp score:  – 0.7 points [95% CI: 1.1,  – 0.3] and  – 0.6 [95% CI: 1.0,  – 0.2] in ANCHOR-1 and ANCHOR-2, respectively; treatment difference for nasal obstruction verbal response scale:− 0.23 points [95% CI: 0.46, 0.00)] and  – 0.25 [95% CI: 0.46, 0.03], respectively) [24]. Across SWIFT-1/-2 and ANCHOR-1/-2, depemokimab also provided sustained suppression of inflammation as assessed by blood eosinophil count relative to baseline at Week 52 (range: 82–86% reductions) [23, 24]. In all of these Phase III studies, adverse events (AEs) reported in the depemokimab 100 mg group were generally similar to that of the placebo group [23, 24], although such a comparison does not account for causality.

Given depemokimab is the first ultra-long-acting biologic, with a long half-life and twice-yearly dosing regimen, a comprehensive AE analysis is essential to further assess its safety and tolerability. In this multi-trial, pooled analysis of AE data from the SWIFT-1/-2 and ANCHOR-1/-2 trials, we aimed to further characterize the safety and tolerability of depemokimab 100 mg administered subcutaneously versus placebo in patients with T2 asthma and CRSwNP in a large patient cohort.

Methods

Study Design

Data from four Phase III, randomized, double-blind, placebo-controlled studies were included in this pooled safety analysis (SWIFT-1/-2 and ANCHOR-1/-2) [23, 24]. SWIFT-1 and SWIFT-2 investigated the efficacy and safety of depemokimab in patients with T2 asthma characterized by blood eosinophil count (GSK study numbers: 206713/213744; NCT04719832/NCT04718103) [23], while ANCHOR-1 and ANCHOR-2 investigated the efficacy and safety of depemokimab in patients with CRSwNP (217095/218079; NCT05274750/NCT05281523) [24].

Patients

Patients enrolled in SWIFT-1/-2 were at least 12 years of age with a diagnosis of asthma, a blood eosinophil count of at least 150 cells/μL at screening (or at least 300 cells/μL during the 12 months prior to the study), had airflow obstruction despite receiving regular treatment with medium-/high-dose ICS, and had a history of exacerbations (≥ 2 in the 12 months prior to the study). Patients were required to use ICS plus at least one other controller for the duration of the study [23].

Patients enrolled in ANCHOR-1/-2 were at least 18 years of age with inadequately-controlled CRSwNP, a bilateral nasal polyps score of ≥ 5 (≥ 2 per nasal cavity), moderate-to-severe nasal obstruction, other CRSwNP symptoms (based on clinical assessment by the investigator), and at least one of the following: previous SCS treatment (within 2 years), prior surgery for CRSwNP, or medical intolerance to SCS [24]. The use of INCS was mandatory, except in Japan [24].

Treatment and Randomization

All patients in SWIFT-1/-2 and ANCHOR-1/-2 were randomized (2:1 in SWIFT-1/-2; 1:1 in ANCHOR-1/-2) to receive subcutaneous depemokimab 100 mg or subcutaneous placebo every 26 weeks for 52 weeks (plus appropriate standard of care [SoC]) [23, 24]. Permitted SoC in SWIFT-1/-2 included inhaled bronchodilators, muscarinic antagonists, theophyllines, and leukotriene antagonists in addition to ICS. Permitted SoC in ANCHOR-1/-2 included nasal saline, antibiotics, and short courses of SCS, in addition to INCS.

Endpoints and Assessments

In all four Phase III studies, safety was assessed by tracking the extent of depemokimab exposure, the frequency, intensity, treatment-relatedness (as judged by the investigator), time to onset, and duration (post hoc) of on-treatment AEs (defined as any AE reported from the start of treatment up to 182 days after the last dose), as well as the frequency of serious AEs (SAEs) and the frequency and duration (post hoc) of AEs of special interest (AESI; including allergic [Type I hypersensitivity], anaphylaxis, Type III hypersensitivity, other systemic reactions and local injection-site reactions). The impact of immunogenicity (i.e., the presence or absence of anti-drug antibodies [ADAs; binding or neutralizing]) on AE profiles was also evaluated.

The intensity of non-SAEs was defined as either mild, moderate, or severe. Mild events were defined as being easily tolerated by the patient, causing minimal discomfort and not interfering with everyday activities. Moderate events were defined as causing sufficient discomfort to interfere with normal everyday activities, while severe events were defined as those which prevent normal everyday activities. An AE that was assessed as severe had a different definition to an SAE. An SAE was defined as any untoward medical occurrence that, at any dose, meets ≥ 1 of the following criteria: requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening, results in persistent or significant disability/incapacity, results in death, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via an authorized medicinal product, or other situations including possible Hy’s Law case and other significant medical events that may put the patient at risk or may require surgical or medical intervention to prevent one of the aforementioned outcomes, based on medical or scientific judgment by the investigator. Asthma was only recorded as an AE when it did not meet the protocol definition of ‘clinically significant exacerbation’. Asthma events recorded as an AE therefore did not require any of the following: SCS for ≥ 3 days or a single intramuscular dose in those not currently taking an SCS; SCS dose increases of at least double for ≥ 3 days where a background SCS was prescribed; Emergency Room visit; or hospitalization. Conversely, asthma events which met the SAE criteria were required to be recorded as SAEs and are present in the AE dataset regardless of whether the definition of ‘clinically significant exacerbation’ was met.

Adverse drug reactions (ADRs) were also evaluated; defined as a response to a drug that is noxious and unintended and occurs at doses normally used in humans, and where a causal relationship between a medicinal product and an AE is at least a reasonable possibility [25]. In contrast, AEs document occurrences without asserting causality to a drug.

Statistical Analysis

The full analysis set included all patients who were randomly assigned to receive depemokimab or placebo in the SWIFT-1/-2 and ANCHOR-1/-2 studies. Safety data were analyzed using the safety population, defined as all patients who received at least one dose of study medication. Sites where concern had been raised about data integrity and compliance with Good Clinical Practice guidelines were excluded from both analysis sets. In this analysis, as no formal hypothesis testing was performed, all data were analyzed and presented using descriptive statistics (i.e., absolute values, percentages, means, medians, standard deviations [SD], relative risk [RR], and 95% CIs). Adjusted cumulative proportions and RRs were calculated using Cochran–Mantel–Haenszel (CMH) methodology.

Ethical Approval

All studies were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and all applicable national and international laws and regulations. All patients were recruited after obtaining written informed consent.

Results

Patient Population

In total, 1290 patients from the four 52-week Phase III studies were included in the full analysis set. Of these, 774 (60%) were assigned to receive depemokimab 100 mg, 516 (40%) were assigned to receive placebo, 1213 (94%) received both doses of the study drug, and 1185 (92%) completed one of the four studies (n = 720 [93%] and n = 465 [90%] for depemokimab and placebo, respectively; Supplementary Fig. 1). The most commonly-reported reasons for study withdrawal in the 774 patients assigned to depemokimab (including those who had completed treatment but not follow-up) were patient decision (n = 30 [4%]), lack of efficacy (n = 8 [1%]), physician decision (n = 7 [< 1%]), and lost to follow-up (6 [< 1%]). The most common reasons for withdrawal in the 516 patients assigned to placebo were patient decision (n = 35 [7%]), AE (n = 5 [< 1%]), lost to follow-up (n = 5 [< 1%]), lack of efficacy (n = 3 [< 1%]) and patient reached protocol-defined stopping criteria (n = 2 [< 1%]). In SWIFT-2, one patient who was assigned to the depemokimab group received placebo for the duration of the study, and was therefore included in the placebo group for safety analyses in line with the predefined analysis sets.

Baseline demographics and characteristics are presented in Table 1 for the populations assigned to receive depemokimab or placebo and were similar for both treatment groups. Overall, patients had a mean (SD) age of 52.8 (14.5) years, a mean (SD) body mass index of 27.8 (5.6) kg/m², 49% were female, and the majority were white (76%), non-Hispanic/Latino (88%), and from Europe (52%). Mean baseline eosinophil counts for the SWIFT-1/-2 and ANCHOR-1/-2 studies have been reported previously and were similar between treatment arms (298–339 cells/μL and 288–359 cells/μL for depemokimab and placebo, respectively) [23, 24]. In SWIFT-1/-2, 14.8% (113/762) patients had comorbid past or current CRSwNP, and in ANCHOR-1/-2, 55.3% (292/528) patients had comorbid asthma [23, 24].

Table 1.

Baseline demographics and characteristics (full analysis set)

	Depemokimab 100 mg SC (n = 774)	Placebo (n = 516)	Overall (n = 1290)
Age, mean (SD), years	53.3 (14.4)	52.0 (14.6)	52.8 (14.5)
Female, n (%)	389 (50)	238 (46)	627 (49)
Race, n	770	512	1282
Asian, n (%)	154 (20)	99 (19)	253 (20)
Black/African American, n (%)	28 (4)	19 (4)	47 (4)
White, n (%)	584 (76)	386 (75)	970 (76)
Other, n (%)a	4 (< 1)	8 (2)	12 (< 1)
Ethnicity, n	770	511	1281
Hispanic/Latino, n (%)	89 (12)	60 (12)	149 (12)
Non-Hispanic/Latino, n (%)	680 (88)	450 (88)	1130 (88)
Unknown, n (%)	1 (< 1)	1 (< 1)	2 (< 1)
Region, n (%)
Europe	400 (52)	271 (53)	671 (52)
US	144 (19)	84 (16)	228 (18)
Rest of world	230 (30)	161 (31)	391 (30)
BMI, mean (SD), kg/m2	27.8 (5.5)	27.7 (5.9)	27.8 (5.6)

^aIncludes Mixed race, American Indian or Alaska native, Hawaiian native or other Pacific Islander, multiple race, or unknown

BMI body mass index, SC subcutaneous, SD standard deviation

Treatment Exposure

Treatment exposures for the safety analysis population (n = 773 for depemokimab and n = 517 for placebo) demonstrated that patients were exposed to study treatment for a mean (SD) of 11.7 (1.5) months, and a median (range) of 12.0 (6.0–13.6) months; these values were the same for each treatment arm. This equated to 751.8 patient-years exposure for depemokimab, and 502.8 patient-years for placebo.

Safety

The overall incidence of on-treatment AEs and SAEs was similar between the depemokimab and the placebo group (Fig. 1). In total, 73% of patients receiving depemokimab and 78% of those receiving placebo experienced at least one on-treatment AE (Table 2). The most common AEs for both depemokimab and placebo were nasopharyngitis (14% and 17% of patients, respectively), COVID-19 (14% and 13%, respectively), and upper respiratory tract infection (10% and 9%, respectively; Table 2). The majority of AEs were mild or moderate in intensity across both treatment groups (69% and 70% of patients, with depemokimab and placebo, respectively) and severe events were infrequent (3% and 9% of patients, respectively). Of the severe AEs, asthma was most common in both depemokimab and placebo groups (< 1% and 2%, respectively). Discontinuations owing to AEs were rare (< 1% and 1% with depemokimab and placebo, respectively), and no fatal AEs were reported (Table 2; Fig. 1). The CMH-adjusted RRs for common (≥ 3%) on-treatment AEs were similar for all events except asthma and back pain, which occurred less frequently in the depemokimab group compared with the placebo group (Fig. 2). The most common on-treatment AEs were also assessed by time to onset and duration. In the majority of cases, AEs in both pooled treatment groups occurred for the first time during the first dosing period (Weeks 1–26) (Supplementary Table 1). Overall, common AEs were typically transient, did not persist throughout the treatment period, and had a similar duration between the depemokimab and placebo groups (Table 3). Of all the common AEs, hypertension, as expected for a chronic condition, had the longest median (interquartile range [IQR]: Q1, Q3) duration but was shorter in the depemokimab group (99.0 [33.0, 197.0] days, n = 23 events), compared with placebo (155.5 [29.0, 258.5] days, n = 24 events).

Fig. 1.

Overview of on-treatment AEs and SAEs (safety analysis population). *AE/SAE relation to study treatment was assessed by investigator. AE adverse event, SAE serious adverse event, SC subcutaneous

Table 2.

Summary of on-treatment AEs occurring in ≥ 3% of patients in either treatment group by maximum AE intensity (safety analysis population)

Preferred term, n (%)	Depemokimab 100 mg SC (n = 773)					Placebo (n = 517)
	Mild	Moderate	Severe	Total	Total rate	Mild	Moderate	Severe	Total	Total rate
Any eventa	228 (29)	310 (40)	27 (3)	565 (73)	1590	163 (32)	194 (38)	44 (9)	401 (78)	1923
Nasopharyngitis	83 (11)	28 (4)	0	111 (14)	162	59 (11)	31 (6)	0	90 (17)	202
COVID-19	64 (8)	43 (6)	3 (< 1)	110 (14)	162	38 (7)	28 (5)	2 (< 1)	68 (13)	149
URTI	32 (4)	42 (5)	0	74 (10)	106	25 (5)	24 (5)	0	49 (9)	104
Headache	40 (5)	8 (1)	1 (< 1)	49 (6)	69	29 (6)	10 (2)	2 (< 1)	41 (8)	88
Bronchitis	11 (1)	22 (3)	0	33 (4)	45	10 (2)	12 (2)	0	22 (4)	45
Influenza	16 (2)	14 (2)	0	30 (4)	41	14 (3)	12 (2)	0	26 (5)	54
Allergic rhinitis	12 (2)	18 (2)	0	30 (4)	41	4 (< 1)	5 (< 1)	0	9 (2)	18
Sinusitis	11 (1)	18 (2)	0	29 (4)	40	6 (1)	14 (3)	1 (< 1)	21 (4)	43
Arthralgia	21 (3)	4 (< 1)	0	25 (3)	34	12 (2)	4 (< 1)	0	16 (3)	33
Rhinitis	21 (3)	4 (< 1)	0	25 (3)	34	12 (2)	7 (1)	0	19 (4)	39
Cough	14 (2)	9 (1)	0	23 (3)	32	19 (4)	4 (< 1)	0	23 (4)	48
Hypertension	11 (1)	9 (1)	1 (< 1)	21 (3)	29	12 (2)	10 (2)	0	22 (4)	46
Back pain	9 (1)	10 (1)	0	19 (2)	26	14 (3)	11 (2)	0	25 (5)	52
Nasal polyps	3 (< 1)	14 (2)	1 (< 1)	18 (2)	24	4 (< 1)	13 (3)	4 (< 1)	21 (4)	43
Asthma	4 (< 1)	7 (< 1)	5 (< 1)	16 (2)	22	7 (1)	7 (1)	10 (2)	24 (5)	50
Nasal congestion	8 (1)	3 (< 1)	0	11 (1)	15	12 (2)	4 (< 1)	2 (< 1)	18 (3)	37

^aAE intensity was defined as: Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; Moderate: an event that causes sufficient discomfort and interferes with normal everyday activities; or Severe: an event that prevents normal everyday activities

Total rate is the incidence rate per 1000 patient-years, calculated as: (Total number of patients with AE)/(Total exposure duration/365.25) × 1000. If an AE occurs during the exposure period, then, for the incidence rate calculation for that AE, the patient’s exposure ends at the start of the AE

AE adverse event, SC subcutaneous, URTI upper respiratory tract infection

Fig. 2.

CMH-adjusted RRs (depemokimab vs. placebo) for the incidence of common (≥ 3%) on-treatment AEs (safety analysis population). AE adverse event, CI confidence interval, CMH Cochran–Mantel–Haenszel, RR relative risk, SC subcutaneous, URTI upper respiratory tract infection

Table 3.

Summary of duration of most common (occurring in ≥ 3% of patients in either treatment group) on-treatment AEs and AESIs (safety analysis population, post-hoc)

Duration (days)	Depemokimab 100 mg SC (n = 773)	Placebo (n = 517)
Common (≥ 3%) on-treatment AEs, number of events (n)
Nasopharyngitis, n	149	124
Median (Q1, Q3)	7.0 (5.0, 12.0)	7.0 (4.5, 11.5)
COVID-19, n  Median (Q1, Q3)	112	72
	8.0 (6.0, 13.0)	9.0 (7.0, 13.0)
URTI, n	106	67
Median (Q1, Q3)	8.0 (5.0, 12.0)	8.0 (5.0, 11.0)
Headache, n	69	55
Median (Q1, Q3)	2.0 (1.0, 6.0)	2.0 (1.0, 8.0)
Bronchitis, n	39	23
Median (Q1, Q3)	10.0 (7.0, 15.0)	8.0 (6.0, 14.0)
Influenza, n	33	29
Median (Q1, Q3)	7.0 (6.0, 9.0)	6.0 (4.0, 9.0)
Allergic rhinitis, n	40	9
Median (Q1, Q3)	21.5 (8.5, 42.5)	7.0 (5.0, 21.0)
Sinusitis, n	34	24
Median (Q1, Q3)	11.0 (8.0, 20.0)	11.0 (8.0, 23.0)
Arthralgia, n	29	24
Median (Q1, Q3)	20.0 (5.0, 126.0)	4.5 (1.0, 66.0)
Rhinitis, n	27	26
Median (Q1, Q3)	11.0 (8.0, 15.0)	11.5 (7.0, 16.0)
Cough, n	40	29
Median (Q1, Q3)	11.0 (3.5, 18.5)	15.0 (6.0, 40.0)
Hypertension, n	23	24
Median (Q1, Q3)	99.0 (33.0, 197.0)	155.5 (29.0, 258.5)
Backpain, n	19	31
Median (Q1, Q3)	9.0 (6.0, 55.0)	6.0 (1.0, 14.0)
Nasal polyps, n	26	28
Median (Q1, Q3)	10.0 (5.0, 19.0)	11.0 (8.0, 14.5)
Asthma, n	23	29
Median (Q1, Q3)	12.0 (9.0, 25.0)	14.0 (8.0, 46.0)
Nasal congestion, n	16	21
Median (Q1, Q3)	9.5 (7.0, 80.0)	28.0 (11.0, 57.0)
AESIs, number of events (n)
Other systemic reactions, n	10	3
Median (Q1, Q3)	5.5 (1.0, 64.0)	1.0 (1.0, 78.0)
Local injection site reactions, n	12	4
Median (Q1, Q3)	3.5 (1.5, 17.0)	1.5 (1.0, 2.5)

Imputed AE start date is considered in case AE start date is partial. Last available date is considered for the duration calculation. Last available date is the last available contact date when available, or the database lock date

AE adverse event, AESI adverse event of special interest, n number of AEs, Q quartile, SC subcutaneous, URTI upper respiratory tract infection

Overall, the incidence of treatment-related AEs was similar for both the depemokimab (5% of patients) and placebo (3%) groups (Supplementary Table 2). No single treatment-related AE occurred in ≥ 1% of patients in either group or > 2 patients in the placebo group. In the depemokimab group, the only treatment-related AEs that occurred in > 2 patients were headache (n = 5), injection-site reaction (n = 5), and fatigue (n = 3; Supplementary Table 2).

On-treatment SAEs were infrequent, occurring in 5% of patients in the depemokimab group and 10% of those in the placebo group (Table 4). The risk of a SAE was 50% lower with depemokimab versus placebo [RR (95% CI) 0.50 (0.34, 0.75)]. The only SAE that occurred in > 2 patients in the depemokimab group was asthma (1%, n = 9) while, in the placebo group, were asthma (3%, n = 13) and pneumonia (1%, n = 6; Table 4). Aside from acute cholecystitis (< 1% [n = 2] with depemokimab, < 1% [n = 1] with placebo), no cardiac or hepatobiliary SAEs occurred in > 1 patient in either treatment group. Furthermore, there were no reports of treatment-related SAEs, or deaths (Fig. 1).

Table 4.

Summary of on-treatment SAEs occurring in ≥ 2 patients in either treatment group (safety analysis population)

SAE, n (%)	Depemokimab 100 mg SC (n = 773)	Placebo (n = 517)
Any event	42 (5)	51 (10)
Asthma	9 (1)	13 (3)
Pneumonia	2 (< 1)	6 (1)
COVID-19	2 (< 1)	2 (< 1)
Acute cholecystitis	2 (< 1)	1 (< 1)
Large intestine polyp	2 (< 1)	0
Pancreatitis	1 (< 1)	2 (< 1)
Radius fracture	0	2 (< 1)
Rib fracture	0	2 (< 1)
Ureterolithiasis	0	2 (< 1)

SAE serious adverse event, SC subcutaneous

AESIs, including other systemic reactions and local injection-site reactions, were infrequent, occurring in ≤ 1% of patients. No allergic (Type I hypersensitivity), anaphylaxis, or Type III hypersensitivity reactions were reported. Events reported by the investigator as other systemic reactions occurred in 1% (n = 9) of patients in the depemokimab group and < 1% (n = 2) patients in the placebo group, and local injection-site reactions occurred in 1% (n = 10) and < 1% (n = 4), respectively. The RRs (95% CI) were 2.45 (0.54, 11.08) for other systemic reactions and 1.66 (0.52, 5.34) for local injection-site reactions. All but one of the other systemic reactions were judged by the investigator to be related to the treatment. All were of a mild-to-moderate intensity, with none classified as severe or serious, and were generally transient. Other systemic reactions had a median (IQR) duration of 5.5 days (1.0, 64.0; n = 10 events) for the depemokimab group and 1.0 day (1.0, 78.0; n = 3 events) for the placebo group (Table 3). Local injection-site reactions had a median (IQR) duration of 3.5 days (1.5, 17.0; n = 12 events) and 1.5 days (IQR: 1.0, 2.5; n = 4 events) for the depemokimab and placebo groups, respectively. Following further qualitative assessments, which considered temporal associations, potential alternative causes, biological plausibility, and clinical judgment of causality, administration-related systemic reactions (non-allergic) and local injection-site reactions were classified as ADRs.

Immunogenicity

In total, 8% (65/771) of patients in the depemokimab group with an available test result were ADA-positive. Of these, 83% (n = 54) reported at least one AE, most commonly COVID-19 (28%, n = 18), upper respiratory tract infection (25%, n = 16), and nasopharyngitis (8%, n = 5). Similarly, of the depemokimab patients who were ADA-negative (92% [706/771]), 72% (n = 511) reported at least one AE, with the most common being nasopharyngitis (15%, n = 106), COVID-19 (13%, n = 92), and upper respiratory tract infection (8%, n = 58). In post hoc assessments, no notable differences in depemokimab efficacy were observed between ADA-negative and ADA-positive populations for asthma or CRSwNP. Across all four studies, < 1% (n = 3) of patients were found to be positive for neutralizing antibodies (NAb). One patient was NAb-positive at Week 52 and reported 5 AEs, the second patient was NAb-positive at Week 26 only (subsequent visits were ADA-negative) and reported 5 AEs, and the third patient was NAb-positive at Week 26 and remained positive until Week 52 and reported 3 AEs. All AEs in patients with NAb positivity were resolved, patients continued with treatment, and no association between AEs and NAb positivity was identified.

Discussion

This was a pooled analysis of data from the Phase III SWIFT-1/-2 and ANCHOR-1/-2 trials investigating the efficacy and safety of depemokimab, the first ultra-long-acting biologic, in patients with T2 asthma characterized by blood eosinophil count or patients with CRSwNP. Combining data from four studies provides increased sample sizes for a more thorough analysis of the safety and tolerability of depemokimab. Overall, the results demonstrate that depemokimab was generally well tolerated in patients across both diseases over the 52-week treatment period, with low discontinuation rates related to AEs (< 1%) and no fatal or treatment-related SAEs. No significant safety concerns were identified in this pooled analysis, compared with the individual Phase III studies and the earlier Phase I study [22–24]. The majority of AEs reported were mild-to-moderate in intensity (3% of patients receiving depemokimab and 9% of those receiving placebo had severe AEs) and were initially observed during the first dosing period (Weeks 0–26). SAEs were infrequent (< 5% of patients in the depemokimab group) and the risk of a SAE was 50% lower with depemokimab compared with placebo. This appeared to be driven by a reduction in asthma SAEs, reflecting the established efficacy of depemokimab in this patient population [23]. AESIs, namely other systemic reactions and local injection-site reactions, were also infrequent (occurring in 1% of patients with depemokimab), generally transient and resolved during treatment. In addition, no association was found between ADA status and depemokimab efficacy for asthma or CRSwNP and the presence of NAb was reported infrequently. However, given the low number of ADA- and NAb-positive patients, it was not possible to definitively conclude an impact of ADA or NAb responses on efficacy.

The most commonly reported on-treatment AEs in both treatment groups were respiratory tract infections (nasopharyngitis, COVID-19, upper respiratory tract infection). As SWIFT-1/-2 took place from February 2021 to April 2024 and ANCHOR-1/-2 from April 2022 to August 2023, COVID-19 in particular is likely reflective of the timing of the studies during the pandemic, rather than any treatment effect [23, 24]. Common AEs, mostly considered unrelated to treatment by the investigator, were typically transient and did not persist for the duration of the treatment period, with no differences observed between treatment groups, although such a comparison does not account for causality. Hypertension was reported with the longest median duration among the common AEs, but was not deemed to be treatment-related. The presence of chronic conditions such as hypertension in this population of patients is to be expected, given the known association of hypertension with asthma [26], and the mean [SD] age of the safety analysis population (52.8 [14.5] years) [26]. As it is well recognized that many AEs reported in controlled trials are events that occur at random and are not related to study treatment, investigators were obliged to assess the relationship between the study intervention and each occurrence of AE/SAE using clinical judgment. In total, 36 patients had AEs that were considered related to depemokimab and 15 patients had AEs that were considered related to placebo. No individual treatment-related AE occurred in ≥ 1% of patients in either treatment group and no treatment-related SAEs were reported overall.

Overall, the findings from this analysis are broadly similar to those reported across randomized clinical trials and real-world evidence studies for other anti-IL-5 biologics currently available for severe asthma and CRSwNP [10–12, 27, 28]. Furthermore, long-term studies of mepolizumab and benralizumab have demonstrated sustained tolerability with no new safety signals identified over extended treatment periods, reinforcing the established safety of IL-5 inhibitors [29–31]. Across several clinical trials of anti-IL-5 biologics and consistent with this current analysis, nasopharyngitis, upper respiratory tract infection, headache, and asthma were among the most commonly reported AEs [10–12, 27, 28]. However, it is notable that no allergic or anaphylaxis events were observed with depemokimab in the SWIFT-1/-2 and ANCHOR-1/-2 studies [23, 24]. In addition, the twice-yearly dosing regimen for depemokimab offers sustained efficacy while reducing treatment burden for patients. A previous cross-sectional cohort analysis of US claims data from patients with asthma, receiving biologics with dosing frequencies ranging from 2 to 8 weeks, indicated that overall adherence to biologics was relatively low [32]. In addition, greater adherence to biologics has been associated with improved patient outcomes versus lower adherence [33, 34]. There has been some evidence to suggest that biologics with a longer dosing interval (4–8 weeks) demonstrate trends towards greater patient preference and better adherence compared with biologics with a 2-week dosing interval [35, 36]. Given that depemokimab is the first respiratory biologic treatment with a twice-yearly dosing schedule, it may improve adherence to biologic therapies in comparison to the typical bi-weekly/monthly administration required by most other monoclonal antibody therapies [37].

The strengths of this analysis include the large and robust analysis population, comprising 1290 patients from four Phase III randomized, controlled clinical trials, which allowed a comprehensive analysis of the safety and tolerability of depemokimab. While the four studies cover two indications, given the considerable overlap in T2 asthma and CRSwNP comorbidities combining these populations for a pooled safety analysis was judged appropriate in order to achieve a large dataset. In addition, the comprehensive safety analyses performed in this pooled population comprised not just tabulated AE/SAE incidence but also RR assessments between the depemokimab and placebo treatment groups. It also provided new insights into the time to onset, duration, and intensity of AEs, as well as additional details on the impact of immunogenicity on AE profiles, thereby reporting data beyond the primary publications [23, 24]. Limitations of the study include the potential for an underestimation in the rate of discontinuations, given the small number of doses (two) administered over the 52-week treatment period in the studies. However, given the similar overall AE profiles of depemokimab and placebo seen in this large, robust clinical trial population, it is likely that the low rate of discontinuations is an accurate assessment. This is further supported by the high proportion of patients (84%, n = 641/762) who continued to enroll in AGILE, the 52-week open-label extension study of SWIFT-1/-2 [23, 38]. Moreover, as there were only two doses of depemokimab or placebo administered in the studies assessed here, study-drug dosing data timepoints were limited, meaning that, if a dose and an AE occurred at a similar time, there was limited opportunity to test the reproducibility of any emerging symptoms. Finally, while the pooled data from these four large clinical trial populations provide valuable insights, there remains a need for additional safety data, including data from long-term extension studies such as AGILE, which has completed and assesses safety outcomes over an additional year in patients with asthma [38], as well as real-world safety data from post-marketing safety surveillance. Nevertheless, we believe these data provide a thorough and appropriate assessment of the safety and tolerability of depemokimab across patients with T2 asthma and CRSwNP.

Conclusion

The results from this large, multi-trial, pooled safety analysis showed that depemokimab 100 mg administered subcutaneously every 26 weeks was generally well tolerated in patients with T2 asthma characterized by blood eosinophil count or patients with CRSwNP over the 52-week treatment period, with no fatal or treatment-related SAEs reported in > 700 patients and no significant safety concerns identified. This supports the benefit–risk assessment of depemokimab with a twice-yearly dosing regimen in these patient populations.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Daniel J Jackson contributed to the study concept or design and data interpretation. Arnaud Bourdin, Shigeharu Fujieda and Marjolein Cornet contributed to data acquisition and data interpretation. Allison Blackorby, Anna Leslie and Natalia Karkoszka contributed to data analysis and data interpretation. Anna Vichiendilokkul and Peter Howarth contributed to data interpretation. All authors reviewed and revised the manuscript critically for important intellectual content, agreed to submit to the current journal, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. All authors had access to the study data.

Funding

This pooled analysis and the parent studies were sponsored by GSK (GSK ID: 206713/213744/217095/218079; ClinicalTrials.gov registration: NCT04719832/NCT04718103/NCT05274750/NCT05281523). The journal’s Rapid Service Fee and Open Access Fees were funded by GSK. The sponsor was involved in study design and implementation, as well as data collection, analysis, interpretation, writing the study report and reviewing this manuscript. The sponsor did not place any restrictions on access to data or statements made in the manuscript.

Data Availability

Please refer to GSK weblink to access GSK’s data sharing policies and as applicable seek anonymized subject level data via the link https://www.gsk-studyregister.com/en/

Declarations

Conflicts of Interest

Daniel J Jackson has consulted for and received grants from Regeneron, Sanofi and GSK, consulted for and was a member of a Data and Safety Monitoring Board for AstraZeneca, consulted for Areteia, Avillion and Genentech (2022), and received a grant from OM Pharma and DSMB for Upstream Bio. Arnaud Bourdin has received grants from GSK, Boehringer Ingelheim and AstraZeneca; has participated in clinical research projects (as an investigator) with GSK, AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Acceleron, Gossamer, Pfizer, MSD and Sanofi; and has received personal fees for advisory boards and other meetings from GSK, AstraZeneca, Amgen, Regeneron‐Sanofi, Novartis, Celltrion and Chiesi. Allison Blackorby, Anna Leslie, Anna Vichiendilokkul, and Peter Howarth are employees of GSK and hold financial equities in GSK. Natalia Karkoszka is a former employee of GSK and holds financial equities in GSK. Shigeharu Fujieda has been an advisory board member for AstraZeneca, GSK, and Sanofi, and has received speaker fees from Kyorin, Mitsubishi Tanabe, Sanofi, GSK and Taiho. Marjolein Cornet has received speaker fees and participated in advisory board meetings for Regeneron Pharmaceuticals Inc., Sanofi Genzyme, GSK, ALK, Chiesi and Stallergenes Greer.

Ethical Approval

All studies were conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and all applicable national and international laws and regulations. All patients were recruited after obtaining written informed consent.