LNP-Delivered mRNA via Inhalation with Ethris' Carsten Rudolph and Thomas Langenickel

How can genetic information be carried into lung tissue for the treatment of asthma and potentially other conditions? In this inaugural episode of In Combination, host Tom von Gunden combines the perspectives of two executives from LNP/mRNA (lipidoid nanoparticle / messenger RNA) formulation and delivery platform developer Ethris: CEO Carsten Rudolph and Chief Medical Officer Thomas Langenickel. The conversation illuminates the value to patients of platform approaches to inhalation-delivered treatments.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to In Combination, the series that offers dual perspectives on drug delivery topics from two industry insiders whose angles of vision on the topic may differ or converge depending on role and experience. My name is Tom von Gunden, Chief Editor and Community Director at Drug Delivery Leader, an online information exchange for drug delivery professionals. Today, I am joined by two folks from Ethris, CEO Carsten Rudolph and Chief Medical Officer Thomas Langenickel, to talk about LNP-delivered mRNA therapeutics and the related delivery mechanisms and routes of administration that do that work.

Welcome, Carsten. Welcome, Thomas.

Carsten, can you trace for us the evolution of approaches? What has been done and what has been tried in terms of treatments and delivery mechanisms and how that leads us to the current moment and the work that you are doing at Ethris?

Carsten Rudolph, CEO, Ethris:

When delivering genetic information to the lung tissue of humans, in the past, dating back more than 20 years, people have delivered plasmids there, for instance, for the treatment of cystic fibrosis. But what we know from the biological mechanism of action is that plasmids are not very efficiently shuttled into the nucleus of a post-mitotic tissue, which is the lung, and so the efficiency was always quite low.

This is why we work on using messenger RNA [mRNA], where you can circumvent the necessity of having the nucleic acid going into the nucleus; it just needs to stay in the cytoplasm. We knew this was much easier to achieve with high efficiency.

For this, you also need the delivery system, which is what we have done. We developed new cationic lipidoid nanoparticle formulations which package the mRNA efficiently and shuttle it into the cells with very high efficiency. These are combined with the technology to stabilize these nanoparticles so that they are not destroyed during the step of nebulization, which is a key step to achieve so that a patient can inhale the mRNA drug.

We have made a lot of improvements when comparing our delivery systems with the ones that have been used in the past. In mice, we know that our systems are about 300x more efficient. This is very important for our cationic lipidoid technology, as it allows the mRNA to be fully retained in the lung tissue where it is delivered. It does not spread [elsewhere] into the body, which you see from commercialized vaccines. They are not fully retained at the site of delivery and distribute [elsewhere] in the body. It’s important to have full activity only where it's needed, which is in the lung tissue. This high precision of delivery is a key element of our technology.

Next is the extraordinary stability of our formulation. It is fully shielded against any mechanical stress, which also allows us to store our formulations with lyophilization combined at room temperature. We can achieve this for more than 15 months.

In the end, that’s what we want to achieve for patients: a very easy-to-use drug product that can be used in a pocket device, this nebulizer, to make it as easy as possible for the patient and [ensure] high compliance. To sum it up, we have four elements: a very high transfection efficiency achieved with our cationic lipidoids, high precision of our delivery so that it's retained where it's needed, high stability of our formulation so that they fully retain their activity, and the ability to be stored at room temperature. These are four very important elements that we believe we can provide with this technology to the patients that we want to treat.

Thomas, I'd like to turn to you on the clinical and patient front. Could you tell us a little bit about what the experience of receiving treatment has been like for patients historically, in terms of their life and their health? Can you talk about what some of these advancements could bring in terms of changes, improvements, and enhancements to the life and health of patients?

Thomas Langenickel, Chief Medical Officer, Ethris:

For that question, we should think about drugs in general and then specifically about ETH47 [Ethris’ asthma treatment]. If we are thinking about drugs in general, what is really important to patients is, first and foremost, safety and tolerability. Second is efficacy, and third is convenience. To ensure that patients take and adhere to the medication, with regards to safety and tolerability, we have to develop a platform that is safe and well tolerated.

We paid attention to reducing any opportunity for immune responses of the body to the medication, specifically to the mRNA, which is immunogenic. We modified it in a way to reduce that immune response of the body to the medication. With regards to efficacy, we have developed an LNP [lipid nanoparticle] platform that is characterized by a very high transfection efficiency and release of the mRNA into the cells for translation that is already effective at very low exposures. This is also an important point, which contributes indirectly to safety and tolerability, because we can work with pretty low doses of the drug product.

When it comes to convenience and compliance, we do need a drug product that is very easily habitable by patients, that is not overly complicated. For example, that does not require any frozen drug product and can be stored at room temperature. This is what we have achieved with the drug product formulation that we have available, either as a drug product suspension or in a lyophilized format.

Specifically, to ETH47, we have now developed an mRNA that encodes for a protein called interferon lambda, which is an important element of the innate immune system of our body, particularly in epithelial surfaces. The respiratory tract is one of those epithelial surfaces. Whenever our body is confronted with a virus infection, the interferon system interferes with virus replication. We now have a product at hand that could be developed to interfere with virus replications in diseases where that is relevant to patients.

Asthma is one of those diseases. We [in the healthcare field] have quite an armamentarium of medications for asthma in the clinic, including inhalers with corticosteroids, long-acting bronchodilators, and biologics for more severe diseases. However, what is common to all of these medications is that they do not prevent virus infection or virus-driven exacerbation of disease. This [inability] is what we can specifically address with ETH47.

One final line of conversation that I'd love to hear from both of you on, especially given the differences in the seats you sit in within Ethris: Carsten, you being the CEO, and Thomas, you being the chief medical officer. In terms of the company and the patient landscape, what are you looking forward to in terms of advancements in treatments, [in] the company, and in patient health?

Rudolph: For me, being the CEO, the question is always, where is the value that we can get for what we do? We are now at the stage where we have the first validation of our platform, and it's a big platform that we are developing in humans and in healthy volunteers. We tackled asthma as our first indication with the lead program, and we also have a program in the rare disease space where we are developing a drug candidate.

Thomas, from your perspective as a medical doctor, where do you see that we could still generate value for our patients with our platform that we have developed?

Langenickel: As I indicated earlier, the platform itself provides versatility in delivering targets. The good thing is that we now have clinical validation of the platform in an indication with high unmet medical need, asthma. But we know that a similar mechanism of action might be beneficial to other patient populations, as well, because there are other diseases where patients suffer from virus-driven, acute disease attacks. One of those diseases is COPD [chronic obstructive pulmonary disease], where you could also envision that ETH47 provides value to patients. In COPD, in contrast to asthma, the armamentarium we have available in the clinic is significantly smaller. The burden of disease is substantial, so patients could really benefit from a mechanism like this.

Beyond that, there are also diseases where absolutely no treatment is currently available, simply due to the fact that we previously did not have the technology at hand to tackle those targets. One of those examples is a rare disease called primary ciliary dyskinesia [PCD], where a protein, or a number of proteins, are missing that are essential to form the cilia in our respiratory tract and get rid of all the mucus and cell debris that we naturally have there. The phenotype of these patients, the disease burden, is not so dissimilar from cystic fibrosis, but based on its nature, we need to replace an intracellular protein. No attempts have been made so far to tackle that disease. I see huge potential to pursue diseases like PCD where this platform could really make a difference for patients.

Rudolph: We [humans] also have genetic diseases that are attractive for all platforms to move forward. We [in the healthcare field] have vaccines on the market which always need an injection. Given that, we [Ethris] have read fantastic data on delivering mRNA vaccines to the respiratory tract with a very easy-to-use nasal spray.

What are your thoughts on that, Thomas?

Langenickel: That's an excellent point. Now, knowing that nasal delivery actually works, that we have shown for the first time that we can express the target protein in the nasal cavity — [a protein] that is encoded by the mRNA: That could be an approach for mucosal vaccination, as well. Indeed, the need from a patient perspective is very high. We know that intramuscular-administered vaccines are efficacious in terms of protecting us from severe disease, hospitalization, and death. We also know that those vaccines are unable to inhibit transmission of viruses, which is still a big problem in the field [and one] that we could tackle with this kind of approach.

Rudolph: We are focusing on using mRNA as our drug substance, but there's a lot of fantastic work in the field of combining this with various genome-editing technologies.

How do you see our platforms exploring those areas?

Langenickel: That's a field that is evolving very rapidly. We know that, with the platform that we have at hand, we can deliver multiple cargo. That means we would be able to deliver the cargo that is required for gene editing. Plus, we have a platform where we can deliver specifically to the lungs without systemic bioavailability of the drug product, which is already a huge step in terms of tissue targeting. These are the hurdles that we have to jump over to utilize the platform for gene editing as well.

Rudolph: Might there be some way in the future to use mRNA that is delivered through inhalation to translate an antibody?

Langenickel: Yes. That could also be a potential application. We know in principle that it works. We can encode antibodies with mRNA, and preclinical data suggests that this works very successfully. If you are thinking about the antibodies that are currently being used to treat patients with asthma, they are all injectables. Having an inhaled drug product that is being self-administered could be a substantial gain in convenience for the patient.

Rudolph: From the various applications we looked at, we believe there is still much for us to explore in the future and develop new mRNA-based drug products to provide patients with better remedies.

That all sounds tremendous. I appreciate both of you sharing some of the inside views on what's promising, what you're targeting, and what you hope to achieve with all the work that's being done at Ethris. I want to thank you both for joining me on this episode of In Combination. See you next time.