Delivering monoclonal antibodies via inhalation: a systematic review of clinical trials in asthma and COPD

ABSTRACT

Introduction

Advances in understanding the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) led to investigation of biologic drugs targeting specific inflammatory pathways. No biologics are licensed for COPD while all the approved monoclonal antibodies (mAbs) for severe asthma treatment are systemically administered. Systemic administration is associated with low target tissue exposure and risk of systemic adverse events. Thus, delivering mAbs via inhalation may be an attractive approach for asthma and COPD treatment due to direct targeting of the airways.

Areas covered

This systematic review of randomized control trials (RCTs) evaluated the potential role of delivering mAbs via inhalation in asthma and COPD treatment. Five RCTs were deemed eligible for a qualitative analysis.

Expert opinion

Compared to systemic administration, delivering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events. Although some of the inhaled mAbs included in this study showed a certain level of efficacy and safety in asthmatic patients, delivering mAbs via inhalation is still challenging and controversial. Further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

KEYWORDS:

• Asthma
• COPD
• inhaled
• monoclonal antibodies
• systematic review

1. Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases and major cause of morbidity, mortality, and health-care use worldwide [1,2].

Although inhaled corticosteroids (ICS) represent the mainstay of asthma management [1], over the last decade the widespread knowledge of asthma pathophysiology led to the development of new therapeutic options for patients with uncontrolled asthma [3]. In this regard, monoclonal antibodies (mAbs), innovative drugs targeting specific inflammatory pathways, are indicated as add-on therapy in patients with severe asthma [1]. To date, the approved humanized mAbs for asthma treatment include the anti-immunoglobulin (Ig) E omalizumab, the anti-interleukin (IL)-5 mepolizumab and reslizumab, the anti-IL-5 receptor α (IL-5 Rα) benralizumab, the anti-IL-4/IL-13 dupilumab, and the anti-thymic stromal lymphopoietin (TSLP) tezepelumab [4].

In COPD patients, airways inflammation poorly responds to corticosteroid treatment [5]. Over the past two decades, advances in understanding the underlying pathophysiology of COPD led the pharmacological research to identify new anti-inflammatory drugs [6–8]. In this respect, several biologic agents or biological response modifiers, which act by inhibiting or modulating inflammatory mediators (i.e. tumor necrosis factor [TNF]-α, IL-1β, IL-4, IL-5, IL-6, IL- 8, IL-13, IL-18, IL-23, IL-33, eotaxin-1 [CCL-11], TSLP, transforming growth factor [TGF]-β) have been investigated [9]. Unfortunately, many of these biologics failed to reach the clinical development stage or failed at clinical investigation phase [10]. Nowadays, no biologic drugs are licensed for the treatment of COPD [11].

All the approved mAbs are systemically (intravenous or subcutaneous) administered. However, parenteral administration exposes non-target organs to potential high doses of drugs with consequent risk of systemic adverse events (AEs) [12]. Moreover, trained medical personnel is required for intravenous administration [13]. Despite safety and feasibility of subcutaneous route of administration, noninvasive alternative methods are needed, particularly in the context of chronic disease [14].

Delivering mAbs via inhalation is an appealing approach for asthma and COPD treatment. This route of administration allows to directly targeting airways and the tissue site of cytokines expression [15]. The large surface area of the lungs (100 m²), the minimal thickness of airways epithelium (0.2–0.7 μm), and vascularization led to rapid absorption and onset of action [15,16]. Furthermore, significantly low drug doses are needed to obtain the pharmacological effect while increasing bioavailability [17], reducing systemic exposure, AEs, and costs [18,19]. Another advantage of inhaled mAbs is that severe asthma patients have experience in inhalers use for disease treatment [15].

Therefore, the aim of this article was to systematically review the evidence across literature on delivering mAbs via inhalation in asthma and COPD.

2. Materials and methods

2.1. Review question

The question of this systematic review was to assess whether the administration of mAbs via inhalation may have a potential role in the treatment of asthma and COPD.

2.2. Search strategy

The protocol has been submitted to the international prospective register of systematic reviews (PROSPERO, submission ID: 423211), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [20], with the relative flow diagram reported in Figure 1. This study satisfied all the recommended items reported by the PRISMA 2020 checklist [21].

Figure 1. PRISMA flow diagram for the identification of clinical trials included in the systematic review concerning the impact of delivering mAbs via inhalation in asthma and COPD treatment. COPD: chronic obstructive pulmonary disease; mAbs: monoclonal antibodies; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols.

The Patient problem, Intervention, Comparison, and Outcome (PICO) framework was applied to develop the literature search strategy and question, as previously reported [22]. Namely, the ‘Patient problem’ included asthmatic and COPD patients; the ‘Intervention’ regarded inhaled mAb; the ‘Comparison’ was performed with respect to placebo; the assessed ‘Outcomes’ were efficacy, safety, and pharmacokinetics (PK) of inhaled mAbs in asthma and COPD.

A comprehensive literature search was performed for clinical trials, written in English, and investigating inhaled mAbs in asthma and COPD. The search was performed in ClinicalTrials.gov, MEDLINE, and Scopus to identify relevant studies available with no time limit up to 9 March 2023.

The research terms entered in ClinicalTrials.gov database were ‘monoclonal AND antibodies’ in Condition or disease field, and ‘inhaled OR inhalation OR inhalable’ in Other terms field. The string used for MEDLINE and Scopus research was as follows: ‘(monoclonal AND antibody) AND (inhaled OR inhalation OR inhalable) AND (asthma OR COPD).’

Literature search results were uploaded to Eppi-Reviewer 4 (EPPI-Center Software. London, UK), a web-based software program for managing and analyzing data in literature reviews that facilitates collaboration among reviewers during the study selection process.

2.3. Study selection

Clinical trials reporting results concerning the efficacy, safety, and PK of inhaled mAbs in asthma and COPD were included in the systematic review.

Two reviewers independently checked the relevant studies identified from ClinicalTrials.gov, MEDLINE, and Scopus. The studies were selected in agreement with previously mentioned criteria, and any difference in opinion about eligibility was resolved by consensus.

2.4. Data extraction

Data from included studies were extracted and checked for study year and references, PMID or ClinicalTrial.gov identifier, study characteristics, phase study, treatment duration, number and characteristics of analyzed patients, drugs, doses and regimen of administration, inhaler device, outcomes, results, and study quality assessment via the Jadad Score [23].

2.5. Endpoints

The endpoint of this systematic review was to evaluate the efficacy, safety, and PK of inhaled mAbs in asthma and COPD.

2.6. Strategy for data synthesis

Data from original papers were extracted and reported via qualitative synthesis. Statistical significance was identified for P < 0.05.

2.7. Quality score

The risk of bias for each included study was analyzed via the Jadad score [23]. The Jadad score, with a scale of 1–5 (score of 5 being the best quality), was used to assess the quality of the papers concerning the likelihood of bias related with randomization, double blinding, withdrawals and dropouts [23]. Studies were considered of low quality at Jadad score < 3, of medium quality at Jadad score = 3, and of high quality at Jadad score > 3.

Two reviewers independently assessed the quality of individual studies, and any difference in opinion about the quality score was resolved by consensus.

3. Results

3.1. Study characteristics

Of the 859 potentially relevant records screened in ClinicalTrials.gov, MEDLINE, and Scopus, 5 randomized controlled trials (RCTs) were deemed eligible for a qualitative analysis. This systematic review included data obtained from studies investigating inhaled mAbs in patients affected by asthma and COPD.

Three RCTs [24–26] were published in full text articles, while two RCTs [27,28] resulted only in the ClinicalTrials.gov repository database. Two of the five RCTs [25,26] were of high quality (Jadad score = 5), one RCT [24] was of low quality (Jadad score = 2), and for two studies [27,28] Jadad score was not calculable since data were reported only in ClinicalTrials.gov. The main characteristics of the studies included in the systematic review are summarized in Table 1.

Table 1. Characteristics of the studies included in the systematic review.

Study, year and reference	PMID/ ClinicalTrial.gov identifier	Study characteristics	Phase	Treatment duration	Number of analyzed patients	Patients’ characteristics	Drugs, doses and regimen of administration	Inhaler device	Age (years)	Male (%)	Outocomes	Jadad score	Main results
Fahy et al. 1999 [24]	10471635	Randomized, double-blind, placebo-controlled, parallel group study	NA	8 weeks	33	Allergic asthmatic subjects with FEV1 ≥ 70% pre- dicted; bronchial hyperactivity to methacholine; serum IgE < 500 IU/mL;positive skin prick test to aeroallergens	Aerosolized recombinant humanized monoclonal antibody- anti-IgE (E-25), 1 mg administered once daily versus E-25 10 mg once daily versus placebo	PARI IS-2 nebulizer powered by a PARI Master compressor. PARI IS-2 nebulizer is a system designed for efficient delivery of drugs to the peripheral regions of the lungs thanks to an ‘open-vent’ type system that allow to additional air to be mixed with the droplets generated by the nozzle	20–46	63.3	FEV1, AM PEF, PC20, serum total IgE levels (free IgE + IgE complexed to E25), serum levels of E25, serum antibody directed against E25, levels of E25 in BAL, total IgE concentrations in BAL	2	E25 delivered by the aerosol route was no better than aerosolized placebo in attenuating the airway responses to inhaled allergen in allergic asthmatic subjects
Burgess et al. 2018 [25]	30146344/NCT02473939	Two-part, randomized, double-blind, placebo-controlled, ascending-dose study	1	10 days	85	Healthy participants with FEV1 and FVC > 80% of the predicted values at screening; subjects diagnosed with asthma for ≥6 months before screening, and had FEV1 and FVC values ≥ 70% of the predicted values, and FeNO level ≥ 35 ppb	Part 1: once-daily inhaled VR942 0.5 mg, 1.0 mg, 5.0 mg, 10 mg, 20 mg versus placebo. Part 2: once-daily inhaled VR942 0.5 m, 5.0 mg, 10 mg, 20 mg versus placebo	Multidose F1P DPI (Vectura Ltd, Chippenham, UK). Multidose DPI have a dose measuring mechanism that guarantee safety preventing double dosing and moisture uptake by the drug formulation	18–50	100	Safety and tolerability of single doses of VR942 (0.5 mg, 1 mg, 5 mg, 10 mg, and 20 mg) in healthy participants, and of multiple ascending doses of VR942 (0.5 mg, 10 mg, and 20 mg once daily for 10 days) in participants with asthma, determination of the PK profile and immunogenicity of CDP7766 (all participants), and the PD effect of VR942 on FeNO level (participants with asthma)	5	Single and repeated doses of VR942 administered via inhalation were well tolerated over a period of up to 10 days in duration; VR942 induced a numerical improvement in pre-dose FEV1 and a durable FeNO reduction
Gauvreau et al. 2023 [26]	36822634/NCT03138811 NCT03138811	Randomized, double-blind, placebo-controlled, parallel-design, multicenter AIC study	NA	12 weeks	28	Subjects with stable mild atopic asthma requiring no asthma medications except SABA less than twice weekly. FEV1 ≥ 70% predicted; PC20 ≤ 16 mg/mL − 1 during the screening MIC; positive skin prick test to common aeroallergens, and positive EAR and LAR to a common inhaled allergen during the screening AIC 16 mg/mL − 1 during the screening MIC; positive skin prick test to common aeroallergens, and positive EAR and LAR to a common inhaled allergen during the screening AIC	4 mg once-daily inhaled ecleralimab versus placebo	Breezhaler dry powder inhaler device, Novartis (Basel, Switzerland)	18–60	39	Allergen-induced LAR on day 84 assessed by LAR AUC3–7 h and LAR% Safety and tolerability of daily ecleralimab administration assessed by AEs and SAEs Day 42 and day 84 EAR AUC0–2 h, EAR%, EARmin and LARmin, Day 42 LAR AUC3–7 h and LAR% Sputum eosinophils FeNO methacholine PC20 blood eosinophil levels	5	Ecleralimab induced attenuation of LAR and LAR%, EAR and EAR%; Ecleralimab reduced sputum eosinophils; and FeNO levels from baseline; ecleralimab was safe and well tolerated
Novartis Pharmaceuticals [27]	NCT04410523	Multicenter, multi-national, double-blind, randomized, parallel-arm, placebo-controlled study	2b	12 weeks	336	Patients diagnosed with asthmawho have been treated with medium or high dose ICS plus LABA with up to 2 additional controllers;morning pre-BD FEV1 value of ≥ 40% and ≤ 85% of the predicted normal;a positive reversibility testACQ-5 score of ≥ 1.5 at screening and end of run-in visits	CSJ117 (0.5 mg, 1 mg, 2 mg, 4 mg and 8 mg) inhaled once daily vs. placebo	Concept1 device, a unit dose, capsule-based DPI which requires loading of the dose prior to each use and delivers a consistent dose of inhaled medication across different inhalation flow rates	18–75	NA	Change from baseline in pre-dose FEV1, FeNO; Anti-Drug immune response; CSJ117 serum concentration; change from baseline in PEF, ACQ-5, AQLQ +12, asthma symptom score, SABA use	NA	NA
Novartis Pharmaceuticals [28]	NCT04882124	Randomized, participant- and investigator-blinded, placebo-controlled, parallel group, multicenter study	2	12 weeks	38	Participants current or ex-smokers who have a smoking history of at least 10 pack years with diagnosis of COPD, for at least 1 year prior to screening visit, prone for exacerbations and symptomatic at baseline despite background maintenance triple therapy (ICS/LABA/LAMA) combination, for at least 3 months prior to screening	CSJ117 (4 mg and 8 mg) inhaled once daily vs. placebo	Concept1 device, a unit dose, capsule-based DPI which requires loading of the dose prior to each use and delivers a consistent dose of inhaled medication across different inhalation flow rates	≥40 years	NA	Change from baseline in E-RS score, CAT score, SGRQ-C score; response in E-RS, CAT, and SGRQ-C decrease from baseline, change from baseline in trough FEV1 after 2, 6, and 12 weeks of treatment, puffs of rescue medication per day, time to COPD exacerbations and rate and severity of COPD exacerbation via EXACT and HRCU, pre-dose trough concentration and accumulation ratio of CSJ117, anti-drug antibodies	NA	NA

ACQ-5: Asthma Control Questionnaire-5; AIC allergen inhalation challenge; AM PEF: peak expiratory flow measured in the morning; AQLQ + 12: Asthma Quality of Life Questionnaire; AUC: area under the curve; BAL: Broncho Alveolar Lavage; CAT: COPD Assessment Test; COPD: Chronic Obstructive Pulmonary Disease; CSJ117: neutralizing antibody fragment (fragment antigen-binding, Fab) directed against human TSLP; DPI: dry-powder inhaler; E-RS score: Evaluating Respiratory Symptoms score; EAR: early asthmatic response; at least 20% decrease in FEV₁ within 2 h of allergen inhalation; EXACT: Exacerbations of Chronic Obstructive Pulmonary Disease Tool; FeNO: fractional exhaled nitric oxide; FEV₁: Forced expiratory volume in 1 second; FVC: forced vital capacity; HRCU: healthcare resource use; ICS: Inhaled Corticosteroids; IgE: immunoglobulin E; IgG: immunoglobulin G; IL-13: interleukin-13; ppb parts per billion; LABA: long-acting beta2 agonists; LAMA: long-acting muscarinic antagonists LAR: late asthmatic response; at least 15% decrease in FEV₁ between 3 and 7 h after inhalation; MIC: methacholine inhalation challenge; NA: not available; PC20: the concentration of methacholine that causes a 20% fall in FEV₁, PEF: Peak expiratory flow; PK: pharmacokinetic; PD: pharmacodynamic; SABA: short-acting beta2 agonists; SGRQ-C score: St. George Respiratory Questionnaire for COPD patients; VR942: dry-powder formulation containing CDP7766, a high-affinity anti-human-IL- 13 antigen-binding antibody fragment.

The inter-rater reliability for data abstraction was excellent before and after the learning process (Cohen’s Kappa 0.92 and 1.00, respectively). The intra-rater reliability produced a Cohen’s Kappa of 1.00 after the learning process.

3.2. Monoclonal antibodies via inhalation in asthma

3.2.1. Anti-IgE mAb

In 1999, Fahy et al. [24] conducted a randomized, double-blind, placebo-controlled, parallel group study in 33 patients with mild allergic asthma to assess the effect of the direct delivery of a recombinant humanized monoclonal antibody anti-IgE (E25) into the airways on early and late phase response to allergen inhalation challenge (AIC). Dermatophagoides pteronyssinus, Dermatophagoides farinae and grass were the allergens used to perform AIC. The main inclusion criteria were forced expiratory volume in 1st second (FEV₁) ≥70% predicted, positivity to methacholine challenge test, serum IgE < 500 IU/mL, a positive skin prick test to aeroallergens. Patients current medications during study period were not specified in the original study although use of any corticosteroids was listed between exclusion criteria.

Patients were randomized to receive two different doses of aerosolized E25 (1 mg and 10 mg) or placebo and data were reported as mean±standard deviation (SD).

Aerosolized E25 was self-administered by patients, once daily (OD) at home for 8 weeks, using a PARI IS-2 nebulizer powered by a PARI Master compressor, a system designed for efficient delivery of drugs to the peripheral regions of the lungs thanks to an ‘open-vent’ type system that allow to additional air to be mixed with the droplets generated by the nozzle [29]. After that, the area under the curve (AUC) for the change in FEV₁ during allergen challenge for early phase (AUC_0-1 h) and late phase (AUC_3-7 h) were assessed.

Treatment with aerosolized E25 at 1 mg induced a significant (P < 0.05) within-group attenuation in the early phase response to allergen (day 0: −1058 ± 310; day 83: −842 ± 527) that, however, was not significantly greater than in the placebo group (day 0: −980 ± 186; day 83: −874 ± 407). Not significant within- or between-group effect (P > 0.05) was induced by treatment with aerosolized E25 at 10 mg (day 0: −925 ± 320; day 83: −880 ± 653).

Among the small subgroup of patients (2 patients in the placebo group, 4 patients in the E25 1 mg group, and 4 patients in the E25 10 mg group) manifesting a late phase response to allergen, no statistically significant difference (P > 0.05) emerged during the treatment (day 0: placebo group −3675 ± 2221; E25–1 mg group −5483 ± 752; E25–10 mg group −3855 ± 2172; day 83: placebo group −4500 ± 8.545; E25–1 mg group −2400 ± 2100; E25–10 mg group −1695 ± 2405).

Detectable serum levels of E25 were found for both the investigated doses and for a single detection on day 0 in placebo group, with no significant (P > 0.05) changes in total serum IgE level (free IgE and IgE complexed to E25) in any of the three groups during treatment. The levels of E25 in bronchoalveolar lavage (BAL) were highly variable. The total IgE concentrations in BAL were 15% and 21% of the total serum IgE concentrations at screening visit and at day 42, respectively.

Overall, aerosolized E25 showed good tolerability. The incidence of AEs among treatment groups did not show statistically significant (P > 0.05) differences. No serious AEs were described during the study. However, in one patient treated with E25 at 10 mg the serum IgG and IgA antibodies directed against E25 were detected, although in the absence of immune-complex-mediated disease.

3.2.2. Anti-IL-13 mAb

Nearly 20 years later the study on aerosolized E25 [24], Burgess et al. [25] performed a Phase I, randomized, double-blind, placebo-controlled, ascending-dose study, to assess the safety, tolerability, PK and pharmacodynamics (PD) of inhaled VR942 in asthma (NCT02473939). VR942 formulation was delivered via the multidose F1P dry-powder inhaler (DPI). Multidose DPI have a dose measuring mechanism that guarantee safety preventing double dosing and moisture uptake by the drug formulation [30]. The formulation was composed by CDP7766, a high-affinity anti-human-IL-13 antigen-binding antibody fragment that inhibits IL-13 binding with the IL-13Rα1 subunit. Data were reported as mean±standard deviation (SD).

The trial was designed as a two-part study. In part 1, 40 healthy subjects received a single inhaled dose of VR942 (0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg) or placebo (randomization 3:1). In part 2, 45 asthmatic patients were randomized to receive OD inhaled VR942 0.5 or 10 mg, or placebo (randomization 2:2:1), or VR942 20 mg or placebo (randomization 3:2), for a total of 10 days treatment. The study included participants receiving stable low-dose ICS, and the use of Short-Acting β₂ Agonists (SABA) was permitted. The use of leukotriene antagonists in the two weeks before screening or Long-Acting β₂ Agonists (LABA) at any time before screening were considered exclusion criteria. Safety and tolerability of VR942 were assessed for single inhaled doses in part 1 and for multiple incremental doses in part 2.

Among healthy subjects, 37% of participants reported AEs, and 33% reported treatment-emergent adverse events (TEAEs). Only two TEAEs were attributed to study medication (aphthous ulcer and cough). Neither AEs nor TEAEs were described for subjects in the placebo group and no patients withdrawal from the study due to AEs and TEAEs.

In part 2, 55% of asthmatic patients manifested AEs, 28 out of 29 AEs were considered TEAEs. Also 56% of subjects in placebo group reported AEs, of which 13 were defined as TEAEs. Sixteen TEAEs were attributed to study medication (intermittent wheezing, presyncope, headache, and rhinorrhea).

In asthmatic patients, VR942 induced a numerical improvement in pre-dose FEV₁ when administered at 0.5 mg and 20 mg (317 ± 299 mL, 266 ± 209 mL, respectively) compared to placebo (109 ± 236 mL). In six patients treated with VR942 20 mg and in five subjects in the placebo group, a transient reduction in FEV₁ was reported after the first administration, at day 1. This reduction was around 30% of pre-dose FEV₁ regardless of the active treatment or placebo. Wheeze was reported in three subjects treated with VR942 at 20 mg and in two subjects in the placebo group, and spontaneously resolved.

Furthermore, in asthmatic participants, a significant (P < 0.05) and durable (for 96 hours) reduction in fractional exhaled nitric oxide (FeNO) level was observed in patients treated with VR942 at 10 mg and 20 mg vs. placebo, after the latest dose administration. No statistically significant effect was observed with VR942 0.5 mg compared to placebo.

PK analysis was not performed because the plasma levels of CDP7766 were below the lower limit of quantification for the analytical assay.

Among all study participants, seven healthy subjects and nine asthmatic patients reported positivity for CDP7766 antibodies, without treatment-related immunogenicity. Only one asthmatic patient in the VR942–20 mg group was considered positive for treatment-related immunogenicity for CDP7766 and manifested an AE (wheezing).

3.2.3. Anti-TSLP mAb

Recently, a randomized, double-blind, placebo-controlled, parallel-design, multicenter study conducted by Gauvreau et al. [26] investigated the efficacy and safety of ecleralimab, an inhaled anti-TSLP mAb fragment, in mild atopic asthmatic patients (NCT03138811). Data were reported as mean 90%CI. Ecleralimab formulation was a PulmoSol engineered powder contained in hard capsules and delivered through respiratory system via a Breezhaler DP inhaler device (Novartis, Basel, Switzerland). PulmoSol is a technology, largely applied for biologicals, that exploit glass stabilization to obtain chemical stability of active pharmaceutical ingredient [31].

The study lasted 12 weeks and enrolled 28 participants, randomized to receive 4 mg OD inhaled ecleralimab or placebo, undergoing AIC. Enrolled subjects were affected by mild atopic asthma requiring no asthma medications except SABA less than twice weekly. No details concerning the allergens used for the challenge were reported in the primary publication. Two sequential cohorts were scheduled. Initially ecleralimab was administered at 4 mg OD in cohort 1 and at 16 mg OD or less in cohort 2 according to safety and PK data. Although safety and PK data did not preclude dose escalation, investigators decided to administer ecleralimab at 4 mg OD also in cohort 2.

At day 84, when compared to placebo, ecleralimab significantly (P < 0.05) attenuated the allergen-induced variation in FEV₁ during the late asthmatic response (LAR) as measured by AUC_3–7 h (−7.18% 90% CI − 11.92 to −2.44) and maximum percentage decrease in LAR (−8.42% 90% CI − 15.66 to −1.18). Ecleralimab also induced a numerical reduction in the early asthmatic response (EAR) at day 84, but without significant difference vs. placebo (P > 0.05). Ecleralimab also elicited a significant (P < 0.05) reduction in allergen-induced sputum eosinophils compared to placebo. No differences in peripheral blood eosinophil counts were detected.

A significant (P < 0.05) reduction in FeNO was observed during the study period, excluded at day 43 and day 85, 24 hours post-allergen challenge.

Overall, 78.6% patients manifested 93 TEAEs. In 66.7% of patients receiving ecleralimab 51 AEs were described, and in 92.3% of subjects receiving placebo 42 AEs were reported. Headache, nasopharyngitis, and oropharyngeal pain have been the most relevant reported AEs.

Despite ecleralimab demonstrated safety and tolerability in mild asthmatic patients, the study was early terminated with intention of confirming the evidence in severe asthmatic patients, representing the target population of treatment with mAbs.

Another RCT, available only in ClinicalTrials.gov (NCT04410523), investigating the effect of an inhaled anti-TSLP mAb was conducted in 336 severe asthmatic subjects [27]. The study was a Phase IIb multicenter, multi-national, double-blind, randomized, parallel-arm, placebo-controlled study [27] evaluating efficacy and safety of multiple inhaled doses of a neutralizing antibody fragment against human TSLP (CSJ117). Participants were on treatment with medium or high dose ICS plus LABA with up to two additional controllers. Multiple doses (0.5 mg, 1 mg, 2 mg, 4 mg, and 8 mg) of CJS117, self-administered OD by Concept1 device, have been tested, compared to placebo, as add-on treatment of asthma standard of care therapy. The Concept 1 Breezhaler device is a unit dose, capsule-based DPI [32] which requires loading of the dose prior to each use and delivers a consistent dose of inhaled medication across different inhalation flow rates [33]. The primary outcome has been identified in pre-dose FEV₁ change from baseline at week 8 and 12. Change from baseline in FeNO, peak expiratory flow (PEF), Asthma Control Questionnaire-5 (ACQ-5), Asthma Quality of Life Questionnaire (AQLQ +12), asthma symptom score, and SABA use were considered secondary outcomes, as well as measure of anti-drug antibodies (ADA), and total CJS117 serum concentrations. The study was terminated in 2022 for sponsor decision and, to date, no results are available.

3.3. Monoclonal antibodies via inhalation in COPD

Efficacy, PK, PD, and safety of CSJ117 administered via inhalation were also evaluated in a Phase II study conducted on 38 COPD patients, available only in ClinicalTrials.gov (NCT04882124). This is a randomized, participant- and investigator-blinded, placebo-controlled, parallel group, multicenter study evaluating two fixed-dose levels of CSJ117 (4 mg, 8 mg) administered OD via oral inhalation by Concept1 device over 12 weeks.

COPD patients enrolled were symptomatic at baseline and exacerbations prone despite maintenance triple therapy with ICS plus LABA plus long-acting muscarinic receptor antagonist combination, for at least 3 months prior to screening.

Primary outcome was change from baseline in Evaluating Respiratory Symptoms (E-RS) score. Change from baseline in COPD assessment test (CAT) score, in St. George Respiratory Questionnaire (SGRQ-C) score, and in trough FEV₁ after 2, 6, and 12 weeks of treatment were considered secondary outcomes. Other investigated secondary outcomes were response in E-RS, CAT, and SGRQ-C decrease from baseline, puffs of rescue medication per day, time to COPD exacerbations and rate and severity of COPD exacerbation via Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT) and healthcare resource use (HRCU), pre-dose trough concentration and accumulation ratio of CSJ117, ADA mensuration to assess CSJ117 immunogenicity. The study resulted completed on 15 September 2022 and, to date, no results are available.

4. Conclusions

Data resulting from this systematic review indicate that the efficacy of mAbs administered via inhalation is controversial. Aerosolized E25 was not effective in attenuating both early and late response to inhaled allergen in asthmatic patients, and despite it was well tolerated, the aerosol route of delivery seemed to be more immunogenic than intravenous or subcutaneous administration. Conversely, inhaled VR942 induced a numerical improvement in pre-dose FEV₁ and a durable FeNO reduction, and ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation in patients affected by mild asthma. Both VR942 and ecleralimab showed a good safety profile and tolerability although VR942 was evaluated for a short study period (10 days). In healthy and asthmatic patients receiving VR942, positivity for CDP7766 antibodies was detected, although treatment-related immunogenicity was described in one of the asthmatic patients. No data are currently available for CSJ117 in severe asthma and COPD. Overall, the evidence raising from this systematic review suggests that adequately powered and well-designed RCTs carried out for at least 12 weeks are needed to really assess whether the administration of mAbs via inhalation may have a potential role in the treatment of asthma and COPD.

5. Expert opinion

Administering mAbs via inhalation is an attractive approach for the treatment of asthma and COPD due to the potential advantages of direct delivery into the airways. Four RCTs exploring the effect of inhaled mAbs in asthma are currently available [24–27], although results of one of these studies are still not published [27]. Only one RCT on inhaled mAbs has been conducted in COPD, but no results are currently available [28]. VR492 and ecleralimab were well tolerated and both were effective in attenuating airway inflammation in mild asthmatic patients. VR942 was effective in improving pre-dose FEV₁ and ecleralimab decreased allergen-induced bronchoconstriction. No effect on bronchoconstriction were observed for aerosolized E25 that, despite good tolerability, showed greater immunogenicity when administered via aerosol than via systemic route. Positivity for CDP7766 antibodies was detected in healthy and asthmatic patients receiving VR942, although treatment-related immunogenicity was observed in only one of the asthmatic patients.

Compared to systemic administration (either intravenous or subcutaneous), administering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure with lower risk of adverse events and improved safety profile [19,34]. Systemic administration results in very low concentrations of mAbs in the lungs [34]. As a matter of fact, previous findings showed that the pulmonary distribution of mAbs may be 500–2000 fold lower than plasma concentrations [35,36]. On the other hand, administering mAbs via inhalation is associated with increased proportion of active drug in the lungs, a condition leading to greater efficacy in the target tissue [37,38]. Detailed information on the PK distribution of mAbs administered systemically or via inhalation are shown in Figure 2.

Figure 2. Systemic and inhaled administration of mAbs. mAbs: monoclonal antibodies.

Of note, omalizumab, dupilumab, and tezepelumab seem to be able to modulate airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR) in asthma. This effect is directly mediated by the interaction with their receptors (FcεRI, IL-4 Rα, and TSLPR, respectively) expressed on ASM, and indirectly by targeting eosinophils and inflammatory cells with a consequent attenuation of the inflammatory cascade [39]. Thus, inhalation route of administration might provide a targeted approach to modulate cytokine pathways directly in lung tissue [38]. In this respect, VR942 induced in asthmatic patients a significant and durable reduction in FeNO level, suggesting a direct inhibition of IL-13 cascade. IL-13 is directly responsible of upregulated expression of the inducible isoform of nitric oxide synthase (iNOS), with consequent enhancement of airways nitric oxide level [40]. Furthermore, the inhaled anti-TSLP ecleralimab was effective in reducing allergen-induced sputum eosinophils and FeNO [], suggesting a constitutive release of TSLP in asthmatic airways [41,42] and the advantage of directly targeting alarmins through inhaled administration.

However, administrating mAbs via inhalation is associated with issues of proteins delivering to the lungs. First of all, physico-chemical degradation can occur during various steps of production or in vivo, leading to loss of biological activity or safety characteristics [43,44]. The drugs need to be administered as small solid or liquid microparticles (1–5 µm) in order to obtain lungs distribution [45]. Particles with diameter between 1 µm and 5 µm are able to reach peripheral airways, whereas those with size smaller than 1 µm or over than 10 µm are exhaled during tidal breathing or deposited in the oropharyngeal region, respectively [45,46]. Of note, biological drugs transport across airways epithelium is size dependent [46]. More specifically, peptides and proteins with molecular weight below 40 kDa quickly cross epithelial barrier, while those with molecular weight above 40 kDa require hours to days to be absorbed through airways epithelium [47–49]. Furthermore, absorption through alveolar epithelium results particularly challenging due to the large molecular weight and hydrophilicity of proteins [50]. Molecules absorption and their consequent pharmacological activity require the release of active drug through aerosol particles dissolution in fluid. However, fluid amount in the lung is limited and varies between central and peripheral airways, thus it is difficult to establish the fluid volume in which inhaled molecules will be dissolved [46]. Moreover, mucus components interact with peptides and proteins, then limiting their absorption [51]. Peripheral airways have a significantly larger absorptive surface than the conductive airways, thus for optimal absorption, small peptides should be delivered deeper in the airways [47]. Nevertheless, mAbs absorption could be influenced by expression of specific receptors [46]. Considering these issues, the optimal sites of inhaled mAbs deposition has not been yet clearly identified [46].

Finally, inhaler misuse could represent a further potential issue to mAbs delivery and efficacy. Inhaler misuse is well-described in asthma and COPD literature [52–55]. The percentage of patients unable to effectively use the inhaler ranges from 50% to more than 80% [53]. Numerous factors associated with inhaler misuse have been identified, including individual ones, like knowledge of inhaler technique and skill, or related to healthcare professionals, responsible of lacking or incorrect education [56]. Inhaler misuse could therefore impair mAbs delivery and pharmacological activity in target tissue with consequent negative impact on disease outcomes and healthcare costs.

Although some of the inhaled mAbs considered in this study showed a certain level of efficacy in asthmatic patients, the main limitation of this systematic review is related to the small number of included RCTs that, moreover, where characterized by intrinsic weaknesses. In this respect, being studies of early phase development, the RCTs included in this systematic review were conducted on a small number of mild asthmatic patients and were of short duration.

To date, mAbs are indicated as an add-on treatment for patients with uncontrolled asthma to reduce disease burden [4]. These patients have a scarce quality of life (QoL) and are at increased risk of exacerbations, hospitalization, fixed airflow limitation, health care resource use, and death [57]. Since biologic therapies are expensive, it is mandatory to identify patients most likely to benefit from these treatments. Furthermore, the reduction in the risk of exacerbation, improvement in lung function, asthma symptoms and QoL, and biomarkers are considered key outcomes to assess the efficacy of mAbs [58]. Therefore, RCTs designed to evaluate the effect of inhaled mAbs should include participants selected for asthma control, lung function, and biomarkers like blood eosinophils count, FeNO, serum total and allergen specific IgE. Nevertheless, most of the RCTs included in this systematic review investigated allergen-induced bronchoconstriction as main efficacy outcome, thus providing just a partial evaluation of the potential benefits of delivering mAbs via inhalation in asthmatic patients.

Overall, all the inhaled mAbs included in this systematic review showed good safety profile and tolerability, except for a greater immunogenicity described for aerosolized E25 compared to systemic administration [24], and positivity for CDP7766 antibodies in healthy and asthmatic patients receiving VR942, although evidence of treatment-related immunogenicity was described in only one asthmatic patients [25]. The greater immunogenicity of inhaled mAbs compared to mAbs parenterally administered might be explained with the high immunogenicity of aggregated proteins [34]. It is known that proteins aggregation, induced in response of various stresses, promotes immunogenicity and induces the production of potential ADA [59]. Unfortunately, the duration of RCTs included in the present systematic review was not superior to 12 weeks. In particular, the effects of VR492 were described for a period of 10 days treatment, representing a limitation to the assessment of the potential for immunogenicity [25].

The qualitative synthesis provided by this systematic review suggests that further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

Article highlights

• Monoclonal antibodies (mAbs) are innovative drugs targeting specific inflammatory pathways.

• To date, mAbs are indicated as add-on therapy in patients with severe asthma while no biologic drugs are licensed for the treatment of chronic obstructive pulmonary disease (COPD).

• Systemic administration of mAbs is associated with low target tissue exposure and risk of systemic adverse events.

• Delivering mAbs via inhalation is characterized by rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events.

• Further adequately powered and well-designed randomized control trials (RCTs) are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

Declaration of interest

P Rogliani discloses a relationship with Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Mundipharma, Novartis. M Cazzola discloses a relationship with Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon. L Calzetta is discloses a relationship with Boehringer Ingelheim, Novartis, AstraZeneca, Chiesi Farmaceutici, Almirall, ABC Farmaceutici, Edmond Pharma, Zambon, Verona Pharma, and Ockham Biotech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.