Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942

Abstract

Background Interleukin-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-human-IL-13 antigen-binding antibody fragment being developed for the treatment of asthma. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled, ascending-dose study at Hammersmith Medicines Research, London, UK, which is now complete. Healthy adults aged 18–50 years (n = 40) were randomized 3:1 to a single inhaled dose of VR942 0.5, 1.0, 5.0, 10, or 20 mg, or placebo. Adults aged 18–50 years who were diagnosed with asthma for ≥6 months before screening, and had forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) values ≥70% of the predicted values at screening (n = 45), were randomized to once-daily inhaled VR942 0.5 or 10 mg, or placebo (2:2:1), or VR942 20 mg or placebo (3:2), for 10 days. All participants were randomized to receive VR942 or placebo based on a randomization list prepared by an independent HMR statistician using SAS® software ( , Cary, NC). The primary outcome was safety and tolerability of VR942 (safety population, defined as all who received at least one dose of VR942 or placebo). This study is listed on ClinicalTrials.gov (NCT02473939). Findings In the VR942 and placebo groups, treatment-emergent adverse events (TEAEs) were reported in 10/30 (33%) and 0/10 (0%) healthy participants, and in 16/29 (55%) and 9/16 (56%) participants with asthma, respectively. Mild intermittent wheezing occurred in 7 participants (VR942 20 mg, n = 4; corresponding placebo, n = 3), resolving spontaneously within 1 h. All TEAEs were mild or moderate; there were no deaths, serious adverse events, or clinically significant changes in vital signs, electrocardiograms, or laboratory parameters. There was no clinically significant immunogenicity, with only one participant with asthma considered positive for treatment-related immunogenicity for CDP7766. Interpretation This study, considered to be the only example of a dry powder anti-IL-13 fragment antibody being administered via inhalation, demonstrated that single and repeat doses were well tolerated over a period of up to 10 days in duration. Rapid and durable inhibition of fractional exhaled nitric oxide (FeNO) (secondary outcome) provided evidence of pharmacological engagement with the IL-13 target in the airways of participants diagnosed with mild asthma. These data, together with the numerical improvements observed for predose FEV 1 , justify further clinical evaluation of VR942 in a broader population of patients with asthma, and continue to support the development of an inhaled anti-IL-13 antibody fragment as a potential...

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

“…stages of clinical evaluations, most with attractive safety profile. Several mAbs have also been clinically evaluated as inhaled aerosols with demonstrated preliminary safety and tolerability(6, 16,37,38), suggesting the practicality of formulating 1212C2 for selfadministered inhalation. Over 90% of all symptomatic COVID-19 patients are not hospitalized, but they all still need treatment to minimize the potential for transmission and limit complications from viral infection.…”

Soluble ligands as drug targets

“…For example, there are three anti-TNF agents -a nanobody, a decoy receptor and a mAb -with an oral administration route for treatment of Crohn's disease and ulcerative colitis in clinical trials, of which the nanobody V565 is the most advanced, having reached phase II trials 117 . An inhaled formulation of a high-affinity antibody fragment, abrezekimab, that targets IL-13 was well tolerated in a phase I safety trial, and is proposed to provide a more rapid onset of action at lower doses than subcutaneous systemic administration for the treatment of asthma 118 .…”

Revisiting IL-13 blockade: can we reach the wonderland the inhaled way?

“…Since the promising Phase II results for lebrikizumab [ 5 ] and tralokinumab [ 4 ] were not confirmed in Phase III trials, a better understanding of the responder population for anti-IL-13 blockade is necessary. In this issue, the study of Burgess et al [ 6 ] provide data of the administration of a humanized, high-affinity, neutralizing, anti-human-IL-13 antibody fragment, administered through the inhaled route, giving an alternative to the systemic administration of monoclonal antibodies for the therapy of asthma and mimicking the usual practice of drug delivery in asthmatic patients. This study has a proof-of-concept element, as the observed FeNO suppression shows an anti-inflammatory effect of this agent, while the numerical increase of FEV 1 (with a mean difference of 150–200 mL versus placebo) shows an important treatment efficacy, both these improvements need to be confirmed in later phase trials.…”

“…The difference in efficacy of this inhaled anti IL-13 antibody compared to injectable anti-IL-13 medicines is something that needs to be considered, as this potential option moves along its development pathway. The fact that in the study of Burgess et al [ 6 ] there is a lack of a dose-response relationship for both FeNO and FEV 1 is a potential issue that needs to be considered in future trials of this agent.…”

“…When evaluating a novel medicine, we should always apply the fundamental principle of Hippocrates “first do not harm”. The study of Burgess et al [ 6 ] shows that inhaled anti IL-13 seems to be safe both in healthy participants and in mild asthmatics. However, following drug inhalation, a significant percentage of these mild asthmatic patients developed bronchospasm and FEV 1 reduction which in some cases was significant and potentially clinically relevant.…”