Episode 1: The Science of Solving for Hypoxia

Episode 1: The Science of Solving for Hypoxia

Episode 1: The Science of Solving for Hypoxia 150 150 Diffusion Pharmaceuticals Inc.

In this episode, Diffusion Pharmaceuticals CEO Robert Cobuzzi, Jr., PhD discusses cellular oxygen deficiency, a condition known as hypoxia, outlines the company’s development plan, and highlights potential future applications for a small molecule therapeutic with a novel mechanism-of-action that enhances oxygen diffusion.

TRANSCRIPT

Lauren Ashburn:
Welcome to fueling life. A podcast brought to you by and all about Diffusion Pharmaceuticals, an innovative biopharmaceutical company developing novel therapies that enhance the body’s ability to deliver oxygen where it is needed most.

I’m your host, Lauren Ashburn. Today we’re speaking with Bob Cobuzzi, CEO of Diffusion Pharmaceuticals. We will explore cellular oxygen deficiency, a condition known as hypoxia, which is a serious complication of many of medicine’s most intractable and difficult to treat conditions. We’ll also discuss trans sodium crocetinate, or TSC. The company’s lead product candidate being developed to enhance the diffusion of oxygen to body tissue with low oxygen levels. And we’ll highlight the development plan for TSC, including a brief overview of three short-term clinical trials that are designed to evaluate TSC’s effects in clinical models of oxygenation.

Hi Bob, it’s a pleasure to speak with you.

Bob Cobuzzi:
Morning Lauren, pleasure to speak with you as well. Thanks for your time today.

Lauren Ashburn:
Our listeners would love to know why you joined Diffusion.

Bob Cobuzzi:
For me, the excitement comes from good science, and it sounds cliche, but I really want to do things that do help people and oftentimes you don’t get an opportunity to work on something that’s really novel where there’s this so called unmet medical need. But I think with Diffusion there really is that opportunity — that we’re trying to make a difference in the lives of patients with the development of trans sodium crocetinate, or TSC. We’ve got a drug that can actually improve the availability of oxygen, and we’re obviously trying to conduct the studies to demonstrate that and support that statement. But, it’s such a need, it’s so pervasive across so many aspects of medicine that I think there’s a real opportunity to do good here and provide something of benefit. To me personally, that’s incredibly exciting and it’s rewarding to have that opportunity. So that’s what brought me to Diffusion.

Lauren Ashburn:
Let’s go back and talk about the history. How did Diffusion begin?

Bob Cobuzzi:
So, Diffusion started in 2001 and it was started based on the work of a professor, John Gaynor, at the University of Virginia. He was working to identify a treatment for a condition known as hemorrhagic shock, which occurs with hemorrhage — a large amount of blood loss, and shock — which is basically the body’s changes and inability to continue to function properly because of that blood loss. One of the biggest consequences of blood loss is that you — when there’s large blood loss in the case of hemorrhage — is that you have lower amounts of oxygen available. 

So, he set about looking for some kind of molecule, a pharmaceutical treatment if you will, that would be able to treat the lack of oxygen that comes from this hemorrhagic blood loss. Through the process, he identified a compound called crocetin, which exists naturally in the spice saffron. He isolated that and went about making some modifications to make a pharmaceutically acceptable version of this, and ended up with a molecule called trans sodium crocetinate or TSC for short. That’s what we’re working on now. That’s the basis of Diffusion. That’s what we’re trying to use to develop a treatment for hypoxia and conditions associated with hypoxia.

Lauren Ashburn:
How pervasive is hypoxia?

Bob Cobuzzi:
Hypoxia itself is very pervasive. It runs the gamut from being part of everyday normal life. If you do intense exercise and you find yourself breathing hard, that usually is an indicator that your body is trying to take in more oxygen to fuel those tissues that have used up the oxygen — that has created a hypoxic state. It also occurs very prevalently as a byproduct of various diseases. 

Right now through the media we hear all the time about COVID-19, and when the COVID pandemic first started, there was a lot of discussion about, what is it you have to do to treat these patients? There was a desperate need to have ventilators be available, so there were a lot of articles about ventilators in the media. And the ventilators intent is to really use positive pressure to drive oxygen through the lungs into the blood and make it available. 

But, there’s a key piece of the process that isn’t addressed by a ventilator, or just flow of oxygen into the body, which is it doesn’t actually help it get from the red blood cells through the blood, into those tissues which are hypoxic and needed. So there’s still a need. That’s the need that we’re trying to address with Diffusion.

Lauren Ashburn:
How are you doing that? Let’s talk about the development plan of TSC. Can you walk us through that?

Bob Cobuzzi:
The company started, as I said, in 2001. Over that period of time there’s been a tremendous amount of nonclinical data, laboratory data if you will, that’s been amassed that shows in various models where TSC can help improve hypoxia. Subsequent to that, there’s been a series of clinical studies, studies in humans that have been conducted. Looking at conditions like peripheral artery disease looking at glioblastoma multiforme, which is a particularly aggressive form of brain tumor. There was a stroke study that was started, and of course, I just talked about COVID-19 in a study that we recently completed in COVID-19 patients. So, we’re setting about now, conducting a series of three studies to address some of the gaps that myself and other members of the management team identified when we started with the company last September. We call these studies the oxygenation trials. The purpose of these trials is to go about looking to see if we can identify an appropriate dose that correlates well with an objective response or a measure of oxygenation in the body. So, there’s a series of three studies that we’ve done to help us collect those data.

Lauren Ashburn:
Tell us more about those studies.

Bob Cobuzzi:
So, the three studies, again what we call the oxygenation trials, are intended to establish, as I said, objective dose response relationship between administering TSC and the availability of oxygen. The first of the three studies we call the TCOM study. TCOM itself stands for transcutaneous oxygen measurement or oxygen monitoring, and that study finished up this summer. What it did was it looked to see if we administered TSC to normal healthy volunteers, could we actually see an improvement in the availability of oxygen in the periphery. These TCOM sensors, these oxygen monitoring sensors go on the lower part of the leg, we did the study in normal, healthy volunteers, and we looked to see if we can improve oxygen as it percolates through the skin. These sensors warm the tissue and allow oxygen to move through the skin, and there’s an electrode in the sensor that measures the concentration of oxygen coming through. What we saw from this was a positive effect, but it was a very small trial. We didn’t reach statistical significance, but we had no way of powering the study to reach statistical significance, so it was more of an exploratory study from the outset anyway, but we were happy that we saw a positive effect. 

The second study — unlike the first, which was normal, healthy volunteers lying sedentary, no reason to believe there’d be hypoxia and the tissues — the second study actually is to create a hypoxic state. We call this the altitude study. And the intent in the altitude study is to put people in a hyperbaric chamber, reduce the pressure, reduce the amount of oxygen, create a situation that’s like being at 15,000 feet where your blood oxygen level would decrease from the normal 99/98% down into the 80 mid 80s, we’ll call it, percent. As a consequence, that’s going to reduce the amount of oxygen available in the blood to support whatever activities go on. The activity component of this is people are going to ride on a bicycle, they’re going to perform exercise. The intent is not to be somehow malicious, these people would be very well monitored from a medical standpoint, but to create an artificial hypoxic state and CFTSC can be used to increase the amount of oxygen available in the blood and actually help with the level of performance that these volunteers are able to do under these conditions. 

The third study looks at yet another aspect of oxygenation. In that study, the DLCO study as we call it, which stands for diffusion through the lungs of carbon monoxide. The intent is to look and see if carbon monoxide — which is preferentially bound to hemoglobin, the carrier in the blood in the red blood cells specifically, for oxygen — if we can see an improvement in carbon monoxide uptake as a surrogate for measuring oxygen availability through the lungs. A study unlike the first two, which were conducted in normal volunteers, this study is going to be conducted in subjects or patients who have a condition known as interstitial lung disease or ILD, which is a condition that results in fibrosing or clogging in a sense of the alveolae, the air sacs in the lungs, where the air goes in and exchanges with the blood and allows the oxygen to travel through the body. 

So, we think that with that study will learn about the ability of oxygen being taken up, the altitude study, we can look to see if TSC actually improves the availability of oxygen to hypoxic tissue. The first study told us that there is some benefit, although importantly not hyperoxia or too much oxygen getting into those tissues of normal healthy volunteers. So, all the way around this will tell us a lot about the dose, we are getting objective information, and will help us design the trials that go forward from there in future.

Lauren Ashburn:
How would you describe the potential for TSC?

Bob Cobuzzi:
I think it’s quite broad. You know, people are always going to tell you there’s always a commercial reason to say that you’ve got this massive opportunity, but genuinely, I think there’s a big opportunity for this drug. The constraints really come in the form of, what’s the route of administration or other physical limitations that might be available. Currently it’s an intravenous administration form that we have. But I do think that we have opportunity to treat some of the really incredibly difficult to treat conditions like solid tumors, like possibly strokes and heart attacks. Many of these things result in hypoxia, it’s one of the debilitating side effects or end results if you will, of the condition. And I think we have a real opportunity with TSC to make a difference.

Lauren Ashburn:
It seems that Diffusion could make a difference, not just specifically with hypoxia, but in the field of medicine at large.

Bob Cobuzzi:
I think so. I mean I don’t want to get too hyperbolic and extrapolating and say we’ve got the cure for everything, but oxygen is important, oxygen is that fuel for life, oxygen is what allows us to have energy made by the little things called mitochondria that are in our cells — the battery, if you will, of the cell. If you don’t have oxygen, you’re not alive. And I think anything we can do. 

TSC is a, we believe, a step forward in helping, as we said, to make sure that we get oxygen from the blood, or into the blood, into the tissues, into those places where it’s needed. So, if we can do that, we think it will help get better outcomes. Certainly, take an instance like COVID-19, we’re not getting rid of the SARS-COV2 infection, but we are helping, we believe — or would help if we were able to develop the drug in that case — to be able to allow oxygen more readily to get into the tissues that are being starved for oxygen by the lungs being clogged in these situations. Or in those situations where patients have clots, much like you would see in a heart attack or a stroke. So, that’s the intent. That’s where we believe there’s some broad use. It’s not the end all to itself, but we do believe the availability of oxygen is again, the fuel for life, and it’s incredibly important.

Lauren Ashburn:
Thank you so much Bob.

Lauren Ashburn:
It’s been a pleasure and I look forward to our next chat on a future episode.

Bob Cobuzzi:
Thank you, Lauren. I really appreciate your time today as well.

Lauren Ashburn:
Thanks for listening. Fueling life is a podcast from Diffusion Pharmaceuticals. Stay tuned for our next episodes and follow us on Spotify or wherever you get your podcasts.

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