Decreasing Nebulizer Size, Increasing Therapeutic Targets With Nebu-Flow's Andrea Cusack

In this episode of Sit and Deliver, host Tom von Gunden talks with Nebu-Flow CEO Andrea Cusack about advances in nebulization science and technology targeting respiratory conditions, as well as systemic conditions reached through the lungs. The discussion focuses on using conveniently sized nebulizers to deliver vaccines, nanomedicines, and other complex biologics that address unmet patient needs with increased bioavailability. 

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the episode.

Today, I have the pleasure of being joined by CEO Andrea Cusack from platform technology developer Nebu-Flow, which is working primarily in the areas of nebulization.

So, welcome.

Andrea Cusack, CEO, Nebu-Flow

Thank you very much, Tom. I'm delighted to be here.

Well, it's my pleasure to have you here. So, I like to start these conversations by looking out over the patient landscape and the therapeutic needs out there. So, we will get into the science and technology that you're working on there at Nebu-Flow. But before we do that, tell us about the space out there that you're focused on. I know you're working on respiratory targets and others, but can you tell us about the

the indications out there, the patient population out there, and historically or even currently, what has been available to those folks that has you thinking about advancements and innovations on the current state?

So, Nebu-Flow is primarily focused on respiratory diseases. That's the inhalation route, and we're looking at delivery to and through the lung. Our focus is primarily on tomorrow's pipelines. Most of our [the inhalation industry’s] devices were developed decades ago in the 1990s for small molecules.

But the pipeline and future of treatment of disease to fix and to cure, led by the biologic category — so that's nanomedicines, vaccines, particularly hard-to-deliver or fragile molecules. [We’re] aimed at doing just that, curing and fixing the underlying problems.

So, our focus is primarily on unmet needs, be that in cystic fibrosis, bronchiectasis, acute respiratory distress syndrome. And, of course, ultimately as we scale, we will want to access those patient populations who are currently using, perhaps, small molecules in COPD, chronic obstructive pulmonary disease, and asthma.

Gotcha. So, let's talk now about the science and technology and the approach that you're taking there. So, obviously, nebulizers, nebulization technology, has been an approach to respiratory conditions for, historically, quite a while, for obvious reasons.

Tell us about what has been available and what kinds of technologies have been out there — to what effect, with what limitations. And how that landscape of available technologies is prompting you to think about advances and what those advances look like in the area of nebulization.

Sure, if I take the broad overview of what's out there, it's generally inhalers, known as metered dose inhalers using propellants, dry powders, and lately some soft mist inhalers.

But again, all of these were developed for small molecules. They all have limitations for patients in terms of high coordination, particularly in and around the use of metered dose inhalers. Actually, also the inhalation technique for patients can often be quite difficult.

And that's really where nebulizers are traditionally used for patients who are struggling with coordination or needing more rescue therapy. And that's typically in the categories of young and old, so pediatric and adult populations.

And if I look at nebulizers and at the physics behind them, the jet nebulizer is based on the Venturi principle of the 1800s. Obviously, it has changed a little bit over time, but ultimately [a typical nebulizer[ is still about backpack size.

We then saw the advancements to ultrasonic in the 1950s, but they suffer from excessive heat. Neither of the two that I've named really are very efficient at delivering drug to the lungs.

[In the] 1990s, we saw the advent of the mesh nebulizers, a little bit more efficient. Up to 50% of the drug may make it to the lung. But these suffer from shear and agglomeration. When you're talking about higher viscosity ranges, they all have one thing in common: they struggle to deliver low surface tension drugs.

And I think we are now in an area, when we look at our biologic formulations, where the parameters have changed a little bit. Those drugs are usually formulated in the first instance for systemic delivery.

But not all drugs are absorbed brilliantly via that route, and often are associated with side effect profiles, toxicity from patients.

And for some of the areas they're treating, it may be better served by delivery to the lung and, if you like, by passing the liver metabolism and providing immediate relief and effect. So, drugs like that would be in the monoclonal antibodies, fragments, or nanobots, and clearly also in the new advancements in development. And we're seeing a surge there in RNA molecules.

Gotcha. So, thanks for the background and leading up to the perfect framing for my next question, which is [to] tell us more about the approach you're taking there. What's different about the science and technology? And how do you hope and anticipate that those differences might lead to differences in results in care —differences in the ability to deliver some of those advanced payloads that you've described?

 So, we were spun out of the University of Glasgow in 2019. And, thereafter, we conducted quite a lot of research into what patients were looking for from their future device, with a focus on tomorrow's pipelines, clearly. But what were the difficulties that patients had in their daily life that was disrupting their quality of life? So, working with Devices for Dignity and Cystic Fibrosis Trust.

We were better understanding the limitations of existing technology for a patient, which I think I can distill down to size of these devices, with one group actually referring to the aesthetics of the devices being difficult to and uncomfortable to be seen out in an open place, describing it simply as looking like a breast pump.

For others, it was a size issue, the noise issued from the devices. So, backpack, shoebox size [nebulizers] are not quite as portable as patients would like. And they were really looking for something that was more akin to their mobile phone in size, but also state-of-the-art delivery.

So, we set about really looking at some of the physics principles and being able to turn that on its head. So, surface acoustic wave technology — it has been used in the marketplace, in bioanalytics, radiomics. And we saw great utility of this platform to create the next generation, state-of-the-art device.

So, in terms of what we are doing different, we're not using reservoirs where we're recirculating liquid. You know, that is one of the aspects, from a physics perspective, that causes shear. We're not using compressor pumps and other pumps that also generate heat and noise issues. And we're not using, in terms of the characterization, similar of the aerosol.

We're looking to delivering that really there is no effort from the patient. They are able to push a button and get the drug dose volume that they require and in an efficient way and in a time that is more akin to their daily life and activities. Some of these patients are having to nebulize up to four times a day, 20 minutes a day.

And I think the corresponding aspect that's not perhaps spoken about as much is the cleaning regime that goes with that for patients. They view that as a really heavy burden.

So,  that has really driven the architecture of our device. So, it is like your mobile phone. It has a base charger. It has a handset. And it has more of a reusable, recyclable, click-and-go, so that the cartridge contains future biologics. We're not washing into the wastewater system, so thereby not impacting from an environmental perspective. And also preventing the rise in antimicrobial resistance.

So, a lot of thought has gone in, particularly around the ergonomics of the device, the human factors principle, and also what these have to be compatible with. So, we're really designing, not for the small molecule but for the large molecule, with this device.

Got it. So, as the work continues there, as those advancements that you're working on move forward, I'm interested in what is in front of you and the folks there in terms of any next steps in terms of challenges to be addressed or problems to be solved or questions to be answered. And I don't want to limit your answer to this, but I'm intrigued when I ask that, in particular, about your comment earlier when you [referred to] delivery to the lungs as well as through the lungs.

So, to get to all of those targets, I'm interested in those sorts of challenges. Any way you want to answer that, what are you focusing on next to move the dial?

We have a basis to tune droplet size. And so, the known range for respiratory is really 1 to 5 microns. And most of the devices — it doesn't matter whether it's a nebulizer, an MDI, or a DPI — are really delivering the larger end of that range.

And outside of that, at the larger end, we [are] focused, with respect to biologics, on wanting to be able to get high efficiency, in both upper and lower airways, and direct to the alveola, which, of course, from an RNA perspective, can aid efficiency in terms of delivery and transfection. Assuming — and I don't say this lightly — assuming you have the right drug delivery formulation, and you are able to pass by the mucosal layer.

So, those are the two drug delivery challenges. But actually, in terms of droplet and ability, we will have the first device, I believe, in the market that is tunable and can reach that lower end of the range and further increase efficiency. [It] may also mean that we can reduce the concentration to be delivered and also end up with better side effect profiles, ultimately. And that will be the goal for the patient, clearly.

Tremendous. Well, that all sounds very promising. So, I’m going to leverage that promise in the way I ask you this question, which is just a way I like to wrap up these sorts of conversations. And that is:

Looking out over the further horizon — however far out that is, near or far: Should these advances take hold in the market at some scale, how do you imagine that the lives and health of patients might look, should these innovations make their way to those patients, in terms of treatment and the regimen, the experience, and the results?

I think for the patient, they're going to possibly have extreme efficiency, but from a lower drug dose level, just simply because we're able to deposit a higher amount of drug, causing fewer side effects. And I think, in certain patient populations, that it's extremely beneficial.

In terms of what the device can do for them is really give them more freedom. That they can sit comfortably and nebulize with a device that is truly handheld, and sit, watch television, use the computer.

And that doesn't have the cleaning regimens that they've been used to or conditioned to. And hopefully not having those. Certainly, in terms of a click-and-go cartridge system, would enable them to perhaps have fewer episodes of antibiotics occurring from infection that comes alongside if you don't clean the device correctly.

So, the future is bright for patients, I believe. This will be something that I think will grow over time with momentum. Clearly, when you are scaling a startup company, you need to start small, and it's why we go for some of the very unmet needs, often drug space to begin with, where there is really very little, at the moment, to give patients relief.

Gotcha. Well, as I mentioned before, it all sounds very promising. I certainly personally appreciate the work and the thought that's being put into it there. Andrea, I want to thank you for joining me for this episode of Sit and Deliver to share your insights with our audience. And to that audience, thanks for joining, and we'll see you next time.