Translating An Early-Stage mRNA Therapeutic Into The Clinic
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
So far, 2025 has been a stellar year for travel. Advancing RNA (and yours truly) has been onsite at three different conferences so far, with another two on the docket by the end of the year. I daresay I don’t need to espouse the benefits of conference attending to most of you; not only does traveling keep me up to date on the overarching trends, themes, and challenges shaping the overall RNA industry, but it’s also a great chance to connect with readers and RNA leaders one on one to learn what’s keeping everybody occupied in their roles today.
A few weeks ago, I attended the Hanson Wade mRNA Therapeutics Summit in Boston. While on-site, I had the great opportunity to meet and sit down with Thomas Langenickel, CMO of Ethris to learn more about the work he’s doing overseeing the translation of the company’s first product from R&D into the clinic. In the following Q&A, Langenickel shares some of his biggest questions and observations about the evolving mRNA therapeutics space that are the most impactful in translating early-stage RNA candidates into the clinic — particularly when that drug product boasts a novel formulation.
Welch: I’m always curious to learn how working in a new therapeutic sector translates into unique challenges for C-suite executives. How has working with mRNA challenged you in your role at Ethris?
Langenickel: Like many others, I started my career working with small molecules and biologics, which are mature technologies. If we look at mRNA, we have a lot of questions to address around the mRNA itself, as well as the delivery of each product that I didn’t have to think about before with mature platforms. We really have had to work our way through and understand, what are the key biophysical properties of the platform? What do we need if we want to develop an mRNA product that we can deliver into the nose or into the lung?
A lot of the challenge comes down to the regulatory paradigm, which, as we know, is still being built globally, with ongoing efforts to harmonize through international guidelines. We’ve found that preclinical packages for clinical entry differ across geographies due to distinct regulatory approaches and definitions of mRNA therapeutics. For instance, in the European Union and United Kingdom, mRNA therapies (excluding vaccines) are classified as Advanced Therapy Medicinal Products (ATMPs), allowing for more flexible preclinical toxicology requirements. These requirements may necessitate toxicity testing in only one species if scientifically justified. In contrast, in the US, mRNA therapeutics are regulated as biologics, requiring toxicity studies in two preclinical species before clinical entry. These differences affect how quickly and under what conditions mRNA therapies can enter clinical development in each region.
This raises questions about how we can utilize data generated in one country to advance clinical development in multiple geographies. How we can utilize prior knowledge in general is a big question we have to address as a space.
Welch: I’m particularly interested in the work you’ve been doing to create a novel formulation of mRNA-LNPs. A previous conversation with Ethris’ CEO, Carsten Rudolph emphasized the importance of early engagement with patient advocacy groups to identify their needs. In addition to your ongoing collaboration with patient groups, what considerations guided you to the current formulation?
Langenickel: Obviously, we need to develop a drug that is convenient to use for the patient. We also need to think about how that new product fits into the current standard of care. What do patients need to do to administer and stay compliant with currently available treatments? What administration practices might be considered a burden to patients? Can this drug/novel formulation be easily integrated into a patient’s life? These types of questions ultimately pointed us in the direction of exploring a dry powder formulation. We also did not want to have a liquid suspension that needed to be in the pharmacy at -20 or kept in a patient’s fridge. We needed something that was stable at room temperature and could be easily carried with the patient.
Welch: In what ways has working with this novel formulation challenged your preclinical development thus far?
Langenickel: From a preclinical perspective, we needed to understand and demonstrate the relationship between dose, exposure and the pharmacodynamic effect of the drug product. These data are part of any standard data package, but this is a question that is not easily addressed with an inhaled drug product. Take a small molecule, for example, which is systemically bioavailable. The dose is orally administered, and the drug is absorbed and available in the systemic circulation. You can then measure the drug’s concentration in the blood. But for an inhaled, aerosolized drug, you need to go through an assessment to understand how much local exposure to the drug there is and how this relates to local and /or systemic effects. This assessment is even more challenging if you have a locally delivered drug that is specifically designed to be not systematically bioavailable like ours. Here we need to rely on the extrapolation of nasal or lung concentrations in preclinical species to humans. So, ending up with the appropriate clinical exposure to test is a big challenge.
Welch: What about from a CMC perspective?
Langenickel: The major challenge here is maintaining the stability of the formulation. We need to ensure that we do not end up with a product that aggregates easily or in which the LNPs fuse together during administration by nebulization. Aggregation could cause several critical downstream effects, including a loss of potency or immunogenicity. Our proprietary lipidoid formulation has been designed to withstand the stresses of drying and reconstitution, maintaining nanoparticle integrity and mRNA stability and biological activity for extended periods.
Welch: You recently released positive data for your first candidate ETH47 in Phase 1 clinical trials and initiated Phase 2. How do you anticipate your clinical strategy may need to adapt over time?
Langenickel: Luckily, we are in a position where our Phase 1 data was strong; we did not see any safety signals, and we have seen the desired dose response with regards to protein expression and target induction. We’re now advancing a Phase 2 challenge trial in patients with asthma. This trial is rather complex, especially in terms of endpoints. Likewise, though patient recruitment is an evergreen challenge in pharma, it’s particularly challenging in early clinical development because we are seeking a select subset of patients that meet certain stringent criteria associated with the trial’s design. Finding the right patients is always more challenging in early clinical development compared to Phase 3, in which you have broader eligibility criteria.
Welch: We always emphasize the importance of “starting with the end in mind.” This phrase is often used in manufacturing, but I can also see it being applicable to clinical development, as well. As you start your Phase 2 trials, what specific steps are you taking — and/or what conversations are you having internally — to ensure you’re prepared to transition your product from Phase 2 into Phase 3 development and to prepare for commercialization?
Langenickel: This is a good question. We initiated a comprehensive evaluation of patients’ needs with asthma and developed a target product profile (TPP) that specified the key characteristics that our drug candidate needs to meet or exceed to address these needs. We subsequently assessed and further refined the TPP based on discussions with physicians, patients, and payers. From my perspective, this is a very critical step to ensure we develop a medicine that provides a meaningful additional benefit to patients and the healthcare system beyond the benefits delivered by currently available medicines. This TPP has ultimately driven the integrated development strategy that has informed all program activities up to this point, including the ongoing Phase 2a proof-of-concept trial in patients with asthma, and is also the basis for transition into full development and commercialization.
If you’re interested in hearing more perspectives from leaders at Ethris, be sure to check out the following content on Advancing RNA: