Background and Aims: Preclinical data shows mTOR pathway upregulation in Familial Adenomatous Polyposis (FAP). Inhibition of this pathway by rapalogues, like rapamycin, suggests promising results, but poor drug bioavailability and toxicity limited effective use of these drugs in FAP trials. Encapsulated Rapamycin (eRapa) offers sustained and controlled absorption of rapamycin. We conducted a trial to determine the safety of eRapa and its impact on gastrointestinal (GI) polyp burden in patients with FAP. Methods:This 12-month, multi-center, open label, dose/schedule-finding trial of eRapa included adults at least 18 years old with genetic or clinical FAP and an intact colon or ileo-rectal anastomosis and > 10 adenomas in the remaining colon/rectum. Patients were sequentially enrolled in 3 dose cohorts: 0.5 mg every other day (Cohort 1), 0.5 mg daily every other week (Cohort 2), and 0.5 mg daily (Cohort 3). Upper and lower endoscopic surveillance done at baseline and every 6 months. Primary endpoints were safety and tolerability of eRapa and percent change from baseline in polyp burden (sum of all polyp diameters). Polyp outcomes were classified as progressive disease (PD: >20% increase), stable disease (SD: ± 20% change) or partial response (PR: >20% reduction in polyp burden). A combo endpoint of non-progressors included SD and PR. Results: 30 patients were enrolled, 10 in each cohort. 6 patients had an intact colon and 24 had an ileo-rectal anastomosis. Baseline clinical characteristics were comparable across cohorts. Median age was 43 years (37-62) and 50% were female. 18/30 (60%) patients had evaluable duodenal polyposis and 29/30 (97%) patients completed a 6-month lower endoscopy by time of data evaluation. 2 related, Grade 3 Serious Adverse Events occurred and no Grade 4 or 5 toxicities noted (Table 1). A significant decrease in overall mean polyp burden occurred at 6 mos (p = 0.04) (Table 1). In the duodenum, 14/18 (78%) patients were non-progressors and 11/18 (61%) had PR. In the colorectum, 25/29 (86%) patients were non progressors including all with an intact colon, including 15/29 (67%) patients with PR including 4 with an intact colon and (Figure 1). Conclusions: eRapa appears safe and well-tolerated in FAP. A 24% reduction in overall polyp burden was observed. Patients in Cohort 1 (0.5 mg every other day) demonstrated greatest reduction in polyp burden (32%) with fewest related AEs. PR was noted in the duodenum and lower GI tract in 61% and 67% of patients, respectively. All patients with an intact colon were non-progressors. This trial shows the potential benefit of low dose eRapa to prevent progression of duodenal and lower tract polyp burden over the first 6 months of treatment. 12-month data will be forthcoming in 2024.

Paul Wise

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