Nasal Delivery of mRNA Therapeutics: A Novel Approach to Drug Development for Asthma

Despite the availability of effective asthma medications, many patients continue to suffer from acute asthma attacks, also known as exacerbations. These attacks, characterized by severe symptoms such as wheezing, chest tightness and difficulty breathing, often require emergency medical care and can be life-threatening. A significant trigger for these attacks is respiratory viral infections, affecting approximately 80 percent of acute asthma cases in both adults and children.

Nasal Delivery of mRNA Therapeutics and Drug Development for Asthma — Thomas Langenickel, MD
Chief Medical Officer
Ethris

The treatment landscape for respiratory diseases is evolving, with mRNA therapeutics emerging as one advancement. Ethris, a biotechnology company, is at the forefront of this change, exploring how nasal delivery of mRNA can be used to manage conditions like asthma. This approach offers a new perspective on asthma treatment, focusing on delivering therapeutic benefits directly to the respiratory system.

In a conversation with Dr. Thomas Langenickel, Chief Medical Officer at Ethris, we explored the implications of an innovative method and what it could mean for the future of respiratory medicine.

XTALKS CLINICAL EDGE: Issue 3 — Interview with Ethris’ Dr. Langenickel

Xtalks Clinical Edge is a magazine for clinical research professionals and all who want to be informed about the latest trends and happenings in clinical trials. This magazine immerses you in a world where industry leaders, patient advocates and top researchers converge to provide the most insightful perspectives on clinical trials.

Addressing the Unmet Needs in Asthma

Asthma remains a challenging condition for millions of patients worldwide, despite the availability of a wide range of medications. Acute asthma attacks, or exacerbations, continue to pose significant risks, often requiring emergency care and sometimes leading to life-threatening situations. These attacks are frequently triggered by respiratory viral infections, which are particularly problematic for asthma patients due to their compromised interferon lambda system—a crucial component of the body’s innate immune defense.

The traditional approach to asthma management has primarily focused on controlling symptoms and preventing exacerbations through the use of inhalers and other medications. However, these treatments do not directly address the underlying issues related to viral susceptibility in asthma patients. This is where the innovative approach of delivering mRNA therapeutics nasally could make a substantial difference.

The Potential of mRNA Therapeutics in Respiratory Medicine

The concept of using mRNA therapeutics to treat respiratory diseases is relatively new but holds immense promise. mRNA therapies work by instructing cells to produce specific proteins that can enhance the body’s natural defenses or correct deficiencies. In the context of asthma, this means potentially restoring the immune response in the respiratory tract to better protect against viral infections that often trigger severe asthma symptoms.

Dr. Langenickel explains, “Patients with asthma are really more susceptible to respiratory viral infections than healthy individuals because they have a dysfunctional interferon lambda system.”

ETH47, Ethris’ investigational mRNA therapeutic, is designed to address this vulnerability by encoding for interferon lambda, a crucial protein in the immune response. “By restoring the production of interferon lambda, we aim to correct the dysfunctional innate immunity in asthma patients, with the potential to protect them from virus-driven acute asthma attacks,” described Dr. Langenickel.

Ethris’ recently announced Phase I trial results mark a significant milestone. The trial demonstrated that nasal administration ETH47 was generally safe and well-tolerated in humans, with local delivery to the respiratory tract resulting in the desired production of the encoded protein.

Dr. Langenickel emphasized the importance of this development, stating, “In this Phase I trial, we’ve been able to really demonstrate for the first time the safety and desired pharmacology of ETH47 in humans. Meaning that the local delivery of ETH47 to the respiratory tract results really in local production of the protein that was encoded with the mRNA.”

This not only validates the clinical translatability of Ethris’ preclinical findings but also confirms the potential of their mRNA platform for broader clinical applications.

Overcoming the Challenges of mRNA Drug Development

Developing mRNA therapeutics for respiratory conditions presents unique challenges, particularly in terms of drug delivery and stability. Unlike more traditional drugs, mRNA molecules are fragile and require careful handling to ensure they remain effective by the time they reach the target cells.

“Based on the emerging data that we and other companies have generated and that other academic groups have generated, I believe that mRNA-based therapeutics have a bright future in respiratory medicine.”

— Thomas Langenickel

Ethris has made notable progress in addressing these challenges. Two key hurdles were thermostability and nebulizability. Ensuring the stability of mRNA drugs without the need for ultra-cold chain requirements was crucial for practical clinical use. Ethris addressed this by developing a formulation that allows storage in a refrigerator and maintains stability at room temperature.

Another challenge was the nebulizability of lipid nanoparticle (LNP) formulations, which tend to form particle aggregates during spraying or nebulizing. These aggregates can trigger unwanted immune responses and reduce transfection efficiency. Ethris overcame this by creating a formulation that delivers pristine LNPs to the respiratory tract, ensuring effective and safe local delivery.

“We again address that through formulation development so that we have a product that is nebulizable and delivers really a pristine LNP into the respiratory tract avoiding all these potential undesired effects that you could get,” Dr. Langenickel noted.

Broader Implications for Respiratory Disease Treatment

With the Phase I trial demonstrating the safety and pharmacology of ETH47, Ethris is now planning a human virus challenge trial in asthma patients. This next step aims to investigate the safety, antiviral efficacy and potential for improving virus-dependent asthma symptoms in a relevant patient population.

While the focus of much current research is on asthma, the potential applications of nasal mRNA delivery extend far beyond this condition. Chronic obstructive pulmonary disease (COPD), another condition characterized by frequent exacerbations often triggered by viral infections, could also benefit from similar therapeutic strategies. Additionally, mRNA therapeutics hold promise for other respiratory viruses, including influenza and respiratory syncytial virus (RSV), particularly in high-risk populations.

Dr. Langenickel envisions a future where mRNA therapeutics play a central role in managing a wide range of respiratory diseases. “We could envision developing mRNA therapies for COPD, and based on its broad antiviral properties, also for prevention of severe disease following infections with any endemic respiratory virus,” he notes.

The Future of mRNA Therapeutics in Respiratory Medicine

Dr. Langenickel is optimistic about the future of mRNA therapeutics in respiratory medicine. The ability to deliver these therapies directly to the respiratory tract, combined with their potential to address viral triggers of exacerbations, could fundamentally change how conditions like asthma and COPD are treated.

As the field continues to evolve, the focus will likely expand to include not only treating symptoms but also preventing the onset of severe respiratory conditions through innovative approaches like protein replacement and mucosal vaccination. Ethris is already working on ETH42, an mRNA therapeutic for primary ciliary dyskinesia (PCD), a genetic condition characterized by the absence of key proteins in the airways.

“I believe that mRNA-based therapeutics have a bright future in respiratory medicine,” Dr. Langenickel reflects. “We are seeing real advances with this platform, not just in the areas I mentioned earlier, but potentially in many others as well.”

The potential of mRNA therapeutics to revolutionize the treatment of respiratory diseases is becoming increasingly clear. Ethris’ work in developing nasal delivery methods for these therapies marks a significant step forward, offering new hope for patients with asthma and other respiratory conditions.

As research continues, the future of respiratory medicine looks set to embrace these innovative therapies, potentially leading to more effective treatments and better outcomes for patients worldwide.