On Monday, May 22, during one of the most popular sessions at the ATS 2023 International Conference, researchers presented results from four highly anticipated trials for the first time in an open public forum.

The session, Breaking News: Clinical Trial Results in Pulmonary Medicine, featured results from the TORREY study of seralutinib in patients with pulmonary arterial hypertension (PAH), the ENHANCE trials of nebulized ensifentrine in chronic obstructive pulmonary disease (COPD), the BOREAS study of dupilumab in COPD patients with type 2 inflammation, and a study of the engineered antibody SAR443765 for mild-to-moderate asthma.

TORREY Study of Seralutinib in PAH

In the phase two TORREY study, inhaled seralutinib significantly reduced pulmonary vascular resistance (PVR) in adults with PAH. Treatment with the novel compound also resulted in significant reductions in NT-proBNP as early as week 12, reported Robert P. Frantz, MD, director of the Pulmonary Hypertension Clinic and professor of medicine, Mayo Clinic.

“The reduction in PVR combined with improvement in pulmonary capacities, in conjunction with reduction in NT-proBNP, indicates that seralutinib is reducing RV afterload and having a beneficial effect on the right heart,” said Dr. Frantz, noting that the primary endpoints of the study were met and a global phase three study in PAH is planned.

Seralutinib is a tyrosine kinase inhibitor targeting PDGFRα/β, CSF1R, and c-KIT, key factors of vascular remodeling of the small pulmonary arteries. Seralutinib was specifically designed to be delivered via a dry powder inhaler for deep lung delivery.

All study participants remained on their standard-of-care background therapies. Most (57 percent) study participants were on a combination of three PAH medications.

Patients in the investigational arm started on 60 mg inhaled seralutinib twice daily, escalating to 90 mg twice daily after two weeks, as tolerated. Seralutinib was generally well tolerated, with treatment-emergent adverse events (TEAEs) reported in 41 (93 percent) and 36 (86 percent) of the patients in the seralutinib and placebo arms, respectively. The vast majority of TEAEs reported in the study were mild to moderate, Dr. Frantz said.

“In the overall pulmonary hypertension space, my sense is that we’re really at the dawn of a new era in how we manage this disease,” said Dr. Frantz, adding that a full reporting of the study results is currently being written and will be submitted for publication soon.

ENHANCE Trials of Nebulized Ensifentrine for COPD

Nebulized ensifentrine demonstrated improvements in lung function, symptoms, and quality-of-life measures in patients with moderate-to-severe COPD enrolled in the phase three ENHANCE-1 and ENHANCE-2 trials, reported Antonio Anzueto, MD, ATSF, professor of medicine and pulmonary section chief of Pulmonary, South Texas Veterans Healthcare System.

Ensifentrine is a first-in-class, dual-inhibitor of the PDE3 and PDE4 enzymes, combining a bronchodilator with non-steroidal anti-inflammatory therapy in a single compound.

The ENHANCE trials were designed to assess ensifentrine as a monotherapy and in combination with a single bronchodilator. The majority of patients in both trials (69 percent in ENHANCE-1 and 55 percent in ENHANCE-2) received background COPD therapy (either a long-acting muscarinic antagonist [LAMA] or long-acting β2-agonist [LABA]), and about 20 percent and 15 percent of participants, respectively, received an inhaled corticosteroid (ICS) with concomitant LAMA or LABA. Baseline characteristics were similar across the two trials, which enrolled 760 and 789 participants, respectively.

Ensifentrine therapy resulted in a 36 percent reduction in the rate of exacerbations in symptomatic COPD patients over 24 weeks in the ENHANCE-1 trial, and a clinically meaningful 43 percent reduction in the rate of exacerbations in symptomatic patients over 24 weeks in the ENHANCE-2 trial, Dr. Anzueto reported. The drug was well tolerated with a safety profile comparable to placebo, and adverse events were low across the two trials, he added.

“Based on these meaningful results, I believe ensifentrine, if approved, will be an important new class of bronchodilator and non-steroidal anti-inflammatory therapy for COPD patients, providing a much-needed alternative to existing treatments,” Dr. Anzueto said.

Verona Pharma plans to submit a New Drug Application for ensifentrine to the U.S. Food and Drug Administration in the second quarter of 2023. Full results of the ENHANCE trials will be submitted for publication soon, Dr. Anzueto said.

Phase 1b Study of SAR443765 in Mild-to-Moderate Asthma

In a phase 1b study of patients with mild-to-moderate asthma, the novel NANOBODY® molecule SAR443765 significantly reduced fractional exhaled nitric oxide (FeNO) following a single dose administered by subcutaneous injection, reported Benjamin T. Suratt, MD, clinical lead for early development, immunity, and inflammation at Sanofi.

SAR443765 is the first NANOBODY® molecule that Sanofi has developed for asthma. The bifunctional antibody, which targets thymic stromal lymphopoietin (TSLP) and interleukin-13 (IL-13), is engineered from the heavy-chain antibodies of llamas and alpacas.

“This is the first report of a novel biologic treatment targeting both TSLP and IL-13 using NANOBODY® technology,” Dr. Suratt said. “Study participants showed a rapid and substantial reduction in FeNO that appears to be greater than that seen in any of the previous studies of monovalent agents. This suggests that combination targeting can lead to additive, if not synergistic, efficacy in asthma.”

Reduction in FeNO was observed in every participant exposed to SAR443765 at every time point in the study, Dr. Suratt reported. Rapid improvement was also seen in FEV₁ and was largely maintained throughout the four-week study following a single dose of SAR443765, he added.

“The study confirms the pharmacodynamic effect of the molecule, with FeNO serving as a clinically relevant biomarker of type 2 inflammation, and we believe the findings suggest the potential for SAR443765 to suppress airway inflammation, preserve airway function, and improve asthma outcomes in further studies,” said Dr. Suratt, noting that a phase 2b dose-response study is planned for fall.

The researchers are currently preparing a manuscript of the phase 1b results and hope to publish it this year.

BOREAS Study of Dupilumab in COPD Patients with Type 2 Inflammation

In the phase three BOREAS study of patients with COPD and evidence of type 2 inflammation, study participants treated with dupilumab experienced fewer COPD exacerbations, improved lung function, improved quality-of-life measures, and less severe respiratory symptoms compared to the placebo group, reported Klaus F. Rabe, MD, PhD, professor, LungenClinic Grosshansdorf, Germany.

Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation, which is present in roughly 20 percent to 40 percent of COPD patients.

The BOREAS study was a double-blind, randomized trial that evaluated the safety and efficacy of dupilumab in COPD patients with type 2 inflammation following treatment with an inhaled triple therapy of ICS, LAMA, and LABA. Patients with an asthma diagnosis were excluded from the study.

Dr. Rabe reported that the annualized rate of moderate-or-severe exacerbations was 0.78 in the dupilumab arm and 1.10 in the placebo group. The prebronchodilator FEV₁ increased from baseline to week 12 by a least-squares (LS) mean of 160 mL with dupilumab and 77 mL with placebo, a difference that was sustained through week 52. At week 52, the St. George’s Respiratory Questionnaire score had improved by an LS mean of -9.7 with dupilumab and -6.4 with placebo. Both groups had similar rates of adverse events.

“Dupilumab reduced the annualized rate of moderate-to-severe exacerbations by 30 percent compared to placebo,” Dr. Rabe said. “It improved lung function, which was rapid and it was constant from 12 to 52 weeks. It significantly improved quality of life and symptoms in the individuals who received it, and it is very, very safe.”

The study’s findings were published in The New England Journal of Medicine during ATS 2023.