DEVELOPMENT OF A NOVEL DRUG DELIVERY SYSTEM (DDS) TO DELIVER DRUGS DIRECTLY TO THE COLONIC MUCOSA TO IMPROVE EFFICACY AND REDUCE SYSTEMIC EXPOSURE FOR THE TREATMENT OF ULCERATIVE COLITIS (UC)

Abstract

Abstract The clinical remission rate in moderate to severe ulcerative colitis (UC) and Crohn’s Disease (CD) has plateaued at ~15-20% despite the approval of multiple therapeutics. Research has shown that an inadequate amount of drug at the disease site in the colon may be responsible for limited clinical benefit. The Drug Delivery System (DDS) is an ingestible electronic targeted delivery device containing a localization system to autonomously identify colon entry based on gastrointestinal (GI) anatomy, independent of the variable GI physiological conditions deliver a bolus dose of a liquid drug formulation to the colon mucosa to improve efficacy and reduce systemic toxicity. Here, we aim to evaluate the safety, tolerability, and functionality of a single dose of the DDS using gamma scintigraphy images as a reference in both normal healthy volunteers (NHV) (PM-601) and subjects with active UC (PM-602) in a fasted state. A total of twelve NHV (N=12) and seven subjects with an endoscopically confirmed history of UC and active UC (N=7) status, defined as having a Mayo score ≥ 2 or elevated fecal calprotectin protein or high sensitivity C-reactive protein within one month of the screening visit, were enrolled and dosed in these studies. Each subject fasted overnight and was dosed with a single DDS device before resuming a normal diet at 4 hours post-dose. Each device was filled with radioactive marker indium-111 DTPA and co-administered with water to which technetium-99m DTPA was added to monitor device GI transit and payload release in the GI tract. The GI transit of the device and delivery location of the radioactive payload were confirmed by serial scintigraphy imaging and compared with the localization data recovered from the devices. GI transit metrics showed a more variable GI motility and frequent bowel movements were observed among active UC subjects compared to NHV (Table 1). The DDS device was well tolerated in both NHV and active UC subjects. One subject with active UC (PM-602) experienced mild intermittent abdominal cramping following device administration possibly related to the device, which resolved on the same day. No other device-related AEs were reported in these studies. The results from these two studies demonstrated a total of 17 out of 19 DDS devices (90%) successfully identified colon entry and 15 out of 19 DDS devices (79%) delivered the radio payload into the colon regardless of variable GI transit time, the level of inflammation, or the presence of blood in the stool (Table 1 & 2). The dispersion of the radiotracer adequately covered the colon from the site of release throughout the remainder of the colon. These results demonstrated that the DDS device was well-tolerated and functioned as intended to deliver radiotracer throughout the colon regardless of variable GI motility, disease, and inflammation status.