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Original Article

Twice-Yearly Depemokimab in Severe

Asthma with an Eosinophilic Phenotype
David J. Jackson, Ph.D., Michael E. Wechsler, M.D., Daniel J. Jackson, M.D.,
David Bernstein, M.D., Stephanie Korn, M.D., Ph.D., Paul E. Pfeffer, Ph.D.,
Ruchong Chen, M.D., Ph.D., Junpei Saito, M.D., Ph.D.,
Gustavo de Luíz Martinez, M.D., Lucyna Dymek, M.D., Ph.D.,
Loretta Jacques, Ph.D., Nicholas Bird, M.Sc., Stein Schalkwijk, Pharm.D., Ph.D.,
Douglas Smith, M.B.A., Peter Howarth, D.M., and Ian D. Pavord, D.M., F.Med.Sci.,
for the SWIFT-1 and SWIFT-2 Investigators*​​

A BS T R AC T

BACKGROUND
Depemokimab is an ultra-long-acting biologic therapy with enhanced binding af- The authors’ affiliations are listed in the
finity for interleukin-5 that may enable effective 6-month dosing intervals. Appendix. Dr. Pavord can be contacted at
­ian​.­pavord@​­ndm​.­ox​.­ac​.­uk or at the Re-
spiratory Medicine Unit and NIHR Oxford
METHODS Biomedical Research Centre, Nuffield
In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the Department of Medicine, University of
efficacy and safety of depemokimab in patients with severe asthma and an eosino- Oxford, Rm. 7400, Level 7EF, John Rad-
cliffe Hospital, Headley Way, Oxford OX3
philic phenotype characterized by a high eosinophil count (≥300 cells per microliter 9DU, United Kingdom.
in the previous 12 months or ≥150 cells per microliter at screening) and a history
*The SWIFT-1 and SWIFT-2 investigators
of exacerbations despite the receipt of medium- or high-dose inhaled glucocorti- are listed in the Supplementary Appen-
coids. Patients were randomly assigned in a 2:1 ratio to receive either depemok­ dix, available at NEJM.org.
imab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus This article was published on September 9,
standard care. The primary end point was the annualized rate of exacerbations at 2024, at NEJM.org.
52 weeks. Secondary end points, which were analyzed in a hierarchical manner to DOI: 10.1056/NEJMoa2406673
adjust for multiplicity, included the change from baseline in the score on the St. Copyright © 2024 Massachusetts Medical Society.
George’s Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 sec-
ond, and asthma symptom reports at 52 weeks.
RESULTS
Across the two trials, 792 patients underwent randomization and 762 were in-
cluded in the full analysis; 502 were assigned to receive depemokimab and 260 to
receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence
interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with
placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI,
0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate
ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-
group difference in the change from baseline in the SGRQ score was observed in
either trial, so no statistical inference was drawn on subsequent secondary end
points. The proportion of patients with any adverse event was similar in the two
groups in both trials.
CONCLUSIONS
Depemokimab reduced the annualized rate of exacerbations among patients with
severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and
SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

I
nadequately controlled asthma can and led to dose-dependent suppression of the
result in episodic severe exacerbations de- blood eosinophil count that was sustained over
spite treatment with medium- or high-dose a 26-week period.19
inhaled glucocorticoids plus additional control- We designed the phase 3A SWIFT-1 and
ler medications.1,2 Patients with frequent asthma SWIFT-2 replicate trials to investigate the efficacy
exacerbations often have a high level of unregu- and safety of depemokimab as an adjunctive
lated type 2 inflammation, which generates the treatment to standard care for patients who had
classic T2 cytokines, interleukin-4, interleukin-5, severe asthma with an eosinophilic phenotype
and interleukin-13.3,4 Interleukin-5 is responsible and a history of exacerbations despite the receipt
for the growth and differentiation, recruitment, of medium- or high-dose inhaled glucocorticoids.
activation, and survival of eosinophils,5 as well
as for influencing the activity of a range of other Me thods
inflammatory and structural airway cells.6-8 Un-
controlled eosinophilic inflammation, which is Trial Design and Oversight
reflective of disease driven by interleukin-5, is a SWIFT-1 and SWIFT-2 were both multicenter, ran-
recognized risk factor for severe disease exacer- domized, double-blind, placebo-controlled trials
bations, airway remodeling, and decline in lung (Fig. S1A in the Supplementary Appendix, avail-
function among patients with asthma.5,9 The able with the full text of this article at NEJM.org).
majority of patients with severe asthma have a SWIFT-1 was conducted from March 17, 2021, to
blood eosinophil count of at least 150 cells per November 21, 2023, in 12 countries at 86 sites;
microliter.10 SWIFT-2 was conducted from February 4, 2021,
In 2009, proof-of-concept trials showed that to April 11, 2024, in 11 countries at 131 sites. Pa-
the anti–interleukin-5 antibody mepolizumab re- tients participated in 17 visits (once every 4 weeks,
duced the frequency of exacerbations in patients with an extra visit 2 weeks after each dosing)
who had a sputum eosinophil count of more from screening to the end of the trial. The on-
than 3% and a history of exacerbations.11 Mepo- treatment period included any events or assess-
lizumab also led to a reduction in the use of oral ments that occurred between the first dose of
glucocorticoids in patients with persistent sputum depemokimab or placebo and 182 days after the
eosinophilia after treatment with oral glucocorti- last dose. Additional details regarding the trial
coids and high-dose inhaled glucocorticoids.12 In a design are provided in the Supplementary Ap-
phase 2 study,13 investigators identified the blood pendix.
eosinophil count as a predictive biomarker of the The two trials were conducted in accordance
response to mepolizumab. Phase 3 trials con- with consensus ethical principles derived from in-
firmed a reduction in exacerbations and in the ternational guidelines, including the Declaration
frequency of oral glucocorticoid use in patients of Helsinki and the Council for International Or-
with severe asthma and a blood eosinophil count ganizations of Medical Sciences, applicable Inter-
of at least 150 cells per microliter at screening or national Council for Harmonisation Good Clini-
at least 300 cells per microliter in the previous cal Practice guidelines, and all applicable laws
year.13-15 Other biologic therapies that target in- and regulations. The institutional review board
terleukin-5 or the interleukin-5 receptor have also or ethics committee at each site approved the trial
been shown to improve outcomes in patients with protocol (available at NEJM.org) and any other
asthma with an eosinophilic phenotype.16-18 relevant documents. Important amendments to
Depemokimab is an ultra-long-acting biolog- the protocol are detailed in the Supplementary
ic therapy with enhanced binding affinity for Appendix.
interleukin-5, which potentially enables effective The trial funder, GSK, designed and oversaw
6-month dosing intervals for patients with asth- the trial conduct, along with the collection and
ma.19 In a single-dose phase 1 study,19 research- analysis of the data. Data were also analyzed by
ers found that depemokimab had an acceptable employees of Veramed, a clinical research orga-
safety profile in adult patients with mild or nization. Details regarding the authors’ contri-
moderate asthma and a blood eosinophil count butions to the trial design, data collection and
of at least 200 cells per microliter at screening analysis, and manuscript development are pro-

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 Depemokimab in Asthma with Eosinophilic Phenotype

vided in the Supplementary Appendix. Medical device. The randomization schedule was generated
writers who were funded by GSK prepared the with the use of RandAll NG software and was
first draft of the manuscript under the authors’ performed by means of interactive-response tech-
direction. The manuscript was reviewed and ed- nology with a block size of six. Separate random-
ited by the authors. The authors made the decision ization schedules were created for each country.
to submit the manuscript for publication and Randomization was stratified according to the
vouch for the accuracy and completeness of the dose of inhaled glucocorticoids (medium or high)
data and for the fidelity of the trial to the protocol. that the patient was receiving at baseline. Trial
staff members, patients, and investigators were
Patients unaware of trial-group assignments.
Key eligibility criteria were an age of at least 12
years, an asthma diagnosis by a physician at least Trial End Points and Assessments
2 years earlier, a blood eosinophil count of at The primary end point was the annualized rate
least 300 cells per microliter during the previous of exacerbations during a 52-week period. An
12 months or a count of at least 150 cells per asthma exacerbation was defined as a worsening
microliter at screening, regular treatment with of asthma leading to the use of systemic gluco-
medium- or high-dose inhaled glucocorticoids corticoids (or at least a doubling in the dose for
in the previous 12 months (as defined according ≥3 days in patients who were receiving oral gluco-
to the 2021 guidelines of the Global Initiative for corticoids), hospitalization, or an emergency de-
Asthma20), current treatment with at least one partment visit.
additional controller for at least 3 months, and a Secondary end points were the change from
history of at least two exacerbations resulting in baseline to week 52 in the total score on the St.
the administration of systemic glucocorticoids in George’s Respiratory Questionnaire, with scores
the previous 12 months. ranging from 0 to 100, with higher scores indi-
All the patients were required to have airflow cating a worse quality of life (minimal clinically
obstruction, as determined by measurement of important difference [MCID], −4.0)21; the change
the forced expiratory volume in 1 second (FEV1) in the score on the Asthma Control Question-
before bronchodilation. Adults (≥18 years of age) naire–5, with scores ranging from 0 to 6, with
were required to have an FEV1 of less than 80% higher scores indicating worse asthma control
of the predicted value, according to the criteria of (MCID, −0.5)22; the prebronchodilator FEV1 as
the third National Health and Nutrition Examina- assessed according to the American Thoracic
tion Survey (NHANES III), and children between Society guidelines23; the scores on the asthma
the ages of 12 and 17 years were required to have nightly and daily symptom diaries, with scores
an FEV1 of less than 90% of the predicted value or ranging from 0 to 10, with higher scores indicat-
a ratio of the FEV1 to the forced vital capacity of ing worse symptoms (MCID, −1.5 for the nightly
less than 0.8. score and −1.2 for the daily score)24; and the an-
Any score on the Asthma Control Question- nualized rate of exacerbations resulting in hos-
naire–5 was acceptable for enrollment. Patients pitalization or an emergency department visit
who were receiving a biologic therapy as part of during a 52-week period. Scores on the asthma
their current maintenance therapy or who had re- nightly and daily symptom diaries were included
ceived an anti–interleukin-5 antibody in the previ- as a secondary end point after trial initiation but
ous 12 months were excluded. Comprehensive before unblinding.
eligibility criteria are detailed in the Supplemen- Other outcomes included the time until the
tary Appendix. first exacerbation and the proportion of patients
at 52 weeks who had a reduction from baseline
Treatments and Randomization of more than 4 points in the score on the St.
Patients underwent randomization in a 2:1 ratio George’s Respiratory Questionnaire and a reduc-
to receive either depemokimab (at a dose of 100 tion of more than 0.5 points in the score on the
mg) or placebo subcutaneously at week 0 and Asthma Control Questionnaire–5. Additional pre-
week 26, in addition to standard care. Both dep­ specified end points are summarized in Table S1
emokimab and placebo were administered with in the Supplementary Appendix.
a prefilled syringe assembled in a syringe safety Safety end points included the occurrence of

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 The n e w e ng l a n d j o u r na l of m e dic i n e

adverse events, serious adverse events, and adverse R e sult s

events of special interest, along with pharmaco-
dynamics (change from baseline in the blood Patient Population
eosinophil count) and immunogenicity (pro- Of the 1285 patients who were screened across
portion of patients with binding or neutralizing both trials, 792 underwent randomization. Of
antibodies). these patients, 762 were included in the full
analysis population (382 in SWIFT-1 and 380 in
Statistical Analysis SWIFT-2); 732 patients (367 in SWIFT-1 and 365
The analysis of all efficacy end points was per- in SWIFT-2) completed treatment (Fig. S1B and
formed in the full analysis population, which S1C). Excluded from the full analysis population
consisted of all the patients who had undergone were 11 patients from one site in SWIFT-1 and
randomization in the two trials and received at 12 patients from two sites in SWIFT-2 because
least one dose of depemokimab or placebo, with of concerns about data integrity, Good Clinical
the exclusion of patients at sites where concern Practice violations, or both after trial initiation.
had been raised about data integrity or violations The demographic and clinical characteristics
of Good Clinical Practice guidelines. Safety end of the patients were similar in the two groups at
points were analyzed in the safety analysis baseline in the two trials (Table 1). Across the
population, in which patients were evaluated two trials and assigned groups, 90% of the pa-
according to whether they had received depe- tients had a blood eosinophil count of at least
mokimab or placebo at all protocol-designated 150 cells per microliter at screening. Aside from
times, regardless of their randomized group inhaled glucocorticoids, the most common treat-
assignment. ments that were received before treatment were
We analyzed the primary end point using a long-acting β2 agonists and leukotriene-receptor
generalized linear model that assumed a nega- antagonists; during the treatment period, long-
tive binomial distribution with covariates of trial acting β2 agonists and systemic glucocorticoids
group, baseline dose of inhaled glucocorticoids were the most common (Table S3).
(medium or high), exacerbation history (2, 3, or The demographic and clinical characteristics
≥4 events), geographic region, and baseline pr- of the patients according to the baseline dose of
ebronchodilator percent of the predicted FEV1 inhaled glucocorticoids are shown in Table S4.
with an offset of loge (total number of years in the The representativeness of the trial population is
trials). In the individual SWIFT-1 and SWIFT-2 described in Table S5.
trials, we used a fixed-sequence hierarchical test-
ing procedure to control for the type I error for Primary End Point
multiplicity arising from the primary and mul- In SWIFT-1, the annualized rate of exacerbations
tiple secondary end points, using a step-down over 52 weeks was significantly lower in patients
closed testing procedure in which the inference who received depemokimab (0.46; 95% confi-
for an end point in the predefined hierarchy was dence interval [CI], 0.36 to 0.58) than in those
dependent on the achievement of statistical sig- who received placebo (1.11; 95% CI, 0.86 to 1.43),
nificance for the previous end points in the hi- for a rate ratio of 0.42 (95% CI, 0.30 to 0.59)
erarchy (Table S2). The score on the St. George’s (P<0.001) (Table 2). In SWIFT-2, the annualized
Respiratory Questionnaire was the first second- rate of exacerbations was also significantly
ary end point that was tested in the hierarchy in lower in the depemokimab group than in the
each trial. Pooled analyses and subgroup analy- placebo group, with an annualized rate of 0.56
ses were not controlled for multiplicity. (95% CI, 0.44 to 0.70) with depemokimab and
The widths of confidence intervals have not 1.08 (95% CI, 0.83 to 1.41) with placebo, for a
been adjusted for multiplicity and should not be rate ratio of 0.52 (95% CI, 0.36 to 0.73) (P<0.001).
used for inferential purposes. Additional details In the pooled analysis, the annualized rate of
about the statistical models, sample-size deter- exacerbations was 0.51 (95% CI, 0.43 to 0.60) with
mination, interim analyses, handling of missing depemokimab and 1.11 (95% CI, 0.92 to 1.33)
data, and pooled analysis are provided in the Sup- with placebo, for a rate ratio of 0.46 (95% CI,
plementary Appendix. 0.36 to 0.59).

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 Depemokimab in Asthma with Eosinophilic Phenotype

Secondary End Points Data regarding the percentage of patients with

In SWIFT-1, the mean change from baseline in a reduction from baseline of more than 4 points
the total score on the St. George’s Respiratory in the score on St. George’s Respiratory Question-
Questionnaire at week 52 was −13.03 (95% CI, naire and a reduction of more than 0.5 points in
−15.22 to −10.84) with depemokimab and −9.67 the score on the Asthma Control Questionnaire–5
(95% CI, −12.71 to −6.64) with placebo, with are provided in Table S6. Results for additional
negative scores indicating a better quality of life. prespecified end points are summarized in Ta-
In SWIFT-2, the mean change from baseline in bles S7 through S19.
the score was −14.80 (95% CI, −16.85 to −12.75)
with depemokimab and −12.49 (−15.36 to −9.63) Subgroup Analyses
with placebo (Table 2 and Fig. S2). At week 52, The results of prespecified subgroup analyses of
the between-group difference in the change in the primary end point in the pooled-data popu-
score (depemokimab minus placebo) was −3.36 lation are shown in Figure 2. A post hoc sub-
(95% CI, −7.11 to 0.39; P = 0.08) in SWIFT-1 and group analysis showed an annualized rate of
−2.31 (95% CI, −5.84 to 1.23; P = 0.20) in SWIFT-2; exacerbations of 0.35 (95% CI, 0.23 to 0.54) in
the difference in the pooled analysis was −2.88 the depemokimab group and 0.67 (95% CI, 0.37
(95% CI, −5.43 to −0.32) (Table 2). Because the to 1.19) in the placebo group for patients with a
between-group difference for this analysis in the baseline blood eosinophil count of less than 150
individual trials was not significant, the multi- cells per microliter (rate ratio, 0.53; 95% CI, 0.25
plicity hierarchy was broken. As such, no statis- to 1.09); an annualized rate of 0.58 (95% CI, 0.43
tical inference can be made on the remaining for 0.78) in the depemokimab group and 1.06
secondary end points in the hierarchy. Results (95% CI, 0.77 to 1.46) in the placebo group for
for the rest of the secondary end points are pre- those with a cell count of 150 to less than 300
sented in Table 2 and in Figures S2 through S5. (rate ratio, 0.54; 95% CI, 0.35 to 0.84); an an-
nualized rate of 0.66 (95% CI, 0.49 to 0.89) in
Other Outcomes the depemokimab group and 0.74 (95% CI, 0.49
In SWIFT-1, asthma exacerbations occurred in to 1.12) in the placebo group for those with a
32% of the patients in the depemokimab group cell count of 300 to less than 500 (rate ratio,
(81 patients with 124 events) and in 46% of 0.89; 95% CI, 0.53 to 1.49); and an annualized
those in the placebo group (61 patients with 151 rate of 0.45 (95% CI, 0.33 to 0.59) in the depe-
events). In SWIFT-2, exacerbations occurred in mokimab group and 1.57 (95% CI, 1.17 to 2.12)
32% of the patients in the depemokimab group in the placebo group for those with a cell count
(81 patients with 159 events) and in 50% of of 500 or more (rate ratio, 0.28; 95% CI, 0.19 to
those in the placebo group (64 patients with 167 0.42) (Fig. S6).
events). These analyses included data that were In the prespecified Chinese subpopulation in
collected during the treatment period and after SWIFT-1, the annualized rate of exacerbations
the week 52 visit or withdrawal from the trial. was 0.32 (95% CI, 0.18 to 0.58) in the depemoki­
An analysis of the time until the first exacer- mab group and 2.08 (95% CI, 1.35 to 3.21) in the
bation showed a probability that patients in the placebo group (rate ratio, 0.15; 95% CI, 0.07 to
depemokimab group would have an exacerba- 0.33) (Table S20). Additional post hoc subgroup
tion event over the 52-week trial of 32% (95% CI, analyses, including assessment according to pa-
27 to 38) in SWIFT-1, 33% (95% CI, 27 to 39) in tients’ characteristics at baseline and geographic
SWIFT-2, and 32% (95% CI, 28 to 37) in the pooled region, are shown in Figure S6 and described in
analysis. In the placebo group, the probability of the Supplementary Appendix.
exacerbation was 47% (95% CI, 39 to 56) in
SWIFT-1, 51% (95% CI, 42 to 60) in SWIFT-2, Safety
and 49% (95% CI, 43 to 55) in the pooled analy- Key safety end points are summarized in Table 3.
sis, for a hazard ratio of 0.56 (95% CI, 0.40 to The proportion of patients with any adverse event
0.79) in SWIFT-1, 0.53 (95% CI, 0.38 to 0.74) in was similar in the depemokimab group and the
SWIFT-2, and 0.54 (95% CI, 0.43 to 0.69) in the placebo group in SWIFT-1 (73% for both) and
pooled analysis (Fig. 1A and 1B). SWIFT-2 (72% and 78%, respectively). There were

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

Characteristic SWIFT-1 SWIFT-2

Depemokimab Placebo Depemokimab Placebo

(N = 250) (N = 132) (N = 252) (N = 128)
Age
Mean 54.1±13.8 53.6±14.9 53.6±16.0 51.2±16.6
Distribution — no. (%)
12–17 yr 3 (1) 5 (4) 12 (5) 10 (8)
18–64 yr 185 (74) 91 (69) 169 (67) 93 (73)
≥65 yr 62 (25) 36 (27) 71 (28) 25 (20)
Female sex — no. (%) 144 (58) 79 (60) 160 (63) 81 (63)
Race — no. (%)†
White 207 (83) 109 (83) 181 (72) 91 (71)
Other 43 (17) 23 (17) 71 (28) 37 (29)
Duration of asthma — yr 22.5±16.1 20.0±16.3 25.6±18.7 24.1±17.9
Age at asthma onset — yr 31.6±18.7 33.5±18.9 28.0±20.9 27.0±21.6
Glucocorticoid use
Inhaled dose — no. (%)‡
Medium 118 (47) 61 (46) 94 (37) 60 (47)
High 132 (53) 71 (54) 158 (63) 68 (53)
Maintenance oral dose — no. (%) 8 (3) 13 (10) 13 (5) 6 (5)
Daily oral dose — mg§ 6.9±2.6 8.5±5.2 5.7±2.8 6.7±3.0
Peripheral-blood eosinophil count — no.
(%)
≥150 cells/μl at screening 224 (90) 123 (93) 219 (87) 118 (92)
≥300 cells/μl in 12 mo before screening 127 (51) 61 (46) 151 (60) 66 (52)
Blood eosinophil count — cells/μl 298 310 339 330
Total IgE — U/ml 144.4 180.4 158.3 189.3
FEV1
Prebronchodilator — liter 1.9±0.7 1.8±0.7 1.8±0.7 1.8±0.7
Prebronchodilator percent predicted 62.3±14.5 60.8±16.6 62.5±16.0 60.9±15.7
Reversibility — % 16.5±15.3 17.9±15.3 17.6±17.5 19.4±17.3
Score on Asthma Control Questionnaire–5¶ 2.22±1.12 2.34±1.10 2.20±1.07 2.13±1.00
No. of asthma exacerbations
Leading to use of oral or systemic gluco-
corticoids in ≤12 mo — no.(%)
0 1 (<1) 0 0 0
1 0 0 0 0
2 210 (84) 118 (89) 188 (75) 90 (70)
3 32 (13) 9 (7) 36 (14) 17 (13)
4 2 (1) 3 (2) 14 (6) 7 (5)
>4 5 (2) 2 (2) 14 (6) 14 (11)

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 Depemokimab in Asthma with Eosinophilic Phenotype

Table 1. (Continued)

Characteristic SWIFT-1 SWIFT-2

Depemokimab Placebo Depemokimab Placebo

(N = 250) (N = 132) (N = 252) (N = 128)
Leading to hospitalization in ≤12 mo —
no. (%)
0 233 (93) 125 (95) 233 (92) 111 (87)
1 13 (5) 4 (3) 6 (2) 12 (9)
≥2 4 (2) 3 (2) 13 (5) 5 (4)
Nasal polyps — no. (%)
Previous 42 (17) 15 (11) 38 (15) 18 (14)
Current 25 (10) 10 (8) 24 (10) 13 (10)

* Plus–minus values are means ±SD. FEV1 denotes forced expiratory volume in 1 second.
† Race was reported by the patients. Other races include Black, Asian, and mixed-race patients, along with ethnic groups of American Indian,
Alaska Native, Native Hawaiian, or other Pacific Islander.
‡ Categories of inhaled glucocorticoid use are based on the 2021 guidelines of the Global Initiative for Asthma.
§ Data are listed as the prednisolone-equivalent dose. For patients who were receiving maintenance systemic glucocorticoids, a doubling of
the existing maintenance dose for at least 3 days was required for the measurement of exacerbations as part of the primary end point.
¶ Scores on the Asthma Control Questionnaire–5 range from 0 to 6, with higher scores indicating worse asthma control (minimal clinically
important difference, −0.5).

no deaths and no serious adverse events that were tient who was not available for follow-up liver
considered by the investigator to be related to tests). Of these patients, three were enrolled in
depemokimab or placebo. In SWIFT-1, a greater SWIFT-1 and two in SWIFT-2. All five discontinu-
proportion of patients in the depemokimab ation events were considered by the investigator
group than in the placebo group had an adverse to be unrelated to depemokimab. Among the
event that was categorized as influenza, al- three patients in SWIFT-1 who met the discon-
though none of these events were considered by tinuation criteria because of abnormal liver val-
the investigator to be related to depemokimab or ues, serious adverse events involving hepatitis A,
placebo; in SWIFT-2, the proportion of patients cholelithiasis, and cholestatic jaundice and an
with influenza was higher in the placebo group adverse event involving an increased level of ALT
(Table S21). The proportion of patients with na- were reported. In SWIFT-2, of the two patients
sopharyngitis was lower in the depemokimab who discontinued depemokimab, one was re-
groups in each trial (12% and 13%, respectively) ported to have a serious adverse event involving
than in the placebo groups (19% and 21%, re- abnormal ALT and bilirubin levels and an ad-
spectively). Details regarding the incidence and verse event involving cholelithiasis and increased
relative risk of adverse events of special interest levels of ALT, aspartate aminotransferase, alka-
during and after the treatment period are pro- line phosphatase, γ-glutamyl transferase, and
vided in Table S22. There were no meaningful blood bilirubin; the other patient was reported
differences between the two groups with respect to have an adverse event involving hepatitis E. Most
to laboratory and electrocardiogram results. liver-related adverse events, including serious ad-
In the depemokimab groups, five patients verse events, had resolved by the follow-up visit,
met the criteria for discontinuation according to and the remainder were reported as resolving.
liver values (alanine aminotransferase [ALT] level
of ≥3 times the upper limit of the normal range Pharmacodynamics and Immunogenicity
[ULN] plus a bilirubin level of ≥2 times the ULN Rapid and sustained reductions from baseline in
or an international normalized ratio [INR] of >1.5, the blood eosinophil count were observed among
an ALT level of ≥8 times the ULN, or an ALT patients receiving depemokimab in both trials,
level of ≥3 times but <8 times the ULN in a pa- with an 83% reduction in SWIFT-1 and an 82%

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 8
Table 2. Summary of Primary and Secondary End Points.*

End Point SWIFT-1 SWIFT-2 Pooled Trials

Depemokimab Placebo Depemokimab Placebo Depemokimab Placebo

(N = 250) (N = 132) P Value† (N = 252) (N = 128) P Value† (N = 502) (N = 260)
Primary end point
Annualized rate of exacerbations at 52 wk (95% CI) 0.46 1.11 <0.001 0.56 1.08 <0.001 0.51 1.11
(0.36 to 0.58) (0.86 to 1.43) (0.44 to 0.70) (0.83 to 1.41) (0.43 to 0.60) (0.92 to 1.33)
Rate ratio (95% CI) 0.42 (0.30 to 0.59) 0.52 (0.36 to 0.73) 0.46 (0.36 to 0.59)
The

Percent between-group difference in annual rate 58 (41 to 70) 48 (27 to 64) 54 (41 to 64)
(95% CI)
No. of exacerbations‡ 120 150 153 167 273 317
Secondary end points
Change from baseline in SGRQ score at −13.03±1.11 −9.67±1.54 0.08 −14.80±1.04 −12.49±1.46 0.20 −13.92±0.76 −11.04±1.06
52 wk§
Treatment difference (95% CI) −3.36 (−7.11 to 0.39) −2.31 (−5.84 to 1.23) −2.88 (−5.43 to −0.32)
Change from baseline in ACQ-5 score at 52 wk¶ −0.82±0.07 −0.77±0.09 −0.81±0.07 −0.70±0.09 −0.81±0.05 −0.73±0.06
Treatment difference (95% CI) −0.04 (−0.27 to 0.18) −0.11 (−0.33 to 0.11) −0.08 (−0.24 to 0.07)
n e w e ng l a n d j o u r na l

Change from baseline in prebronchodilator FEV1 at 0.16±0.03 0.16±0.04 0.24±0.03 0.18±0.04 0.20±0.02 0.17±0.03

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52 wk — liter
of

Treatment difference (95% CI) −0.01 (−0.089 to 0.088) 0.06 (−0.04 to 0.15) 0.03 (−0.04 to 0.09)
Change from baseline in asthma nightly symptom −1.39±0.12 −1.30±0.17 −1.18±0.09 −0.97±0.13 NA
diary at 52 wk‖
Treatment difference (95% CI) −0.09 (−0.50 to 0.31) −0.21 (−0.52 to 0.09)
m e dic i n e

Change from baseline in asthma daily symptom −1.33±0.10 −1.25±0.14 −1.13±0.08 −0.93±0.11 NA
diary at 52 wk‖
Treatment difference (95% CI) −0.08 (−0.42 to 0.26) −0.21 (−0.48 to 0.07)
Annualized rate of exacerbations leading to hospi- NA 0.05 0.11 0.02 0.09

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talization or ED visit at 52 wk (95% CI)** (0.02 to 0.09) (0.05 to 0.22) (0.01 to 0.04) (0.05 to 0.15)
Rate ratio (95% CI) NA 0.42 (0.16 to 1.13) 0.28 (0.13 to 0.61)

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Percent reduction in annual rate (95% CI) NA 58 (−13 to 84) 72 (39 to 87)
Number of exacerbations 5 13 16 18 21 31
 Depemokimab in Asthma with Eosinophilic Phenotype

reduction in SWIFT-2 relative to baseline at week

§ Scores on the St. George’s Respiratory Questionnaire (SGRQ) range from 0 to 100, with higher scores indicating a worse quality of life (minimal clinically important difference [MCID],
‡ In SWIFT-1, 169 patients (68%) in the depemokimab group had no exacerbations during the on-treatment and post-treatment periods as compared with 71 patients (54%) in the pla-

** In line with the statistical analysis plan, the annualized rate of exacerbations leading to hospitalization or an emergency department (ED) visit was not calculated in SWIFT-1 because
52 (Fig. S7). On the basis of each patient’s worst
* Plus–minus values are least-squares means ±SE. The widths of the confidence intervals have not been adjusted for multiplicity and should not be used for inferential purposes. NA

† For secondary end points, P values are not presented for end points in the multiplicity hierarchy after the calculation of the first nonsignificant P value. No hierarchy or multiplicity

‖ Scores on the nightly and daily symptom diaries range from 0 to 10, with higher scores indicating worse symptoms (MCID, −1.5 for the nightly score and −1.2 for the daily score).
postbaseline result, antibodies to depemokimab
developed in 12% of the patients in SWIFT-1 and
in 5% of those enrolled in SWIFT-2 (Table S23).
Two patients in SWIFT-2 tested positive for neu-
tralizing antibodies against depemokimab.

fewer than 20 such exacerbations occurred. However, the pooled analysis included the number of events from both trials to calculate the annualized rate.
Discussion
In the phase 3A SWIFT-1 and SWIFT-2 replicate
trials, we investigated the efficacy and safety of
¶ Scores on the Asthma Control Questionnaire–5 (ACQ-5) range from 0 to 6, with higher scores indicating worse asthma control (MCID, −0.5).

depemokimab, an ultra-long-acting anti–inter-

leukin-5 biologic therapy, in patients with severe
asthma. Depemokimab, which was administered
every 6 months for 52 weeks, was associated
with significant reductions in the annual rate of
exacerbations in the two trials. Findings appeared
to be generally consistent among subgroups and
subpopulations. A clear relationship between the
efficacy of depemokimab and the blood eosino-
phil count at baseline was not evident in our
trials, although such an association was sug-
cebo group; in SWIFT-2, the corresponding numbers were 171 patients (68%) and 64 patients (50%).

gested in earlier randomized, controlled trials of

shorter-acting anti–interleukin-5 biologic thera-
pies.13,18 Our ability to determine such an effect
was limited by the requirement that patients
who had a blood eosinophil count of fewer than
150 cells per microliter at baseline needed to
have had an eosinophil count of at least 300 cells
adjustment was performed in the pooled analysis, so no P values are reported.

per microliter within the previous year, along

with the relatively low exacerbation rate in pa-
tients with an eosinophil count of 300 to fewer
than 500 cells per microliter.
In the two SWIFT trials, depemokimab had
an acceptable safety profile, with a frequency of
adverse events that was similar to that in the pla-
Pooled analyses of these data were not performed.

cebo group. No serious adverse events or deaths

were considered by the investigator to be related
to depemokimab. These findings add to the ex-
isting safety data from our phase 1 trial.19 In
SWIFT-1 and SWIFT-2, stopping criteria that were
based on liver measurements were met by five
patients in the depemokimab groups. However,
among these patients, no liver-related event or as-
denotes not applicable.

sociated adverse event or serious adverse event was

considered by investigators to be related to depe-
mokimab, and all events were reported as “re-
solved” or “resolving” by the follow-up visit. A low
level of binding antibodies was detected, and only
−4.0).

two patients across both trials tested positive for

the presence of neutralizing antibodies.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Our findings add to previous data showing 4 to 8 weeks.14,16-18 Our findings regarding depe-
that biologic therapies targeting interleukin-5 or mokimab represent a potential advance in pa-
its receptor (e.g., mepolizumab, reslizumab, and tient quality of life because therapies that have a
benralizumab) improve patient outcomes.11-15 reduced dosing frequency are associated with a
Previous phase 3 trials of biologic therapies have lower patient-reported treatment burden in those
shown reductions in the frequency of exacerba- with long-term conditions, along with an ex-
tions in patients with asthma ranging from 17 pected reduction in health care use.25
to 59%, as evaluated in different patient popula- The effect of depemokimab on exacerbations
tions and with dosing schedules ranging from was not associated with a significant effect on

A Time to First Exacerbation in SWIFT-1

First dose Second dose
100
90
Patients Patients
Cumulative Incidence (%)

80 No. of with ≥1 with 0

70 Patients Event Events
60 Placebo no. (%)
50 Placebo 132 61 (46) 71 (54)
Depemokimab 250 79 (32) 171 (68)
40
30 Hazard ratio, 0.56 (95% CI, 0.40–0.79)
20
10 Depemokimab, 100 mg subcutaneously
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks to Event
No. at Risk
Placebo 132 115 105 99 94 89 81 76 74 72 71 71 69 55
Depemokimab 250 239 230 222 212 208 199 186 179 178 174 168 165 132

B Time to First Exacerbation in SWIFT-2

First dose Second dose
100
90
Patients Patients
Cumulative Incidence (%)

80 No. of with ≥1 with 0

70 Patients Event Events
Placebo no. (%)
60
50 Placebo 128 64 (50) 64 (50)
Depemokimab 252 81 (32) 171 (68)
40
30 Hazard ratio, 0.53 (95% CI, 0.38–0.74)
20
10 Depemokimab, 100 mg subcutaneously
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks to Event
No. at Risk
Placebo 128 114 105 95 90 85 81 74 72 69 65 63 62 41
Depemokimab 252 242 237 225 214 203 200 193 185 183 179 171 163 128

Figure 1. Kaplan–Meier Analysis of the First Asthma Exacerbation.

Shown are the results of analyses performed with the use of a Cox proportional-hazards model in the SWIFT-1 trial (Panel A) and
SWIFT-2 trial (Panel B). The covariates in these trials were the assigned group, baseline dose of inhaled glucocorticoids (medium or
high), exacerbation history according to the number of events, geographic region, and baseline prebronchodilator percent of the predict-
ed forced expiratory volume in 1 second. The proportional-hazards assumption was met for these analyses. The shaded areas indicate
95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and should not be used for in-
ferential purposes.

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 Depemokimab in Asthma with Eosinophilic Phenotype

quality of life, according to the score on the St. cal trials, because an increasing number of pa-
George’s Respiratory Questionnaire. A similar dis- tients have received previous biologic therapy.
connect between exacerbation reduction and Consistent with this hypothesis is the large reduc-
changes in patient-reported and symptom-based tion of 85% in the exacerbation rate with depemok­
outcomes has been seen with shorter-acting bio- imab in the Chinese subpopulation in SWIFT-1,
logic therapies targeting interleukin-5 and the in which many of the patients with severe asthma
interleukin-5 receptor,13,17 although treatment ef- were unlikely to have received previous biologic
fects on these outcomes have been seen with most therapy.27 The relatively low exacerbation rate in
earlier studies.14,17,18,26 Potential explanations in- the placebo group as compared with the previ-
clude the consideration that mechanisms driving ous year highlights the challenges in conducting
these different outcomes are distinct to some ex- trials of biologic therapies involving patients with
tent and change over time in patients with severe severe asthma, because not all patients with
asthma who are recruited to participate in clini- asthma that is considered to be “difficult to

Subgroup No. of Patients Rate Ratio (95% CI)

Overall 761 0.46 (0.36–0.59)
Sex
Female 463 0.47 (0.35–0.65)
Male 298 0.44 (0.29–0.65)
Age group
12–17 yr 30 0.57 (0.15–2.13)
18–64 yr 537 0.50 (0.37–0.66)
≥65 yr 194 0.36 (0.22–0.59)
Geographic region
Europe 408 0.51 (0.37–0.72)
United States 186 0.45 (0.27–0.76)
Other 167 0.38 (0.23–0.61)
Body-mass index
<24.0 190 0.32 (0.20–0.52)
24 to <27.6 191 0.63 (0.38–1.05)
27.6 to <31.4 190 0.46 (0.28–0.74)
≥31.4 190 0.51 (0.32–0.81)
IGC dose at baseline
Medium 322 0.39 (0.26–0.58)
High 429 0.51 (0.38–0.70)
Blood eosinophil count at baseline
<150 cells/µl 122 0.52 (0.25–1.09)
150 to <300 cells/µl 218 0.54 (0.35–0.84)
≥300 cells/µl 421 0.43 (0.31–0.59)
Total IgE at baseline
<61.6 KU/liter 188 0.43 (0.26–0.72)
61.6 to <184.4 KU/liter 187 0.46 (0.28–0.75)
184.4 to <466.1 KU/liter 187 0.50 (0.31–0.81)
≥466.1 KU/liter 188 0.46 (0.28–0.74)
0.125 0.250 0.500 1.000 2.000 4.000 8.000

Depemokimab Better Placebo Better

Figure 2. Subgroup Analysis of the Primary End Point.

Shown is the annualized rate of asthma exacerbations (the primary end point) during a 52-week period in pooled
data from the SWIFT-1 and SWIFT-2 trials, according to subgroup. Only subgroups with at least 20 patients were in-
cluded in the statistical analysis. A post hoc subgroup analysis according to body-mass index (the weight in kilo-
grams divided by the square of the height in meters) is included in place of the prespecified analysis according to
weight. Definitions of the inhaled glucocorticoid (IGC) dose are based on the 2021 guidelines of the Global Initia-
tive for Asthma. The widths of the confidence intervals have not been adjusted for multiplicity and should not be
used for inferential purposes.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Adverse Events.

Event SWIFT-1 SWIFT-2

Depemokimab Placebo Depemokimab Placebo

(N = 250) (N = 132) (N = 251) (N = 129)*
Any adverse event — no. (%) 183 (73) 97 (73) 180 (72) 101 (78)
Related to depemokimab or placebo† 8 (3) 5 (4) 11 (4) 1 (1)
Leading to permanent discontinuation or 3 (1) 2 (2) 2 (1) 1 (1)
withdrawal from trial
Leading to dose interruption or delay 1 (<1) 0 0 0
Serious adverse event — no. (%)‡ 15 (6) 22 (17) 19 (8) 13 (10)

* In SWIFT-2, one patient who was assigned to the depemokimab group received placebo and was therefore included in the placebo group for
safety analyses in line with the predefined analysis sets.
† The determination that an adverse event was related to depemokimab or placebo was made by the investigator.
‡ No serious adverse events were considered by the investigator to be related to depemokimab or placebo, and no serious adverse events
resulted in death.

treat” have severe asthma requiring escalation to imab in patients with different T2 biomarker
biologic therapy.28 In addition, it should be noted combinations. Finally, although a history of in-
that adherence to standard care was not moni- terleukin-5 therapy during the 12 months before
tored in the SWIFT trials. screening was an exclusion criterion, we did not
A further limitation of these trials is that collect earlier data regarding exposure to bio-
SWIFT-1 was initiated during the coronavirus logic therapy or the rationale for not continuing
disease 2019 pandemic, which potentially had such therapy. Additional studies involving pa-
an effect on the overall rate of exacerbations29 tients with severe asthma that capture the quan-
and the ability to conduct routine lung-function tifiable variables described above are clearly in-
testing.30 Moreover, the two trials were conducted dicated.
across multiple regions, with a corresponding Our data showed that the administration of
potential for variability in standard care. A small depemokimab every 6 months reduced the annual-
number of adolescents were included in the tri- ized rate of exacerbations among patients with
als, which limits the assessment of efficacy and severe asthma with an eosinophilic phenotype.
safety among this important subpopulation. Also, Supported by GSK.
we did not evaluate the level of exhaled nitric Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
oxide, because the benefits of biologic therapy A data sharing statement provided by the authors is available
targeting interleukin-5 have previously been shown with the full text of this article at NEJM.org.
to be independent of this measure.31 However, the We thank the patients who participated in the trials and their
families and the clinicians who treated them; and Eva Kane,
lack of data regarding exhaled nitric oxide limits Ph.D., of Fishawack Indicia, part of Avalere Health, for providing
the ability to ascertain the efficacy of depemok­ medical writing support.

Appendix
The authors’ affiliations are as follows: Guy’s Severe Asthma Centre, Guy’s and St. Thomas’ NHS Foundation Trust, and the School of
Immunology and Microbial Sciences, King’s College London (David J. Jackson), Barts Health NHS Trust (P.E.P.), and GSK (L.J., N.B.,
S.S., P.H.), London, and the Oxford Respiratory NIHR Biomedical Research Centre, Nuffield Department of Clinical Medicine, Univer-
sity of Oxford, Oxford (I.D.P.) — all in the United Kingdom; National Jewish Health, Denver (M.E.W.); the University of Wisconsin–
Madison, Madison (Daniel J. Jackson); the University of Cincinnati College of Medicine and Bernstein Clinical Research Center, Cincin-
nati (D.B.); Clinical Research Center, Respiratory Medicine, IKF Pneumologie Mainz, Mainz, and Thoraxklinik Heidelberg, Heidelberg
— both in Germany (S.K.); State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Joint
International Research Laboratory of Respiratory Health, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guang-
zhou Medical University, Guangzhou, China (R.C.); Fukushima Medical University, Fukushima, Japan (J.S.); Hospital Vithas Xanit In-
ternacional, Málaga, Spain (G.L.M.); Centrum Medyczne Lucyna Andrzej Dymek, Strzelce Opolskie, Poland (L.D.); and GSK, College­
ville, PA (D.S.).

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 Depemokimab in Asthma with Eosinophilic Phenotype

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