Oral insulin (ORMD-0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study

Aims: To assess the safety and efficacy of multiple daily doses of oral insulin (ORMD-0801) in subjects with type 2 diabetes (T2DM) over 12 weeks. Materials and Methods: Participants with T2DM on metformin or combination oral therapy with glycated haemoglobin (HbA1c) levels ≥ 7.5% (58 mmol/mol) were randomized to receive ORMD-0801 8 mg or 16 mg once (QD) or twice (BID) daily, or 32 mg QD, BID or three times daily (TID) over a 12-week period. Results: A total of 373 subjects were randomized to active treatment or placebo (~60% male, age ~ 56 years, HbA1c 9%-9.8%; 75-84 mmol/mol). Placebo-adjusted HbA1c changes from baseline to Week 12 were observed with ORMD-0801 8 mg BID (−7.15 ± 3.57 mmol/mol [−0.65% ± 0.33%]; P = 0.046). However, a significant site interaction was observed in two sites. After excluding these, HbA1c reduction was observed with 8 mg QD (−0.81 ± 0.37%; −8.89 ± 4.01 mmol/mol; P = 0.028, n = 15), 8 mg BID (−0.82 ± 0.37%; −8.95 ± 4.08 mmol/mol; P = 0.029, n = 17), 32 mg QD (−0.54 ± 0.26%; −5.89 ± 2.78 mmol/mol;P = 0.036, n = 69) and 32 mg BID (−0.53 ± 0.26%; −5.80 ± 2.83 mmol/mol; P = 0.042, n = 68). No effect was observed with 16 mg QD (0.25 ± 0.37%; 2.76 ± 3.99 mmol/mol; P = 0.48, n = 18), 16 mg BID (−0.36 ± 0.40%; −3.97 ± P = 0.36, n = 15) or 32 mg TID (−0.45 ± 0.27%, −4.89 ± 2.90 mmol/mol; P = 0.093, n = 69). Continuous glucose monitor and serum glucose measurements showed similar trends but were not significant. ORMD-0801 was safe, well tolerated and not associated with weight gain or hypoglycaemia. Conclusions: Oral insulin (ORMD-0801) induced greater reductions in HbA1c when compared to placebo, and was safe and well tolerated in individuals with uncontrolled T2DM. The efficacy and safety findings support continued development of the 8-mg dose at bedtime, which is currently being evaluated in two Phase 3 trials.