Treating Cardiopulmonary Disease with Inhaled Targeted Therapies

Pulmonary arterial hypertension is a rare and progressive condition characterized by high blood pressure in the arteries of the lungs due to their narrowing or a blockage. This causes the heart to work harder to pump blood and leads to heart failure, the need for lung transplantation, and death. Aerami is developing an inhaled form of the targeted cancer therapy imatinib as a treatment for PAH. We spoke to Josh Ziel, chief operating officer and interim CEO of Aerami, about pulmonary arterial hypertension, the company’s experimental therapy to treat the condition, and its efforts to build a pipeline of therapies that make use of its proprietary inhalation technology.

Daniel Levine: Josh, thanks for joining us.

Josh Ziel: Thank you so much, Danny. I really appreciate you having us on today and looking forward to the discussion.

Daniel Levine: We’re going to talk about pulmonary hypertension, Aerami, and its experimental inhaled therapy to treat two serious rare forms of the condition. Aerami’s lead experimental candidate is an inhaled therapy for the rare and progressive condition pulmonary arterial hypertension. For listeners not familiar with the condition, what is it?

Josh Ziel: Yeah, I think the easiest way to understand pulmonary hypertension is to think of it as high blood pressure, but specifically in the blood vessels within the lung. So, essentially you can get pulmonary hypertension for many different reasons. There’s actually five different types. We call them clinical classifications, but fundamentally they manifest themselves in similar ways, insofar as when you perform a test called a right heart catheterization, you see elevated pressures within the pulmonary vasculature, and so that really defines pulmonary hypertension. Now, I think you also brought up how Aerami is focused on this, and we’re looking, right out of the gate with our lead program AER-901, at two different forms of pulmonary hypertension. Going back to those five different types that I mentioned up front, the first and I’d say this is probably a place where we’re putting a lot of focus, is a kind called pulmonary hypertension associated with interstitial lung disease, and this happens after someone develops a serious type of lung condition called interstitial lung disease that causes fibrosis and scarring of the lung. The other type that we look at is pulmonary arterial hypertension, and this is something that can develop in people because they have a genetic mutation or because they’ve been exposed to different types of substances in the past or in some cases without any real known cause. So, one thing that’s really important, regardless of the type of pulmonary hypertension, to know is that these can be very serious conditions, oftentimes, unfortunately, leading with disease progression to right heart failure and the need potentially for a heart or heart/lung transplant, or in some cases, it can be fatal.

Daniel Levine: Separate from clinical measure, from a patient’s point of view, how does the condition affect them and how does it progress?

Josh Ziel: Yeah, I think that’s a great question. It’s actually one of the real challenges in this area. So unfortunately, many of the common symptoms of pulmonary hypertension in general—so not talking about any one of the individual types—they’re pretty non-specific. They might be, you know, initially fatigue, a shortness of breath, things that could be caused by any number of conditions. And I think one of the challenges in this space is that patients can go for a long period of time before actually getting an accurate diagnosis, and what that means is that by the time they see a specialist that can treat their pulmonary hypertension or at least manage it in some cases, there really are no great treatments today. They might be pretty far along in the course of their disease and it becomes really critical to get them on effective therapy as soon as possible.

Daniel Levine: How is the condition generally treated today and what’s the prognosis for someone who has the condition?

Josh Ziel: Well, it really depends, and I’m going to go back to what we talked about right in the beginning. You mentioned, and I sort of discussed, the two types of pulmonary hypertension that Aerami is really focused on today. So, first I’m going to talk about PH-ILD or pulmonary hypertension associated with interstitial lung disease. In this case, there really are very few treatments for patients. There’s one drug that was approved in just the past few years, but unfortunately it’s only available in the United States. And the way that it works is to cause the blood vessels within the heart and the lungs to relax. That helps with some of the problem, but unfortunately, in pulmonary hypertension, the root cause is actually an overgrowth of the cells that line the blood vessel that actually causes the narrowing of the blood vessels within the lung. And so even when you cause that vessel to relax, the blood still has a hard time flowing through. And so, this drug is a really important advance for those people, but it’s not going to do the whole job. And there’s really, other than managing the underlying lung disease for patients with PH-ILD, not much else that can be done for their condition. And that’s why I think we’re really motivated and excited to look at AER-901, our lead asset, within this area as a potential therapy for these patients. The other type of pulmonary hypertension that we talked about, pulmonary arterial hypertension, in this case actually the details of what’s happening inside of the lung, very similar to what’s happening in PH-ILD. We know that same sort of overgrowth of the cells within the blood vessels is occurring, but we still don’t have any treatments in PAH that are really directed at that process. Just like in PH-ILD, there are therapies available. In this case, there are more. I think there’s about 15 drugs that are currently approved for pulmonary arterial hypertension at least in the U.S., but what they do is, again, cause those blood vessels to relax rather than necessarily f repairing or reversing the underlying problem. Does that make sense?

Daniel Levine: Yes. Aerami has platform technology for delivery of inhaled therapies to the lung. What’s the case for delivering medicine through the lungs?

Josh Ziel: Yeah, well, I think one of the earliest concepts that got people excited about inhalation, and it’s been around as a drug delivery route for a long time, is the idea that if you have a pulmonary condition, when you inhale medicine, maybe you’re getting it right to the site of the disease, right to the site of damage. And that’s actually exactly what we think is happening when you inhale therapy for pulmonary hypertension. Fundamentally, what I’ve said is that we think the problem is happening within the vessels of the lung. And when you inhale the medication that could potentially treat that you’re getting it basically right into the tissue where it can take an effect. The other real reason to look at inhaled delivery is to reduce systemic exposures and potentially side effects. And that’s really kind of the hypothesis that underlies our lead program. We are taking a drug, it actually has been tested in pulmonary hypertension in the past, and we know that it can work. In a phase 3e trial, it had actually pretty substantial efficacy of the kind we really haven’t seen before, but it just had a lot of tolerability and safety issues. And so, by targeting the lung, what we think we can do is reduce the dose and achieve similar efficacy, but with a greatly improved side effect profile. And that’s really, I think, part of the promise of the platform potential that we’re bringing with AER901 for pulmonary hypertension, today certainly for PH-ILD and PAH, but we hope in the future to be able to look at other types of pulmonary hypertension as well.

Daniel Levine: Your therapy is delivered through what’s known as a smart nebulizer. What is this an how does Aerami’s work?

Josh Ziel: Yeah, it’s actually pretty cool. So, what we have is a handheld device. It’s really important that as you’re developing a drug, it’d be something that patients can use effectively, but also, in a condition like pulmonary hypertension where you’re talking about chronic treatment are going to be able to use it for the long term. So, the fact that this is more mobile, portable, easy to clean that’s really important from our perspective, but the device really does go beyond that. So, one of the really important things with inhalation is making sure that the medication gets to the right spot, right? When you inhale a drug, I think you can imagine, with many types of inhaled delivery, you can either breathe too fast or too slow. and what happens is the medication either ends up in your mouth or ends up in the back of your throat and you just swallow it. And so, if we’re talking about these lower doses, what happens is you end up with a sub-therapeutic oral dose. What our device does is it actually tells a patient while they’re inhaling if they’re breathing at the right rate for that drug to go deep into the lung. Essentially it glows green if you’re doing it right, and if you’re breathing too fast or too slow, it actually turns red and it cuts off the flow. And that’s really important because with other types of inhaled delivery, what we know often happens is either there’s a learning curve or just over time using things like a dry powder inhaler requires a fair amount of coordination and consistency in how you breathe. And so over time, oftentimes patients, unfortunately, have errors in dosing and might not always get the full dose. And we can be relatively confident when we go into our phase 2 study and then in the future, hopefully in use as an approved therapy, that patients are actually getting the dose that we intend.

Daniel Levine: Beyond that, does the device collect any data and can a patient use that in any way?

Josh Ziel: You know, I’m so glad you asked that question. Right now, it doesn’t, but the really great thing about these smart nebulizers is they’re pretty cool high tech devices. They certainly have the capability to interact with mobile devices via Bluetooth. That’s not something we’ve turned on today, but I think that could be a really nice value add for patients taking a therapy. If you think about connecting it with some of the other apps that you might use on a day-to-day basis or things that help you keep track of treatment, we’re not doing that yet, but it’s certainly something that’s on our radar, and I think for many companies working in this space.

Daniel Levine: Aerami’s lead experimental therapy, which you had mentioned is an inhaled form of imatinib, a drug that’s approved to treat cancer. What’s the case for using this as a treatment for PAH?

Josh Ziel: Yeah, well, I mentioned upfront that actually the fundamental problem in PH, certainly the manifestation is high blood pressure in the vessels of the lungs, but it’s that proliferative overgrowth of the cells inside of the blood vessels that is causing that problem. And it’s maybe a simple way of thinking about things, but in a way part of that could be related to similar mechanisms that cause the overgrowth of cancer cells and in fact the pathway or one of the several pathways that imatinib targets. We think that it hits certain receptors. One of them is called platelet derived growth factor receptor and when it inhibits that receptor, it actually tamps down some of that proliferative overgrowth. And actually, what’s really exciting in animal models, preclinical models of pulmonary hypertension, it doesn’t just slow the growth, it actually can reverse the damage. And so, it was initially tested in its oral form, and I think I mentioned this earlier, it actually showed on top of two or three background standard of care therapies, vasodilators drugs that cause relaxation of the pulmonary vasculature. On top of those drugs, it actually showed clinically meaningful and statistically significant improvements in blood pressure in the lungs, or something we call pulmonary vascular resistance. But it also helped patients be more active. It improved a measure called six minute walk distance, which is essentially a measure of exercisability. And so, those types of effects were things that really hadn’t been seen before. You know, the oral form of the drug was tested, certainly not on top of two or three background therapies. So, it’s really got a potent effect from an efficacy perspective, and that really leads us to believe that the inhaled form, if we target the drug to the lungs, get it right where it can make a difference, we can lower the dose and hopefully achieve that same efficacy, but with fewer side effects, because that’s really why the oral program didn’t proceed.

Daniel Levine: What is the development path forward?

Josh Ziel: Yeah, so we’re really excited, we’re gearing up for phase 2, but as I mentioned upfront, we’re approaching this a little bit differently than other companies have done typically in pulmonary hypertension. And the way that we’re looking at it is how can we really advance drug development more quickly, just in light of the tremendous unmet need. And so, we’re looking at two types of pulmonary hypertension in the same trial. So, I always like to think of it as almost a two for one phase 2 study. We’re going to have one cohort that enrolls people with pulmonary hypertension associated with interstitial lung disease, and we’re going to have another cohort that enrolls patients with pulmonary arterial hypertension. And one of the really great things is that—and this is all planned at the moment, we haven’t actually started the trial—within about 18 months, we think we can get an answer that will help us determine the path forward into phase 3.

Daniel Levine: The company is not only looking at pulmonary hypertension, but among the other products in development as an inhaled insulin. There was a lot of big pharma excitement around the possibility of inhaled insulin, but the products fizzled once they reached the market. Physicians and patients didn’t embrace these products as expected. Why pursue this?

Josh Ziel: Yeah, it’s a really great question and I’m glad you asked it. So, our company was actually founded a number of years ago by a gentleman who really is, I think, one of the founding fathers of modern inhaled therapies. And I think the vision at the time was to bring forward inhaled insulin in part because there’s a tremendous unmet need for patients with type 1 and type 2 diabetes that really in many cases can’t, or won’t, accept daily frequent injections. Now, I think you pointed out some of the challenges that those drugs have had coming to market. We still think that there’s a path forward for inhaled insulin, but today, Aerami is very much focused on our cardiopulmonary disease programs and the high unmet need in those rare diseases. So, we do think there could be a path forward for inhaled insulin. It probably will be outside of Aerami.

Daniel Levine: Aerami had been readying to merge with a SPAC in 2022. The deal was mutually ended. The company did raise about $22 million toward the end of 2021. But how far will existing cash take you and what’s the plan for raising additional capital?

Josh Ziel: Yeah, it’s a great question. So, just to unpack a few things there. You called out the SPAC deal, and I think the number one thing for any biotechnology company like us that’s really looking to push the envelope and bring important therapies potentially to patients is securing the funds to do that. And historically, the company has explored a number of avenues. Right now, we have the cash that we need to basically complete all of the steps to get ready for phase 2 and we’re currently looking and working to raise the cash to initiate and complete that study. So, really our path forward at this point is to find the right partners who see the potential in AER-901 that our investigators, our team, and I think really an outstanding network of advisors who’ve helped us build the program in AER-901 to really help us take that program forward.

Daniel Levine: When we initially scheduled this interview it was with Lisa Yanez, who was CEO of Aerami. Lisa died suddenly in May as a result of a car accident. This was stunning news. She had been CEO since the end of 2022. What’s been the impact of her death on the company?

Josh Ziel: Yeah. I’d just like to start by saying a few words about Lisa if you don’t mind. I think Lisa’s passing was a tragedy for her family. I think it deeply affected everyone on our team. Lisa was a dear friend of mine as well as a mentor and our CEO, and I know she was very close with a number of patients and physicians really known throughout the pulmonary hypertension community as a force for good and for patients. And I think everyone is working through the news of her passing. For the team, I think what it has really done is refocused us on the vision that she had for Aerami and for patients. She saw the potential in this therapy and worked every day to advance the clinical program and the resources needed to take the program forward. And I think it’s really renewed our commitment as a team at Aerami to work with the experts in the field, with the patients who we hope will participate in our trials, and the entire network in pulmonary hypertension, to advance that vision and hopefully deliver life-changing therapy for patients. That’s really the bottom line goal that Lisa was focused on, and what I’m really focused on.

Daniel Levine: You’ve stepped in as COO and interim CEO. Is the long term plan for you to remain in that position, or is the company conducting a search for a new CEO?

Josh Ziel: Yeah, I think right now the company is focused on advancing the program, getting into phase 2 and really moving the ball forward with AER901. The unmet need is very high and the opportunity to close that gap with this, this product is quite real in terms of future management changes. Right now, there’s no current search ongoing. This team that I worked closely with Lisa to assemble, I think you may have noticed, we also recently brought on Dr. Gary Burgess as our chief medical officer, as well as Sarah Fritchley, who’s our SVP of Clinical Development and Operations. We really have the right folks to drive this program forward into phase 2 and you’re looking at the folks who are going to do it. For my own part, I’ve been working closely with Lisa for the past five years. I’ve learned from her, and I’m really excited to partner with both Sarah, Lisa, the rest of our team and the entire network of KOLs, experts, investigators that have gotten excited about AER-901 and see this program through.

Daniel Levine: Josh Thiel, COO and interim CEO of Aerami. Josh, thanks so much for your time today.

Josh Ziel: Thank you.

This transcript has been edited for clarity and readability.