Molecule targets TSLP, IL-13 to reduce FeNO in mild to moderate asthma

Key takeaways:

• The treatment group had reductions in FeNO 1 week after a single dose.
• Reductions were significant compared with placebo at week 4.
• The treatment group also saw reductions in blood-based type 2 biomarkers.

WASHINGTON — Patients with asthma experienced fast and substantial reductions in fractional exhaled nitric oxide with the SAR443765 bifunctional NANOBODY molecule, which blocks thymic stromal lymphopoietin and IL-13, according to a study.

These reductions surpassed those seen in monovalent treatments that target either pathway, Benjamin T. Suratt, MD, clinical lead, early development, immunity and inflammation, Sanofi, said during his presentation at the American Thoracic Society International Conference.

“This study supports our broader scientific strategy dedicated to exploring disruptive mechanisms of action, driving us toward first or best-in-class medicines that improve the lives of people living with chronic inflammatory diseases,” Surratt told Healio.

FeNO often remains elevated in moderate to severe asthma despite the use of standard-of-care medicines, Suratt said, indicative of continued airway inflammation and associated with increased risk for exacerbations and ongoing loss of lung function.

“We believe in the potential of the NANOBODY platform and this dual targeting approach to break efficacy ceilings,” he continued. “TSLP and IL-13 are two well-characterized targets, with positive impact in asthma, and our hypothesis was that by leveraging the NANOBODY platform for dual targeting we might be able to see a synergistic effect.”

Study design, results

The single-dose, randomized, placebo-controlled, double-blind safety and proof of mechanism study involved 36 patients with mild to moderate asthma and FeNO of 25 ppb or higher.

Elevated FeNO has been associated with increased risks for exacerbations, worse FEV₁, and accelerated loss of lung function, Suratt said.

Patients received a single dose of SAR443765 or placebo administered by subcutaneous injection, and then they were assessed 4 weeks later.

The treatment group experienced reductions in FeNO as early as week 1, with significant reductions vs. placebo at week 4 (point estimate, –40.9 ppb; 90% CI, –55.43 to –26.39).

Reductions in blood-based type 2 biomarkers including IL-5, eotaxin-3, TARC, IgE and eosinophils were consistent with these reductions.

Although lung function was normal to nearly normal at baseline, Suratt continued, there also was rapid and numerical improvement in pre-bronchodilator FEV₁ as early as week 1 and largely maintained through day 29.

The most common treatment-emergent adverse events in both groups were nasopharyngitis and injection site reactions, and all of these events were classified as mild to moderate.

Conclusions, next steps

Suratt called the reduction in FeNO from baseline vs. placebo rapid and substantial.

“FeNO is a marker of poor asthma control and type 2 airway inflammation, linked to exacerbation risk and long-term loss of lung function, that often remains elevated in severe asthma despite the use of standard-of-care medicines,” he said.

Although conclusions from cross-trials comparisons are limited and cannot be definitive, Suratt cautioned, the reduction in FeNO was numerically greater than the reduction in FeNO observed in clinical trials for drugs that target either pathway alone in mild to moderate asthma.

“This effect on FeNO based on targeting both mechanisms together would suggest a synergistic effect compared to TSLP or IL-13 alone in asthma,” he said.

These results also indicated that SAR443765 has potential for superior suppression of airway inflammation and preservation in airway function in asthma, Suratt said.

“This is novel, as a combination of two targets that results in synergy has not been demonstrated previously for asthma,” he said. “These results suggest that it may be possible to exceed the efficacy ceiling of individual targets with this dual targeting approach.”

Phase 2b and phase 3 studies would be necessary for firmer conclusions about SAR443765’s potential for breakthrough efficacy, Suratt said, adding that phase 2 planning is underway.