Maximum exogenous insulin concentrations were highest for PO insulin (625360 U), followed by DU (453436 U) and SC (10145.7 U) insulin. Peak absorption was reached within a mean 0.750.29 h and 0.50.6 h in the PO and DU sessions, respectively, and by 0.380.22 h for the SC insulin. Mean exogenous insulin area under the curve was similar between the two PO and DU sessions (414246 μU/ml*h and 423526 μU/ml*h, respectively), and significantly higher than after SC delivery (18142.6 μU/ml*h). Relative bioavailability of PO insulin and DU insulin was 5.42.3% and 8.39.9%, respectively. Of note, high inter-animal variability in absorption of exogenous insulin was observed. Onset of action was typically immediate for the DU and SC insulins and with a lag of 15 min for the PO insulin. Overall effects on plasma glucose concentrations were similar across delivery modes and was maximal 1-1.5 h after oral dosing and returned to baseline within 4h of dosing. The Glucose-Reducing Effect of Oral Insulin (ORMD-0801) versus Placebo Treatment in T2DM Patients 1Miriam Kidron, 2Kenneth Homer, 3Joel Neutel 1Oramed Pharmaceuticals, Jerusalem, Israel; 2 Integrium, LLC, Cedar Knolls, NJ, USA; 3 St. Joseph Hospital, Tustin, CA, USA TABLE 1. STUDY CONDUCT AND PATIENT DEMOGRAPHICS Placebo ORMD-0801 (16 mg) (24 mg) Patients randomized, n 64 61 63 Patients completed study, n 62* 56# 61& Age, mean (SD) 58.6 (9.2) 57.9 (8.0) 57.3 (8.9) Male, n (%) 29 (45.3) 39 (63.9) 34 (54) White, n (%) 53 (82.8) 50 (82.0) 55 (87.3) Black/African American, n (%) 7 (10.9) 8 (13.1) 4 (6.3) Asian, n (%) 2 (3.1) 2 (3.3) 2 (3.2) Native Hawaiian/Pacific Islander, n (%) 1 (1.6) 0 (0) TABLE 2. OVERVIEW OF ADVERSE EVENTS Placebo ORMD-0801 (16 mg) (24 mg) N=64 N=61 N=63 Total Adverse Events*, n 34 42 TEAEs# , n 19 Severe TEAEs, n 1 Serious TEAEs, n Related TEAEs, n 2 Hypo/Hyper-glycemia events, n 4 BACKGROUND RESULTS Consensus regarding the convenience of oral insulin, alongside the proposed therapeutic advantages of this administration route over systemic exposure, have fueled numerous attempts at design of such a formulation. Oramed Ltd. had developed an oral insulin formulation (ORMD-0801), which harnesses excipients to both hinder proteolysis in the small intestine and enhance translocation of insulin across the gut epithelial lining. Once transported across the gut wall, the insulin is ferried to the hepatic portal vein, mimicking the natural route of endogenous pancreatic insulin, and then subjected to first-pass metabolism in the liver, before being delivered to peripheral sites of action. The PK/PD profile of ORMD-0801 is well suited for the control of fasting blood glucose due to the delayed onset of action. Therefore, Oramed is pursuing the bed-time oral administration of ORMD-0801 for the treatment of elevated fasting blood glucose in adult patients with T2DM. Of the 188 patients randomized to a specific cohort, 179 completed the full course of treatment (Table 1) ORMD-0801 proved safe, well-tolerated and nonimmunogenic, with no serious adverse drug-related events reported. No significant difference in incidence and types of adverse events, including hyper/hypoglycemia, was noted between cohorts (Table 2). CGM data indicated a significantly smaller change from baseline in nighttime glucose levels in the pooled ORMD-0801 (1.7 mg/dL) as compared to the placebo (13.7 mg/dL, p=0.012) cohort (Figure A). Mean 24-hour glucose readings remained stable among ORMD-0801-treated patients (mean difference: -0.32 mg/dL), whereas patients receiving placebo demonstrated a mean 13.26 mg/dL change from baseline in these readings (p<0.0001) (Figure B). Similarly, mean change from baseline in fasting (5AM-7AM) and daytime (6AM-10PM) CGM glucose were significantly smaller among ORMD-0801-treated patients as compared to those treated with placebo (-0.4 mg/dL vs. 16.0 mg/dL [p<0.0001] and 0.9 mg/dL vs. 11.9 mg/dL [p<0.001] respectively) (Figures C-D). In parallel, the mean change from baseline in HbA1c levels in the combined ORMD-0801 cohorts (-0.01%) was significantly smaller as compared to the placebo cohort (0.2%; p=0.01; Figure E). * Withdrawn consent (n=1), lost to follow-up (n=1). # Withdrawn consent (n=2), noncompliance (n=2). & Lost to follow-up (n=1), protocol violation (n=1) * Non-Hyper/hypoglycemic events # TEAE: Treatment-emergent adverse event OBJECTIVES A B C D E Nighttime 24 Hours Fasting 5AM to 7AM Daytime 6AM to 10PM HbA1c Placebo 0.20 ORMD-0801 -0.01* To assess the safety of ORMD-0801 To assess the pharmacodynamic effect of ORMD-0801 on mean night glucose levels. To assess the pharmacodynamic effect of ORMD-0801 on fasting and morning blood glucose and HbA1c levels. Placebo 13.70 Placebo 15.95 Table 2 CONCLUSIONS DESIGN p = 0.0117* Placebo 13.26 Placebo 11.88 B In this Phase IIb, randomized (1:1:1), double-blind, placebo-controlled, multicenter (n=33) study, 192 adult patients with T2DM, participated in a 14-day single-blind placebo run-in period, followed by a 28-day treatment period with 16 mg ORMD-0801, 24 mg ORMD-0801 or placebo, self-administered at bedtime. Glucose levels were monitored, via a blinded continuous glucose monitor (CGM), during the last 7 days of both the run-in and treatment periods. Inclusion criteria: Male or female; T2DM patients; ages 20-75, inclusive, HbA1c ≥7.5% if naïve to antidiabetic therapy or ≥6.5% and ≤10% if on metformin ≥1500 mg daily or ≥7.0% if on metformin <1500 mg daily or ≥6.5% and ≤9.5% if on monotherapy with drug other than metformin; BMI 25-40 mg/m2, inclusive; fasting blood glucose ≥ 126 mg/dL prior to randomization. Change from glucose (mg/dL) run-in – 80% trim Change from glucose (mg/dL) run-in – 80% trim Change from glucose (mg/dL) run-in – 80% trim Change from glucose (mg/dL) run-in – 80% trim Day 29 HbA1c (%) change from baseline ORMD-0801 treatment elicited a sustained and highly significant reduction in mean nighttime, fasting, daytime and 24-hour glucose concentrations and proved safe for use. In addition, a marked reduction in HbA1c levels was observed, with a projected 0.5% drop from baseline following 12 weeks of treatment. ORMD-0801 -0.32* ORMD-0801 0.88* ORMD-0801 1.66* ORMD-0801 -0.41* Last 2 days of treatment Last 2 days of treatment Last 2 days of treatment Last 2 days of treatment For more information: estee@oramed.com U.S.:1-646-240-4193; Intl.:+972-2-566-0001 Figure 1. Mean change in blood glucose concentrations: last two days of run-in vs. last two days of treatment period Patients underwent a 14-day, single-blind placebo run-in period, during which, they were monitored with the CGM for the last 7 days. Patients were then randomized to receive either placebo, 16 mg ORMD-0801 or 24 mg ORMD-0801. for 28 consecutive days and monitored with a CGM for the last 7 days. Data from the last two days of monitoring that contained at least 80% of the readings were used for the comparative analysis between run-in and treatment phases for patients in both the placebo-treated cohort and ORMD-0801-treated cohort. No significant difference in readings was observed between the two treatment groups and data are therefore presented as a pooled ORMD-0801 treatment cohort. HbA1c is presented as the difference between Day 29 measures and baseline. www.oramed.com