Gerard J. Criner, MD, FACP, FACCP, discusses the AIRFLOW-3 study which evaluates the efficacy of targeted lung denervation for patients with COPD.
Oh hello I'd like to speak to you about targeted London innovation. My name is Gerard Criner and professor and chair of the department of thoracic surgery medicine at Lewis Katz School of Medicine at Temple University in philadelphia. These are my disclosures for the study of received research funds. In regards to the therapy. I'm going to discuss with you. So this is what targeted along the innovation is about targeted lung. The innovation or T. L. D. Is a novel bronchus coptic therapy that disrupts the parent sympathetic nerves input to the lung to reduce the consequences of neural hyper activity that can contribute to air flow obstruction, increased mucus hyper secretion and contribute to the development of frequent or severe exacerbations. This is what the concept is based on. These are some studies that were conducted in cheap by marty mais and colleagues. And as you can see by this cross section this is where the bronchial nerves reside well below the bronchial epithelial, the sub epithelial layer, the bronco cartilage. And this is where the bronchial nerves are nested at the right and left. Main stem bronchus and in the more distal airways. Also this is looking at a cross section of a sheep about 303 or 30 days post T. L. D. And then 640 days post T. L. D. Would blow up, shown down here and as one can see before and then after target along the innovation. The nerve bundle is reduced in size and over a period of time is replaced by fibrosis with preservation of the cartilage and the bronchial epithelium, this is demonstration of the decrease in nervous input and preservation of the bronco and perry bronchial structures. With use of different staining for the neural bundles. You can see a marked decrease in numbers of the neural bundles as one goes out to 3300 and 65 640 days, both in a proximal and the distal portions of the airway that was looked at. And there was some control animals that showed no change overall. So this seemed to be promising from an in vivo standpoint and he also balance it against the side effects to the airway wall as well as to the lung prank mama. There was no impact on the lung prank mama And in the bronchial wall there was a decrease in acute and chronic inflammation. Following the procedure at 30 days and then at 365 and 640 days. All that was durable was the fibrosis that was seen in this peri neural area. So important benefit of decreasing neural impulse, balanced against no evidence of structural abnormality to the airway wall or lung prank Emma. Over time this is how the procedure works, targeted lung de innovation or T. LD is a non surgical procedure that interrupts nerve signals and may reduce COPD symptoms, helping you to breathe easier. A standard bronchoscopes has passed through the patient's mouth and into the lungs and a special catheter is passed through the bronchoscopes to provide the treatment. Once the catheter is in place, the balloon is inflated. Notice the silver electrode on the inflated balloon. When activated, the electrode delivers a type of electrical energy called radio frequency energy, which penetrates to interrupt the nerves located just outside of the airways. After the energy has been delivered in one position, the balloon is deflated and rotated to the next position. This is continued for four total treatment positions upon completion the catheter is removed and the animation shows that the nerves distal to the treatment site have been interrupted, decreasing nerve signals throughout the lung on that side, the catheter is then placed in the lung on the opposite side and the treatment is continued in four positions. The entire treatment is now complete and the catheter and bronchoscopes are removed. Notice how the nerves from the treatment site and below have been interrupted. As shown by the color change from yellow to dark green. The magnification demonstrates how the treatment effect extends all the way from the actual tree treatment site out to the smallest airwaves. Following T. L. D. We expect to see a relaxation of the airway, a decrease in mucus production and a decrease in airway wall inflammation. With these improvements, the air can now more readily pass into and out of the lungs, breathing becomes much less labored and lung function may improve. So that's in concept how it works. Let's talk a little bit more in detail about the catheter and why it does work. How can you do renovate the lungs deeper from the airway wall and not affect the airway wall or its sub mucosal structures all the way this is made is this is a balloon is inflated to adhere the electrode, which is seen here in the blue against the airway wall and keep it in position as you visually look through the scope and I'll show you an example of that to make sure you're in a proper location. So this ends up providing constant contact of the electrode in a stable way with the airway wall, but it's also provided with this generator and fluid pump with cooled D5W that protects the inner surface of the airway, focused while focusing the heating effect and tight trading it to the depth of the nerves. So you're cooling the adjacent airway and you're providing the energy deeper from the airway wall to the nervous bundle. So this is the first study that was done was a pilot study for moderate to severe COPD this done by sleep boss and colleagues in the Netherlands. This is visually what was seen. You can see endoscopic lee that you have coupled the approximate portion of balloon to the end of the broncos scope. So you can see through the balloon, you can see the electrode against the airway wall. You can see two visible airways, the upper lobe and lower lobe distal to you and you can see the good contact that the R. F. A. Electrode has with the airway wall. This is one of the earlier does titrate. Asian studies comparing 15-20 watts on changin spectrometry. And uh you can see that the higher wattage here, 20 watts improved F. E. V. One and improved FCC. And also those who were treated a higher energy could do a lower extremity cycle or geometry longer and had a reduction in SGR que a reduction in str. Q. Is a beneficial change that was more pronounced at the higher wattage than patients at the lower wattage. Subsequent studies went up to 30 watts and looked at patients over time and found even more pronounced change. So this is a subsequent study. This is called air flow to this is a double blind randomized sham controlled trial in a larger number of patients. Um there was 82 patients in the study overall not so much change in S. E. R. Q. Or pulmonary function sham controlled study compared to the unlined and study that I just showed you the first demand pilot Bisley bows, but what was seen was a profound decrease in total And more profound in severe exacerbations in a contact of the study and patients that were followed over 700 days in the trial. So this was an important signal that exacerbation reduction. Maybe the prime benefit of targeted along the innovation. How's the safety? Well this again is the airflow to safety data. And what they found was uh some patients had problems with Um Dysplasia. 13 patients within the 1st 30 days after the procedure than the rest of the complications are the usual complications with COPD exacerbation that's seen in this patient group. Um there wasn't any other significant problems with airway wall or other changes over time Again in that first in human, there's also a slight signal of gastro priestess that was seen in one out of the 12 individuals. So what was done after airflow too is to refine the study by using a contrast field esophageal balloon where you look at the electrode flores, ka pik lee and measure the distance from the lateral border of the nearest wall of the esophagus to the nearest portion of the electrode. And use this to titrate the energy to decide if the patient would not be treated or treated with low power or treated with high power relative to the distance of the electrode from the from the esophagus. This has substantially decreased any issues regarding with gastro priests or dysplasia. So this is the targeted lung de innovation Clinical program development kind of like uh scheme over time. The phase one. A feasibility study proof of concept. Multi center trial was done in europe. The phase two optimization of dose ranging of the wattage for the power of the R. F. A. To deliver narrow ablation in the phase two study. and then phase two B. Was the same thing. 121 randomized sham controlled double blind study to reaffirm the power wattage and to really optimize the power selection based on distance from the soft joe balloon. And now we're airflow three which is the pivotal study. Uh that's looking at the safety and effectiveness in a multi center trial in the US and europe. And 1 to 1 randomized sham controlled double blind fashion. To look at the effect of targeted lung de innovation versus control therapy. Optimized medical therapy to decrease moderate or severe exacerbations in patients with COPD. And a secondary objective here is that compared to long term safety and other efficacy assessments such as changing cats. Change in S three RQ between the targeted lung de innovation and the champ procedure. Again, these are the numbers of patients that will be enrolled into the study. So if you have any further questions about this study or have patients that you think might be potential candidates, please email us or call us at the information provided below. Thank you very much for your attention