touchRESPIRATORY coverage from ERS 2025:

TIDE-Asthma (NCT05421598) was a randomized, double-blind, placebo-controlled phase 2 study investigating the efficacy and safety of amlitelimab, an OX40-Ligand (OX40L) inhibitor, as an add-on therapy for the treatment of moderate-to-severe asthma. Targeting key immune pathways offers a new approach to managing moderate-to-severe asthma, aiming to better control inflammation and improve outcomes for patients who remain underserved by current treatments.

touchRESPIRATORY spoke with Professor Praveen Akuthota (UC San Diego Health, San Diego, CA, USA) around the mechanism of action of amlitelimab, the aims, design and clinical endpoints of the phase 2 TIDE-Asthma study, the findings presented at ERS and the impact of the results.

The abstract “Amlitelimab phase 2 clinical trial results in patients with moderate-to-severe asthma” was presented at ERS 2025, 27 September–1 October, Amsterdam, The Netherlands.

Q. What is the mechanism of action of amlitelimab, and the rationale for investigating this therapy in moderate-to-severe asthma?

Amlitelimab is a fully human, non-T cell depleting monoclonal antibody that blocks OX40L. OX40L is a key immune regulator implicated in T-cell immune-mediated disorders, including moderate-to-severe asthma, which is why we sought to further understand its utility in the TIDE-Asthma study. Amlitelimab works by targeting OX40L on antigen-presenting cells, aiming to normalize the overactive immune system without depleting T cells.

Q. Could you describe the aims, design and inclusion criteria of the TIDE-Asthma phase 2 study?

The TIDE-Asthma phase 2 study is a randomized, double-blind, placebo-controlled, dose-ranging study, evaluating amlitelimab as an add-on therapy in 437 adults with moderate-to-severe asthma. Participants were on standard-of-care medicines with medium-to-high doses of inhaled corticosteroids and up to two other controllers. The study included three dose levels of amlitelimab, each with a loading dose administered every 4 weeks for the first 24 weeks, followed by once every 12 weeks until week 60, with participants randomized 2:1:2:2 to receive one of the three active doses or placebo.

Inclusion criteria included age (between 18–75 years); a moderate-to-severe asthma diagnosis for >12 months, according to stages 4 and 5 of the Global Initiative for Asthma (GINA); use of medium-to-high-dose inhaled corticosteroids (ICS) for >3 months; >1 severe asthma exacerbation in the past year, with at least one exacerbation during treatment with ICS; pre-bronchodilator forced expiratory volume in one second (pre-BD FEV1) between >40% and <80% of predicted normal; asthma control questionnaire (ACQ-5) score >1.5 at randomization; at least 12% reversibility and 200mL post-BD FEV after administration of albuterol/salbutamol or levalbuterol/levosalbutamol; and weight (between >40 kg and <150 kg).

Q. What were the primary and secondary outcomes, and how well were they met?

The primary endpoint of the TIDE-Asthma study was the annualized rate of severe asthma exacerbations (AAER). Key secondary endpoints include lung function (pre-BD FEV1) and asthma control (ACQ-5).

In the intent-to-treat (ITT) population, the following results were observed for the primary endpoint, assessed by AAER reduction at Week 48 compared to placebo:

While the primary endpoint did not reach statistical significance at the 250mg dose, notable improvements were observed across key secondary endpoints, including pre-BD FEV₁ and improvements in ACQ-5 scores:

In a post-hoc analysis, patients with potential evidence of mixed-type inflammation based on elevated blood neutrophils [≥4000 cells/µL] and eosinophils [≥300 cells/µL] showed the greatest benefit with amlitelimab, including greater reductions in AAER, and larger improvements in pre-BD FEV₁ and ACQ-5 scores:

Q. Could you describe the safety profile of amlitelimab?

Amlitelimab was well-tolerated, with no new safety concerns having been identified in this study. The incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs resulting in treatment discontinuation was similar between the amlitelimab groups and placebo in the overall safety population. Three deaths occurred in the study, which were all in amlitelimab treated patients; all were considered unrelated to treatment by the investigator.

The most frequent adverse events (occurring in ≥5% of participants in any arm, and more frequent with amlitelimab occurring in ≥1% than with placebo) were COVID-19, bronchitis, acute sinusitis, and headache. None of these events were serious or severe, considered related to treatment by the investigator, or resulted in treatment discontinuation.

Q. What is the impact of these findings, and how will they affect the phase 3 study?

Asthma represents one of the most common chronic diseases globally, affecting approximately 262 million people worldwide, yet it can manifest differently for each person and vary in its symptoms, severity and treatment required. While advancements in Type 2 inflammation research have significantly advanced care, including the emergence of biologics, there is still a large subset of patients with critical unmet needs. The results from the TIDE-Asthma study demonstrate the potential for amlitelimab to offer clinically meaningful improvements in exacerbations, lung function and symptom control in patients with potential evidence of mixed-type inflammation, which could fill a critical gap in asthma care.

Comments from Sanofi: 

• We are continuing to analyze results from the TIDE-Asthma study to inform next steps for future clinical studies.

• It would be premature to discuss next steps while this analysis is underway.