October 06, 2025
5 min read
Key takeaways:
- Interferon lambda-encoding messenger RNA drug ETH47 was generally safe in healthy individuals.
- A phase 2a trial is assessing nasal ETH47 vs. placebo in adults with asthma.
Interferon lambda concentrations in nasal lining fluid fell in or above the predicted therapeutic range with a nasally delivered messenger RNA therapeutic in healthy individuals, supporting its candidacy for preventing asthma exacerbations.
These results on the interferon lambda-encoding messenger RNA (mRNA) drug ETH47 (Ethris) were presented at the European Respiratory Society International Congress.
Notably, interferon lambda, which is dysregulated in patients with asthma, is critical for anti-viral mucosal immunity and host resistance, according to the presentation given by Thomas H. Langenickel, MD, PhD, chief medical officer of Ethris.
In the phase 1 ETH47-101 trial, Langenickel and colleagues assessed 40 healthy individuals who received one of five doses of ETH47 nasal spray or placebo to gain insight on the safety and target engagement of the drug in humans.
The smallest dose of ETH47 given was 0.0072 mg, followed by 0.036 mg, 0.175 mg, 0.7 mg and 1.4 mg, according to the presentation. Under each dose level, six individuals received ETH47 and two individuals received placebo.
Ten individuals experienced a treatment-emergent adverse event, including one in the 0.0072 mg group, one in the 0.175 mg group, four in the 0.7 mg group, two in the 1.4 mg group and two in the placebo group.
Within the total population, only one individual experienced a drug-related treatment-emergent adverse event, and they were in the placebo group.
Across all groups, no individual reported severe treatment-emergent adverse events, serious treatment-emergent adverse events, treatment-emergent adverse events leading to discontinuation or treatment-emergent adverse events leading to death, according to the presentation.
In addition to adverse events, researchers assessed vital signs, physical examinations, ECGs, biochemistry, hematology, coagulation, chemokines, cytokines, urine analysis and anti-polyethylene glycol adenosine deaminase but did not observe any changes or trends in these measures.
Using interferon lambda concentrations in nasal lining fluid to analyze target engagement, the presentation revealed that these concentrations differed based on dose. Notably, interferon lambda concentrations in the 0.036 mg and 0.175 mg ETH47 groups were in the predicted therapeutic range, and concentrations in the two highest ETH47 dose groups went above this range.
Researchers also collected serum measurements of mRNA, lipidoid nanoparticle (LNP) and interferon lambda to examine bioavailability and found no systemic bioavailability of these drug products.
The next step in this research is a double-blind, randomized, placebo-controlled, phase 2a rhinovirus challenge trial that evaluates nasal ETH47 vs. placebo in 50 adults with asthma on stable maintenance therapy with ICS or ICS plus LABA and a sero-negative test result to RV-A16, according to the presentation.
Healio spoke with Langenickel to learn more about ETH47, the phase 1 study findings and progress in the phase 2a study.
Healio: What prompted the development of ETH47 and this study?
Langenickel: The development of ETH47 was driven by a critical unmet medical need in asthma care. Viral infections are the predominant trigger for asthma exacerbations, accounting for approximately 80% of acute asthma attacks. This creates a significant burden for patients and health care systems, with severe asthma and exacerbations causing approximately seven times higher annual health care expenditures compared with mild asthma patients.
Current asthma treatments focus on managing inflammation or providing symptom relief but do not address the viral triggers that initiate many of these exacerbations. Research showed that people with asthma have a dysfunctional interferon lambda response, which results in higher viral loads, worse symptoms and reduced lung function when exposed to respiratory viruses.
ETH47 was specifically designed to fill this treatment gap by targeting the upstream viral trigger rather than just managing the downstream inflammatory response. ETH47 is an LNP-formulated mRNA encoding interferon lambda, a cytokine crucial for epithelial host resistance at mucosal surfaces including the airways. It is delivered nasally to provide local protection at the primary viral entry site.
Healio: Were any of the study findings unexpected or surprising?
Langenickel: To our knowledge, this study is the first time to demonstrate that nasally delivered mRNA therapy results in the dose-dependent expression of the target protein and, subsequently, to desired target engagement, as indicated by dose-dependent upregulation of interferon-stimulated genes in the nasal epithelium.
Furthermore, we were able to confirm the absence of relevant systemic exposure to the mRNA, interferon lambda protein or lipidoid nanoparticle components in the bloodstream, following nasal delivery. This finding, already observed in preclinical studies and now confirmed in the clinical setting, demonstrates that ETH47 works precisely where it is needed: in the respiratory tract. This was particularly encouraging as it strongly validated our stabilized, non-immunogenic (SNIM) RNA and stabilized nanoparticle (SNaP LNP) platform’s ability to deliver targeted respiratory therapy without causing side effects related to systemic exposure.
Healio: Would you briefly characterize what the impact of the findings are for the everyday clinician?
Langenickel: ETH47 represents a paradigm shift in asthma management. Currently, clinicians utilize unspecific and specific anti-inflammatory treatments and bronchodilators. These therapies are very efficacious, but do not address viral triggers of exacerbations. ETH47 offers the potential to prevent asthma exacerbations at their source.
Based on the virus- and mutation-independent mechanism of action of ETH47, it could provide broad protection against the more than 150 rhinovirus types as well as other respiratory viruses that are associated with asthma exacerbations. ETH47 could therefore be the first intervention specifically designed to prevent the viral triggers that cause up to 80% of asthma attacks.
In addition, ETH47 has been shown to be very safe and very well tolerated in the first clinical trial, without any adverse events suggestive of local or systemic innate immune activation such as nasal stuffing, runny nose or elevated body temperature. This excellent safety profile, combined with the nasal delivery route that enables easy self-administration of ETH47, is very likely to result in broad acceptance by patients.
Healio: How will future studies be different? What is next in nasal ETH47 development?
Langenickel: Ethris has already advanced ETH47 into phase 2a development, with the first patient dosed in August. The phase 2a trial is a rhinovirus challenge trial in patients with mild to moderate asthma. The trial will investigate if treatment with ETH47 can prevent worsening of asthma symptoms, reduce viral load in the nasal cavity and lungs and prevent reduction of lung function following virus infection. This study design is particularly innovative because the controlled rhinovirus challenge model allows us to directly assess whether ETH47 can prevent virus-triggered asthma symptoms under controlled conditions, providing robust proof-of-concept for the drug’s intended mechanism of action.
Beyond the clinical development of ETH47 itself, we are also excited about translating the progress we are making with the development of mRNA/LNP spray drying into a dry powder formulation for ETH47. Furthermore, we are interested in leveraging the biological activity and extraordinary safety we have seen with ETH47 for the development of nasal mRNA vaccines. Both development of spray dried formulations and nasal vaccine are supported by a grant from the Coalition for Epidemic Preparedness Initiative.
We are also happy to see that our now clinically validated SNIM RNA/SNaP LNP platform is gaining broad inbound interest from industry and academia alike. To facilitate broad availability of our platform to interested parties, we entered into strategic collaborations with Thermo Fisher Scientific and Evonik, leveraging our partner’s end-to-end non-GMP and GMP manufacturing and scale-up capabilities.
In addition, we are further exploring the broader therapeutic potential of mRNA medicines utilizing our innovative and differentiated SNIM RNA and SNaP LNP platforms. This includes nasal vaccines development, as mentioned earlier, but also other mRNA therapies for respiratory and infectious disease and regenerative medicine indications within musculoskeletal and neuroscience therapeutic areas.
For more information:
Thomas H. Langenickel, MD, PhD, can be reached at bd@ethris.com.
