Martin Grasse, Gradient Denervation Technologies - Pulmonary Hypertension Treatment | LSI Europe '22

Transcription

Martin Grasse  0:08  

My name is Martin Grasse. I'm CEO of Gradient Denervation Technologies gradient is a Paris based medical device company operating within the Sofinnova MD start incubator for medical device innovation. Gradient is developing a catheter based solution for pulmonary artery denervation. This is a therapy that's emerged over the past few years to treat patients with heart failure and elevated pulmonary vascular resistance or pulmonary hypertension. This is a large unmet need with very high mortality morbidity in patients who are symptomatic and patients are in and out of the hospital very frequently. Creatine is a device that is designed specifically for the pulmonary artery anatomy, which comes with with its own engineering challenges. We are building on early feasibility data from other devices that have been repurposed from other indications and shown a signal of efficacy. And now we've built a device that is built for this anatomy. Specifically, we have licensed foundational IP from Stanford University with granted method claims that give us a very nice platform upon which to operate and build. The company was founded within Stanford Biodesign and came to MIT start in 2020, has been incubated since then, with funding to prepare for our first in human studies. We're raising a series A financing now, this will fund our European first inhuman and early feasibility studies in the United States. At a very high level, the pulmonary vascular resistance within heart failure is caused and maintained by a link between two parts of the anatomy and physiology. On the one hand, the sympathetic nervous system drives over activity within the within the distal pulmonary vasculature. On the other hand, this causes vasoconstriction, which then pushes blood back to the right ventricle making the heart work harder, leading to the progression of left heart failure into right heart failure with significantly worse outcomes for patients. The data you see on the right hand side of the slide is an example of this. This is showing patients with heart failure and preserved ejection fraction, stratified based upon pulmonary vascular resistance. Those are the top line in both graphs is that those patients with heart failure and preserved ejection fraction alone. The bottom line is those patients with heart failure preserved ejection fraction plus elevated PVR. And you can see a significantly worse mortality and hospitalization to call out one data point on slide. There's approximately a 50% mortality rate in these patients at about four years after diagnosis. So an incredibly serious disease. We are focused initially on heart failure with preserved ejection fraction, we believe based on early data that this would also work in heart failure with reduced ejection fraction. However, there are drugs and devices that work in those patients. In contrast to heart failure with preserved ejection fraction. Therefore, we're focused on F ped first, that represents about 50% of heart failure patients. And then from there somewhere between 30% and 50% of those patients have elevated PVR. There are no approved treatment therapy treatment options. In fact, the drugs that are approved and so called group one pulmonary hypertension without heart failure, are contraindicated in this patient group that were heart failure is present. And finally, this represents a huge economic cost for the systems. To put some numbers to this, when we start with heart failure and then progressed down to those patients with half path plus elevated PVR. We're talking to about two and a half million patients between the US and Europe. This will double approximately when we include back in those patients with reduced ejection fraction. At a basic physiology level, what I'm showing here is some work that was done in 1980, with a large animal model for pulmonary hypertension. And what you can see is the researcher was able to create this model and then induce pulmonary hypertension in these animals, and then through both chemical and then surgical denervation show that that he could turn this off, proving the link between the sympathetic nervous system and the pulmonary vasculature. Since then, there's been a significant amount of work in the space and both human and animal trials, again proving that that this pathophysiology is able to be affected by a denervation procedure to trials that I'll talk specifically about one is the PA dn five study. This is done by a company in China called PL novo. Pl Novo has a radiofrequency device with electrodes around the circle around a loop type of a catheter. They enrolled 98 patients in group to pulmonary hypertension or those with heart failure. They randomized one to one against a sham procedure plus a visa dilator called sildenafil. And they showed a significant improvement in both six minute walk testing and a separation and the risk factors that these patients have met within the heart failure groups. The other study is trophy one trophy one is done by an Israeli company called Sanofi. Sanofi uses a catheter that's been repurposed from a renal denervation indication, they enrolled 23 patients with group one pulmonary hypertension at centers in Europe and Israel and showed improvements in both hemodynamics six minute walk and the number of risk factors that these patients have met. So it's based on this preliminary work that we are now moving forward with our purpose built device to perform pulmonary artery denervation. The design inputs for this purpose built device are several and as I mentioned before, there are some unique challenges from an engineering perspective to build the device for this anatomy. Number one is understanding where the nerves lie. We know that from published literature that the nerves lie around the pulmonary arteries in the main, the left and the right. These Bullseye graphs illustrate the the nerves from cadavers, studies in patients with pulmonary hypertension, we know that more than half of the nerves are within within about five millimeters of the vessel wall. And the average depth is about two millimeters. From an engineering perspective, there are three main indications or three main drivers design inputs for for designing our device. Number one, the vessel wall is very thin, it's down to about a half millimeter thick in many places, kind of a papery thin type structure. This has implications for the energy source that we choose, leading us away from sources that are require intimate contact with the vessel wall to transfer heat. Number two is the large diameter range, we know the range in the anatomy that we care about is between one and a half and three and a half centimeters. So these are big, big vessels. And number three is their significant motion. And these vessels were right next to the right ventricle. So there's significant cardiac and pulmonary motion, requiring stabilization in order to get a consistent thermal dose deposited into the adventitia and connective tissue around the vessel. So we think we've solved these problems, we've frozen the design of our device, we have a size adaptable device that fits this entire range of diameters, we're using an energy modality that preserves the intima and does not damage it. We're doing our preclinical safety studies and we're on track for a first inhuman in the beginning of next year. We have a team that has extensive experience developing interventional cardiology and electrophysiology devices. And we we have the expertise internal to the company to allow us to move forward into our first inhuman, we anticipate growing the team in the new year. From an IP perspective, I've mentioned before we've licensed IP from Stanford University, we have very broad granted method claims on pulmonary artery denervation, and feel confident in our ability to move forward. And we're now developing our own company owned IP to cover our specific device embodiment. clinical perspective, I mentioned we're pursuing a first inhuman in the Republic of Georgia and the beginning of next year, this will be 10 to 20 Subjects with have PEF plus elevated pulmonary vascular resistance. We're utilizing our physician consultants to help us both with screening and execution of these procedures. And we're working with a CRO in country who has extensive experience helping companies operate there. We're also going to be submitting the same data package to the United States for an early feasibility study. This will be two to three subjects in the US, we've engaged with the FDA several times on mapping out what this looks like as well as the data that's going to be required to support the submission. We're targeting 10 patients with heart failure with preserved ejection fraction plus PVR, very similar inclusion exclusion to the first inhuman, and we anticipate submitting the same data package in both places. From a value creation timeline perspective, this slide shows kind of where we've come from what we're doing now and where we're going. The company came to me started in 2020, seed funding was invested and with that the company moved through all of the early stage work that we needed to do in terms of IP generation, assembling a team, building our plan for our clinical studies and our target patient population, developing the catheter and freezing the design, we have yet to execute or rather we're midstream, executing our preclinical safety study and are working on our design verification testing. We anticipate wrapping these up by the end of the year, we are raising a series A financing. This will support our clinical program for some human study and early feasibility study, as well as any device iterations that are required following that clinical work. And from there, we would move forward into randomized controlled trials to to prove the efficacy of the device. To wrap up, elevated pulmonary vascular resistance brings significant additional mortality and hospitalization risk in those patients with heart failure. There are no approved treatment options in this patient group. Early data from other devices repurposed from other indications indicate that this is a pathophysiology that can be affected by a procedure. We have foundational IP which enables development of a built for purpose device, we frozen the divine design of our catheter and we're doing our preclinical safety studies. We're developing within MD start the premier European med tech accelerator. We have an experienced team in place and we're raising A new financing to support our clinical program. Thank you for your time and attention.