Safety Profile of Tozorakimab (an Anti-IL-33 Monoclonal Antibody): Data from the FRONTIER Phase 2 Program

Abstract

Rationale

Interleukin-33 (IL-33) is a key orchestrator of broad-spectrum downstream host-response mechanisms, including inflammation, tissue homeostasis, and repair. Dysregulation of IL-33 signaling is associated with several pathological conditions. The FRONTIER program comprised four phase 2 signal-finding studies of tozorakimab, an anti-IL-33 human immunoglobulin G1 monoclonal antibody, in diabetic kidney disease (FRONTIER-1), moderate-to-severe atopic dermatitis (FRONTIER-2), moderate-to-severe asthma (FRONTIER-3), and moderate-to-severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER-4). This analysis assessed the safety data from these clinical studies.

Methods

FRONTIER-1–4 were randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of tozorakimab in adults. Participants received subcutaneous tozorakimab (FRONTIER-1, 30–300 mg; FRONTIER-2, 60–600 mg; FRONTIER-3, 300–600 mg; FRONTIER-4, 600 mg) or placebo every 4 weeks for 4–7 doses, with follow-up periods ranging from 24–36 weeks from the first dose. Safety (adverse events [AEs], serious AEs, and AEs of special interest) and immunogenicity endpoints from the FRONTIER studies were summarized.

Results

In total, 1076 patients were included in this analysis (tozorakimab, n=738; placebo, n=338). Deaths occurred only in FRONTIER-1, in similar proportions between treatment groups (tozorakimab, 0.9%; placebo, 0.8%), and were unrelated to tozorakimab. The proportion of participants experiencing at least one treatment-emergent AE (TEAE) or serious TEAEs was generally similar between tozorakimab and placebo groups. The proportion of participants experiencing AEs of special interest, including events of progression of heart failure, was low (tozorakimab, 0.0–1.5%; placebo, 0.0–0.8%), with no meaningful differences between groups; the frequency of injection-site reactions was however higher in tozorakimab than in placebo recipients (tozorakimab, 1.2–20.9%; placebo, 0.0–4.9%). No clinically significant trends were observed in laboratory or vital-sign parameters, and immunogenicity was low.

Conclusion

Tozorakimab was well tolerated across a range of inflammatory diseases, with no safety concerns identified.

Introduction

Interleukin (IL)-33 is an IL-1 family upstream alarmin cytokine that is a key orchestrator of broad-spectrum downstream host-response mechanisms, including inflammation, and tissue homeostasis and repair.¹ This cytokine exists in both a reduced (IL-33^red) and oxidized form (IL-33°^x), signaling via distinct receptor complexes and controlling different downstream pathways.^2,3 IL-33^red signals via the serum stimulation-2 (ST2) receptor to play a key role in type 1 and 2 inflammation and mediating regulatory responses to external stimuli. IL-33°^x signals via the receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR) complex to drive airway mucus hypersecretion and impaired epithelial defense and repair functions.^1–3

Although IL-33 has a protective role in the initiation of innate and adaptive immunity, IL-33 signaling dysfunction is implicated in chronic and persistent inflammation.⁴ Notably, dysregulation of IL-33 is implicated in a range of inflammatory diseases, including chronic obstructive pulmonary disease (COPD),² asthma, viral lower respiratory tract disease (LRTD),^2,5–9 chronic kidney disease (CKD),^10,11 and atopic dermatitis (AD).^12–14

For example, in patients with COPD, excess levels of IL-33 and ST2 correlate with disease severity and exacerbation risk,^2,15,16 and IL-33 expression is increased in endobronchial biopsies in patients with asthma, particularly in those with severe forms of the disease.^10,17 Furthermore, studies have shown that excess IL-33 is associated with poor outcomes in patients with coronavirus disease 19 (COVID-19).^6,18,19 Taking all the evidence together, the pathogenic role of IL-33 in inflammatory diseases provides a compelling scientific basis for investigating anti-IL-33 therapies.

IL-33 has also been shown to have a broader physiological role, including potential involvement in cardiovascular pathophysiology,^20,21 with preclinical data showing both a protective and pathogenic effect of the IL-33^red–ST2 pathway in animal models of heart failure (HF) and endothelial dysfunction.^22,23 However, the precise role of IL-33 in cardiovascular pathophysiology has yet to be fully elucidated.²⁴ Given the wide-ranging, and some potentially unknown, effects of IL-33, it is essential that the safety profile of any IL-33-targeted therapy is carefully evaluated.

Several monoclonal antibodies targeting IL-33 signaling are currently under development, including the anti-ST2 monoclonal antibody astegolimab,²⁵ and the anti-IL-33 monoclonal antibodies itepekimab and tozorakimab.^2,3,26 Tozorakimab is a high-affinity anti-IL-33 human immunoglobulin G1 monoclonal antibody with a novel mechanism of action capable of inhibiting both IL-33^red–ST2 and IL-33°^x–RAGE/EGFR activity.^2,3

Tozorakimab is currently under development for COPD, severe viral LRTD, and asthma, but cross-indication safety data were lacking. The FRONTIER program was a series of four phase 2 signal-finding studies of tozorakimab in diabetic kidney disease (DKD) (FRONTIER-1, NCT04170543),¹⁰ moderate-to-severe AD (FRONTIER-2, NCT04212169),²⁷ moderate-to-severe asthma (FRONTIER-3, NCT04570657),²⁸ and moderate-to-severe COPD and chronic bronchitis (FRONTIER-4, NCT04631016).²⁹ The cumulative data from the phase 2 FRONTIER program allowed a side-by-side review of the safety and tolerability of tozorakimab across the different indications.³⁰ This analysis assessed the safety and tolerability of tozorakimab compared with placebo across all four FRONTIER studies, with a focus on adverse events of special interest (AESI), including events of progression of HF.

Methods

Clinical Study Designs and Participants

FRONTIER-1–4 were phase 2, randomized, double-blind, placebo-controlled studies conducted to evaluate the efficacy, safety, immunogenicity, and pharmacokinetics of tozorakimab in four different indications from December 2019 to November 2023. Tozorakimab, or matched placebo, was administered subcutaneously every 4 weeks for either 4, 6, or 7 doses (Table 1), and participants were monitored for 24–36 weeks from the first dose. Tozorakimab doses varied across the studies (FRONTIER-1 [DKD], 30–300 mg; FRONTIER-2 [AD], 60–600 mg; FRONTIER-3 [asthma], 300–600 mg; FRONTIER-4 [COPD and chronic bronchitis], 600 mg) (Table 1 and Figure 1a–d).

Table 1.

Key Study Characteristics

	FRONTIER-1 DKD	FRONTIER-2 Moderate-to-Severe AD	FRONTIER-3 Moderate-to-Severe Asthma	FRONTIER-4 Moderate-to-Severe COPD and Chronic Bronchitis
	N = 558	N = 148	N = 235	N = 135
Study datesa	Dec 2019 to May 2023	Dec 2019 to Sept 2022	Nov 2020 to Feb 2023	Dec 2020 to Nov 2023
Study treatment lengthb	24 weeks	16 weeks	16 weeks	28 weeks
Total follow-up timec	34 weeks	24 weeks	24 weeks	36 weeks
Participants in the safety analysis set	558	148	235	135
Tozorakimab 600 mg	N/A	55	77	67
Tozorakimab 300 mg	148	18	77	N/A
Tozorakimab 120 mg	93	N/A	N/A	N/A
Tozorakimab 60 mg	89	19	N/A	N/A
Tozorakimab 30 mg	95	N/A	N/A	N/A
Placebo	133	56	81	68
Total number of SC doses	6	4	4	7

Notes: ^aDates range from the date of the first participant enrolled in the study to the last participant’s last visit. ^bStudy treatment length: 4 weeks after the last dose. ^cTotal follow-up time relates to the time from the first dose.

Abbreviations: AD, atopic dermatitis; COPD, chronic obstructive pulmonary disease; DKD, diabetic kidney disease; N/A, not applicable; SC, subcutaneous.

Figure 1.

Study designs of (A) FRONTIER-1 (DKD), (B) FRONTIER-2 (moderate-to-severe AD), (C) FRONTIER-3 (moderate-to-severe asthma), and (D) FRONTIER-4 (moderate-to-severe COPD and chronic bronchitis). ^aStable dose for at least 6 weeks before screening. Participants with documented intolerance to ACEi or ARBs were also eligible. Participants taking sodium–glucose cotransporter 2 inhibitors had to be on a stable dose for at least 4 weeks before randomization. ^bParticipants were randomized 3:1:1:3 to receive placebo (0.8 mL or 4 mL), tozorakimab 60 mg (0.8 mL), tozorakimab 300 mg (4 mL), or tozorakimab 600 mg (4 mL). ^cDefined as documented physician-diagnosed asthma before 25 years of age. ^dDefined as a total daily dose > 250 µg fluticasone dry powder or equivalent, for ≥ 12 months, and on a stable dose for ≥ 3 months before the first screening visit. ^eStable for ≥ 3 months before the first screening visit. Treatment with additional asthma controller therapies (eg oral corticosteroids, long-acting muscarinic antagonists, leukotriene receptor antagonists, or theophylline) was allowed. ^fDefined as a documented history of COPD for ≥ 1 year and a documented history of chronic bronchitis as evidenced by frequent productive cough in the 2-year period immediately before screening, along with a mean score ≥ 2 in both the cough and sputum domains of the Breathlessness, Cough, and Sputum Scale assessed in the 14 days preceding randomization. ^gDefined as a documented history of one or more moderate or severe AECOPD requiring systemic corticosteroids and/or antibiotics for ≥ 3 days or hospitalization for an AECOPD in the 24 months before screening. ^hDefined as either dual (ICS plus LABA, or LABA plus LAMA) or triple (ICS plus LABA plus LAMA) therapy, for ≥ 3 months before enrollment and to remain on therapy during the study. Information from^11,27–29.

Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ACQ-6, Asthma Control Questionnaire-6; AD, atopic dermatitis; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; ARB, angiotensin II receptor blocker; BD, bronchodilator; BSA, body surface area; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DKD, diabetic kidney disease; EASI, Eczema Area and Severity Index; eGFR, estimated glomerular filtration rate; EOT, end of treatment; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; IGA, investigator’s global assessment; LABA, long-acting beta-2 agonists; LAMA, long-acting muscarinic antagonists; Q4W, every 4 weeks; QD, daily; SC, subcutaneous; SOC, standard of care; T2D, type 2 diabetes; TCS and/or TCI, topical corticosteroids and/or topical calcineurin inhibitors.

Full details of the FRONTIER study designs have been published previously.^{10,11,27–29}

The FRONTIER-1 study consisted of a 35-day screening period, followed by 24 weeks (168 days) of treatment, and a safety follow-up visit 10 weeks (70 days) after the last treatment was administered. The primary objective was to assess the effect of tozorakimab on albuminuria in patients with DKD by comparing change from baseline in urine albumin–creatinine ratio between tozorakimab and placebo.

The FRONTIER-2 study comprised 4 weeks of screening and a washout period for topical corticosteroids and topical calcineurin inhibitors, followed by a 16-week treatment period and an 8-week follow-up period. The primary objective was to assess the effect of tozorakimab on AD disease severity in adults with moderate-to-severe AD, by measuring the percent change from baseline to week 16 in the Eczema Area and Severity Index score.²⁷

The FRONTIER-3 study consisted of a screening period of up to 5 weeks, a 16-week treatment period, and a follow-up period of 8 weeks. The primary objective was to assess the effect of tozorakimab on lung function in adults with uncontrolled moderate-to-severe asthma through changes from baseline to week 16 in pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV₁).²⁸ The FRONTIER-4 study comprised a screening period of up to 5 weeks, a treatment period of 24 weeks, and a follow-up period of 12 weeks. The primary objective was to assess the effects of tozorakimab versus placebo on pulmonary function in participants with COPD and chronic bronchitis as measured by change from baseline to week 12 in pre-BD FEV₁.²⁹

This analysis included patients in the safety analysis set from FRONTIER-1–4 who were randomized and received any study intervention. The participants were analyzed according to the study intervention they received. Further details on the inclusion and exclusion criteria and secondary objectives across the four studies can be found in the supplementary materials.

All studies were approved by local independent ethics committees and institutional review boards and were carried out in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice. For further details on the ethical approvals received for these studies please refer to Supplementary Tables 1–4, and to the original publications of the FRONTIER studies.^10,27–29 Written informed consent was obtained from all participants.

Safety Analysis Outcomes and Assessments

Safety endpoints in the FRONTIER studies included the frequency of treatment-emergent adverse events (TEAEs), serious TEAEs, deaths, TEAEs leading to discontinuation of study drug, and AESIs. AESIs included, but were not limited to, COVID-19 disease, serious infections (including opportunistic infections), serious hypersensitivity, gastrointestinal adverse events (AEs), and injection-site reactions, as well as events of progression of HF. Progression of HF was defined as the recurrence of an HF event during the study in a participant who had a prior medical history of HF or who had previously experienced an HF AE during the study. TEAEs were coded by the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). The TEAE type, incidence, severity, and relationship to study drug were summarized for each study. Laboratory measurements, vital-sign measurements, and electrocardiogram parameters were reported. The presence of anti-drug antibodies was also reported. As the studies were conducted during the COVID-19 pandemic, testing for SARS-CoV-2 occurred at all physical study visits. Descriptive statistics were used to summarize safety assessments for each FRONTIER study. No statistical comparisons between studies were performed.

Results

Baseline Demographics and Clinical Characteristics

In total, 1076 participants were included in this analysis (FRONTIER-1 [DKD], n = 558; FRONTIER-2 [AD], n = 148; FRONTIER-3 [asthma], n = 235; FRONTIER-4 [COPD and chronic bronchitis], n = 135). Key demographics and baseline characteristics are presented in Figure 2. Demographics and baseline clinical characteristics were generally balanced between the tozorakimab and placebo groups across the studies (Supplementary Tables 5–8).

Figure 2.

Key demographics and baseline characteristics of participants included in the phase 2 FRONTIER program.

Abbreviations: AD, atopic dermatitis; COPD, chronic obstructive pulmonary disease; DKD, diabetic kidney disease; EASI, Eczema Area and Severity Index; eGFR, estimated glomerular filtration rate; IGA, investigator’s global assessment; pre-BD FEV₁, pre-bronchodilator forced expiratory volume in 1 second; SD, standard deviation.

Safety

Exposure

For each study, all participants in the safety analysis set received at least one dose of randomized treatment, and the length of exposure was consistent across all treatment groups. At least 76%, 72%, 90%, and 82% of participants within each treatment group across the FRONTIER-1–4 studies, respectively, received their protocol-planned doses. Significant inhibition of circulating IL-33 was achieved across all four studies.^27–29

Categories of TEAEs

The proportions of participants with at least one TEAE were generally similar between treatment groups within each study (Table 2). Across all four studies, the most common TEAE by PT (≥ 5% of participants in either treatment group) was COVID-19 (tozorakimab, 2.2–22.4%; placebo, 5.3–20.6%). Aside from this, in FRONTIER-1 the most common TEAEs were hyperkalemia (tozorakimab, 5.4%; placebo, 3.8%) and hypertension (tozorakimab, 5.2%; placebo, 2.3%). In FRONTIER-2 the most common TEAEs were ear pain (tozorakimab, 0.0%; placebo, 5.4%), headache (tozorakimab, 1.1%; placebo, 5.4%), injection-site reaction (tozorakimab, 5.4%; placebo, 0.0%), and nasopharyngitis (tozorakimab, 6.5%; placebo, 1.8%). In FRONTIER-3 the most common TEAEs were injection-site erythema (tozorakimab, 7.1%; placebo, 2.5%) and nasopharyngitis (tozorakimab, 7.1%; placebo, 4.9%). In FRONTIER-4 the most common TEAEs were injection-site erythema (tozorakimab, 14.9%; placebo, 0.0%), headache (tozorakimab, 11.9%; placebo, 4.4%), and nasopharyngitis (tozorakimab, 4.5%; placebo, 10.3%) (Supplementary Table 9). Overall, the proportions of participants who experienced serious TEAEs across the four studies were similar between tozorakimab and placebo recipients (tozorakimab, 3.2–20.9%; placebo, 2.5–13.2%) (Table 2). Other than serious TEAEs related to the disease under study, there were no serious TEAEs by PT experienced by ≥ 6% of participants in the FRONTIER-1–4 studies. TEAEs leading to study drug discontinuation were low and generally similar between treatment groups within each study (tozorakimab, 0.6–6.0%; placebo, 0.0–3.0%) (Table 2). Deaths were reported in only one study (FRONTIER-1 [DKD]) and occurred in similar proportions for both tozorakimab and placebo. No deaths were attributed to tozorakimab.

Table 2.

Summary of Proportions of Participants with TEAEs and Serious TEAEs

	FRONTIER-1 DKD		FRONTIER-2 Moderate-to-Severe AD		FRONTIER-3 Moderate-to-Severe Asthma		FRONTIER-4 Moderate-to-Severe COPD and Chronic Bronchitis
	N = 558		N = 148		N = 235		N = 135
	Tozorakimab n = 425	Placebo n = 133	Tozorakimab n = 92	Placebo n = 56	Tozorakimab n = 154	Placebo n = 81	Tozorakimab n = 67	Placebo n = 68
Any TEAE	228 (53.6)	67 (50.4)	55 (59.8)	37 (66.1)	102 (66.2)	45 (55.6)	53 (79.1)	50 (73.5)
Death (grade 5 severity)	4 (0.9)	1 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Serious TEAEs	42 (9.9)	15 (11.3)	3 (3.3)	2 (3.6)	5 (3.2)	2 (2.5)	14 (20.9)	9 (13.2)
TEAEs leading to drug discontinuation	8 (1.9)	4 (3.0)	2 (2.2)	0 (0.0)	1 (0.6)	1 (1.2)	4 (6.0)	0 (0.0)
Any AESI	96 (22.6)	27 (20.3)	37 (40.2)	21 (37.5)	56 (36.4)	22 (27.2)	33 (49.3)	24 (35.3)

Notes: Data are presented as n (%). Information from^11,27–29.

Abbreviations: AD, atopic dermatitis; AESI, adverse event of special interest; COPD, chronic obstructive pulmonary disease; DKD, diabetic kidney disease; TEAE, treatment-emergent adverse event.

AESIs by Special Interest Group and PT

AESIs by special interest group and PT are reported in Table 3. The most common AESI across each study was COVID-19 disease (tozorakimab, 5.2–23.9%; placebo, 5.3–19.8%; Table 3). The frequency of injection-site reactions was higher for participants treated with tozorakimab than for placebo (tozorakimab, 1.2–20.9%; placebo, 0.0–4.9%; Table 3). The proportion of participants who experienced an AE in the AESI category of progression of HF was low (tozorakimab, 0.0–1.5%; placebo, 0.0–0.8%; Table 3), with no meaningful differences between the groups. No participants from FRONTIER-2 or FRONTIER-3 experienced an AE in the AESI category of progression of HF.

Table 3.

AESIs^a by Special Interest Group and Preferred Term

	FRONTIER-1 DKD		FRONTIER-2 Moderate-to-Severe AD		FRONTIER-3 Moderate-to-Severe Asthma		FRONTIER-4 Moderate-to-Severe COPD and Chronic Bronchitis
	N = 558		N = 148		N = 235		N = 135
AESIsa, b by special interest group and Preferred Term, n (%)	Tozorakimab	Placebo	Tozorakimab	Placebo	Tozorakimab	Placebo	Tozorakimab	Placebo
	(n = 425)	(n = 133)	(n = 92)	(n = 56)	(n = 154)	(n = 81)	(n = 67)	(n = 68)
COVID-19 diseasec	22 (5.2)	7 (5.3)	4 (4.3)	7 (12.5)	32 (20.8)	16 (19.8)	16 (23.9)	11 (16.2)
COVID-19	17 (4.0)	7 (5.3)	2 (2.2)	7 (12.5)	25 (16.2)	11 (13.6)	14 (20.9)	11 (16.2)
Injection-site reactions	5 (1.2)	0 (0.0)	9 (9.8)	2 (3.6)	17 (11.0)	4 (4.9)	14 (20.9)	0 (0.0)
Injection-site erythema	0 (0.0)	0 (0.0)	1 (1.1)	0 (0.0)	11 (7.1)	2 (2.5)	10 (14.9)	0 (0.0)
Injection-site reaction	0 (0.0)	0 (0.0)	5 (5.4)	0 (0.0)	2 (1.3)	1 (1.2)	1 (1.5)	0 (0.0)
Progression of HF	5 (1.2)	1 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.5)	0 (0.0)
Acute pulmonary edema	1 (0.2)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Cardiac failure	2 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Cardiac failure congestive	2 (0.5)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Left ventricular failure	1 (0.2)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.5)	0 (0.0)

Notes: ^aAESIs were categorized by special interest group and Preferred Term. The data are displayed for any Preferred Term category in which the frequency in the total tozorakimab and placebo groups was at least 5% in any study as well as all events classified under the AESI of progression of HF. This excluded any event under the Preferred Term of AD. Patients are counted once for each special interest group and Preferred Term, regardless of the number of events. ^bAESI may either be grouped MedDRA Preferred Terms or individual MedDRA Preferred Terms (MedDRA: FRONTIER-1, version 26.0; FRONTIER-2, version 25.0; FRONTIER-3, version 25.1; FRONTIER-4, version 26.0). Categories of AESI are not mutually exclusive; a Preferred Term might be displayed in more than one category. ^cThe overall AESI term is COVID-19 disease, and the Preferred Terms that contributed to this were COVID-19, asymptomatic COVID-19, and SARS-CoV-2 test positive.

Abbreviations: AD, atopic dermatitis; AESI, adverse event of special interest; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 19; DKD, diabetic kidney disease; HF, heart failure; MedDRA, Medical Dictionary for Regulatory Activities; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Clinical Laboratory Evaluation

No clinically meaningful trends in hematology, clinical chemistry, or urinalysis parameters over time were observed for any study. No notable observations were made with respect to vital-sign variables, electrocardiograms, left ventricular ejection fraction, or N-terminal prohormone of B-type natriuretic peptide in any study. There were no clinically meaningful additional physical findings or other observations related to safety.

Immunogenicity

The occurrence of anti-drug antibodies was generally low across the studies (tozorakimab, 1.5–10.4%; placebo, 0.0–1.2%; Supplementary Table 10). In patients receiving tozorakimab, anti-drug antibodies occurred alongside decreased serum tozorakimab concentrations in no patients in FRONTIER-3 and FRONTIER-4, and in less than 2% of patients in FRONTIER-1 and FRONTIER-2. Owing to the low frequency of anti-drug antibodies, their effects on efficacy, pharmacokinetics, or AEs were not formally evaluated.

Discussion

Interest in anti-IL-33 biologic therapies that target inflammatory diseases is increasing, owing to IL-33’s role in mediating not only high-T2 immune responses,^1,31 but also its potential to regulate non-T2 inflammation pathways.^31–35 This manuscript reports a comprehensive safety analysis of data from the phase 2 FRONTIER program, in which 738 participants received tozorakimab, an anti-IL-33 antibody, and is the largest analysis of the safety of tozorakimab to date. Across all four FRONTIER studies, tozorakimab was well tolerated across multiple indications, with no safety concerns identified. Importantly, no deaths were attributed to tozorakimab.

The proportions of participants with TEAEs and serious TEAEs were generally similar between tozorakimab and placebo groups within each study. Of note, the proportions of participants in the FRONTIER-4 study who experienced a serious TEAE were slightly higher in the tozorakimab than in the placebo group (n = 14, 20.9% vs n = 9, 13.2%). However, after excluding events related to the disease under study, no other serious TEAEs by PT were observed in more than a single patient.

The most common TEAE across both treatment groups in all studies was COVID-19, consistent with the studies being conducted during the COVID-19 pandemic and the inclusion of testing for SARS-CoV-2 at all physical study visits. Apart from COVID-19, the number of TEAEs was overall low and balanced between studies and treatment groups, with no clear patterns observed. It is therefore difficult to conclude whether the pandemic had any substantial effects on TEAE patterns or in the different disease populations included in the FRONTIER studies.

IL-33 has been associated with protective effects in animal models of HF and endothelial dysfunction.²² As such, progression of HF may be considered a theoretical potential risk for any anti-IL-33 antibody. The risk of recurrent HF events is especially relevant for participants with DKD and COPD, compared with those who have asthma or AD, because HF shares risk factors with these conditions, such as hypertension, systemic inflammation, aging, and smoking.^36,37 However, the proportions of participants who experienced an AE in the AESI category of progression of HF (including acute pulmonary edema, cardiac failure, cardiac failure congestive, and left ventricular failure) were low across all four FRONTIER studies, with no meaningful differences between the groups. Furthermore, no notable trends were observed with respect to HF-related clinical laboratory measures, for any treatment group, across the four studies. Of note, across the four phase 2 FRONTIER studies, a history of significant heart disease (defined by ejection fraction of less than 40% or New York Heart Association functional class III–IV), a history of HF, or a family history of HF were exclusionary criteria for participation. In summary, these results are encouraging and indicate that tozorakimab was well tolerated in participants treated to date.

The results from this analysis also complement the favorable safety profile observed in another phase 2 study of tozorakimab in patients hospitalized with COVID-19 (ACCORD-2).³⁸ The ACCORD-2 study was a randomized, adaptive-platform, phase 2a study designed for the rapid assessment of multiple treatments added to standard of care for patients hospitalized with COVID-19.³⁸ In addition to tozorakimab, other monoclonal antibodies targeting IL-33 or ST2 that are currently in development have also demonstrated a good safety profile. A systematic review of the anti-ST2 monoclonal antibody astegolimab indicated that, in over 580 participants with asthma, AD, COPD, or COVID-19 pneumonia, no safety concerns were identified.^25,39 Similarly, in phase 2 studies of the anti-IL-33 monoclonal antibody itepekimab, a favorable safety profile was demonstrated in participants with COPD⁴⁰ and asthma.⁴¹ Therefore, therapies targeting IL-33 signaling appear to be well tolerated, as observed across several indications, but continued monitoring of the safety profiles of these antibodies is important.

Given the preliminary, phase 2 nature of the presented data and the lack of adjudication of TEAEs, further studies are needed to confirm the findings of this analysis. A phase 2b study (NCT06932263) in patients with asthma,⁴² and several studies in the phase 3 LUNA program (NCT05166889 [OBERON]; NCT05158387 [TITANIA]; NCT06040086 [MIRANDA]; and NCT05742802 [PROSPERO])^43–46 are ongoing with tozorakimab. Additionally, a phase 3 study is also ongoing in severe viral LRTD (NCT05624450).⁴⁷ These studies will provide further evidence regarding the efficacy and safety of tozorakimab. Inclusion of the controlled long-term extension study (PROSPERO)⁴⁶ and the extension phase of MIRANDA in the phase 3 LUNA program will also provide an opportunity to assess the long-term safety of tozorakimab in a broad population of participants with COPD.

A key strength of this study was the collection of data from four phase 2 studies, which allowed for an analysis of safety data from over 1000 participants across multiple indications. Additionally, safety across a wide range of tozorakimab doses (30–600 mg) was tested. However, it should be noted that individual dose groups within studies were limited in sample size, so dose-dependent effects on safety could not be easily assessed. Other limitations of the FRONTIER program should also be acknowledged. These studies were relatively short in duration, conducted in different populations, and varied in size and design, which limited the ability to directly compare results across indications. Patient populations across the four studies also shared different levels of disease severity, with participants with DKD (FRONTIER-1) presenting with higher rates of comorbidities than those across the other FRONTIER studies, therefore impacting the ability to compare results across trials. Finally, the nature of the AEs observed in the studies may have been influenced by the COVID-19 pandemic.

Conclusions

In the 738 participants who received tozorakimab across all four phase 2 FRONTIER studies, tozorakimab was well tolerated with no safety concerns identified. Overall, the proportions of TEAEs and serious TEAEs were similar between treatment groups, and AESI occurrence was low. Several studies are ongoing to further collect essential data on the efficacy, short- and long-term safety, and tolerability of tozorakimab in COPD (NCT05166889, NCT05158387, NCT06040086, and NCT05742802), severe viral LRTD (NCT05624450), and asthma (NCT06932263).

Funding Statement

The FRONTIER studies were funded by AstraZeneca.

Data Sharing Statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available, which outlines further details here: https://vivli.org/ourmember/astrazeneca/.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

RP, DB, EG, RM, AH, CK, GLS, HP, MJ, and IP are employees of AstraZeneca and may hold stock or stock options. The authors report no other conflicts of interest in this work.

The abstract of this paper was presented at the American Thoracic Society International Conference, May 16–21, 2025, San Francisco, CA, USA, as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in the American Journal of Respiratory and Critical Care Medicine [https://doi.org/10.1164/ajrccm.2025.211.Abstracts.A1373].