FrostBite-DMR - A new Drug-Free Approach for Treating Type 2 Diabetes Supplemental Request

Type 2 diabetes mellitus (T2D) is increasing in incidence throughout the world with nearly 552 million people who may be afflicted with this disease by 2030. There are now over 50 different drugs that can be used to treat T2D but about half of patients do not respond well to these agents and their hyperglycemic condition remains a life-threatening problem. Indeed, the first line drugs such as Metformin, GLP-1 receptor agonists (e.g. Semaglutide), DPP-4 inhibitors, SGLT2 inhibitors and others have documented side effects that include hypoglycemia, gastrointestinal side effects, pancreatitis, pancreatic cancer, thyroid cancer, gallbladder issues, cardiovascular changes, acute kidney injury, diabetic retinopathy, allergic reactions, increase in biliary disease, change in taste and headaches. As an alternative to these drugs, the first in human report was published in 2016 showing that duodenal mucosal resurfacing (DMR) of T2D patients could improve their hyperglycemic conditions as well as several hepatic indices without having to use these front line drugs. This study was initiated, in part, because of the well documented and surprising observation that bariatric surgery also resulted in a similar benefit to T2D patients that was independent of consequential weight loss. Since 2016 several clinical studies have been conducted on DMR and all showed benefit to patients with T2D who weren’t responding to traditional medical treatments or who were non- compliant with medications. While promising, DMR has been reported to have a high rate of technical failure due to catheter malfunctioning suggesting that improvements in the technical-functional aspects of current devices need to be addressed. Furthermore, one such DMR device that has shown benefit in several clinical trials uses hydrothermic ablation (hot water at 80 to 90°C) to achieve DMR. Like radiofrequency ablation, HiFU, microwave and other heat ablation technologies used to target and ablate tumors and treat cardiac arrhythmias, the passive spread of heat can’t be easily controlled and has shown to result in collateral tissue damage such as muscular segmental necrosis and serosa bleeding with postoperative adverse events from DMR hydrothermic ablation reported to be an issue with 64% of the cases. CPSI Biotech intends to capitalize on this emerging DMR market that is currently in its infancy and develop an improved DMR thermal ablation probe that uses freezing (cryoablation) rather than heat for duodenal resurfacing. The advantages of the proposed FrostBite- DMR cryoballoon include (a) freezing is self-limiting in contrast to heat and presents less opportunity for collateral damage to adjacent deeper duodenal tissue; (b) cryoablation has been shown to be more effective, safer and have fewer complications than heat based ablation in numerous tissues including cardiac, esophageal, renal, prostate and pancreatic among others; (c) CPSI’s PSN cryoablation systems can generate and deliver ablative temperatures faster and colder than any other known cryoablation systems currently on the market thus decreasing procedural time and, as such, will offer improved versatility and safety compared to current technologies. The Specific Aims of this project are the following: (SA1) Determine the thermal ablative dose of duodenum cells subjected to cryoablation; (SA2) Develop FrostBite-DMR™, a flexible endoscope compatible cryoballoon, and (SA3) Test the efficacy of FrostBite in ex vivo and in vivo models. The overall intent of the project is to capitalize on the documented success of DMR published in the last few years as well as CPSI’s expertise in developing improved cryoablation catheters so that an improved DMR ablation device can be developed that is safer, more efficient, and can be better operator controlled leading to more successful DMR for T2D patients who do not respond well to current T2D drug treatments. This is a supplemental equipment request under the parent grant, 1R43DK135117-01, to replace a -80o freezer that given its age is no longer repairable. CPSI currently has no -80o freezer and needs to acquire one to satisfy the specific aims detailed in the parent Phase I grant application.