Novel Two-Prong Biologic Shows Promise in Asthma

The unique dual inflammation blockade of investigational lunsekimig showed promise for moderate-to-severe asthma in the phase II AIRCULES study.

Targeting both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, lunsekimig at various doses achieved statistically significant reductions in asthma attacks, with a 55.3% reduction in exacerbations at 48 weeks when comparing the highest dose of 300 mg every 28 days against placebo (P=0.0016).

This was supported by secondary endpoints favoring lunsekimig at this dose, reported Njira Lugogo, MD, of the University of Michigan in Ann Arbor, at the European Respiratory Society (ERS) Congress in Barcelona.

“This trial is very impactful,” Lugogo said. “Lunsekimig achieved a statistically significant and clinically meaningful reduction in asthma exacerbations. You saw a change in lung function that was rapid and sustained. Patient-centric outcomes also improved, and improvements were observed across subgroups, with a greater magnitude of response in those with greater disease severity, including frequent exacerbations. It was well tolerated at all doses.”

“Results from this phase II study support dual TSLP and IL-13 targeting to address unmet needs in individuals with moderate to severe asthma,” she concluded.

Targeting both TSLP and IL-13 purportedly gets at both an upstream initiator of inflammation and a downstream driver of inflammation.

ERS session discussant Lena Uller, PhD, MSc, of Lund University in Sweden, cautioned that important questions remain regarding lunsekimig’s mechanism of action. 

“The question is if it really targets both these upstream and downstream mediators. And, of course, this effect that you see, is it an additive effect or is it really a synergistic effect?” she posed. “I think for future research, it’s really important to do studies where you can compare its effectiveness against other biological treatments, such as anti-TSLP, to really compare efficacy.”

One such TSLP blocker is tezepelumab (Tezspire), a human monoclonal antibody that has been FDA approved for add-on maintenance treatment of severe asthma since 2021. Also relevant is the IL-4 and IL-13 blocker dupilumab (Dupixent), approved since 2018.

Still more options for asthma biologics on the market include omalizumab (Xolair), reslizumab (Cinqair), mepolizumab (Nucala), and depemokimab (Exdensur).

During the session’s Q&A, an audience member asked what lunsekimig’s dual blockade adds to the current biologic landscape.

“The majority of our patients are partial responders, many because they have discordant upper and lower airway responses to biologics,” said Lugogo. “I do think that biologics we currently have tend to target one pathway, but there is redundancy in inflammation.”

“So, the question is, could we, as we go into the next generation of biologics that are dual-, maybe tri-specific targeted biologics, could we start to achieve complete remission? That’s always been our dream,” she noted. “I think this is the next frontier, and we’ll learn a lot more as we start to engage in targeting duplicative and redundant pathways, and so I’m very excited about this new trend towards targeting multiple inflammatory pathways in asthma.”

Lunsekimig remains under investigation for high-risk asthma in the phase II AIRLYMPUS study and the open-label AIRPHRODITE extension study. In chronic obstructive pulmonary disease, the biologic has proceeded further, with phase III testing in the PERSEPHONE and THESEUS studies.

AIRCULES was a double-blind trial conducted on several continents. The investigators sought to enroll people ages 18-80 in Global Initiative for Asthma step 4-5, on medium- to high-dose inhaled corticosteroids, with at least one asthma exacerbation in the past year, among other criteria.

The study included 685 patients randomized to placebo or various subcutaneous doses of lunsekimig (ranging from 60 mg once every 8 weeks to 300 mg once every 4 weeks).

Mean age was about 52, and 35% were men. The group most commonly had two recent prior exacerbations (49.3%) or one (36.8%). Baseline fractional exhaled nitric oxide (FeNO) was 37.0 ppb on average, eosinophils were a mean 0.377 × 10⁹/L, pre-bronchodilator predicted forced expiratory volume in one second was 60.8%, the average 5-Item Asthma Control Questionnaire score was 2.8, and the Standardized Asthma Quality of Life Questionnaire mean score was 4.1.

Lugogo reported a higher magnitude of response in patients with two or more recent exacerbations or high type 2 inflammation (FeNO 25+ ppb). There were consistent responses to lunsekimig in those with and without high eosinophil levels, which prompted applause in the room.

Safety-wise, adverse events were “pretty much what you would expect in an asthma trial,” said Lugogo, reporting that the most frequent events were upper respiratory tract infections (12.2%) and nasopharyngitis (9.6%) in the lunsekimig group. There were no treatment-emergent adverse events leading to death, and importantly, anti-drug antibody titers were generally low and had no impact on pharmacokinetics, efficacy, or safety.