Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

BACKGROUND: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin. RESEARCH DESIGN AND METHODS: In this open-label, active-controlled trial, patients with T2D, HbA1c ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose. RESULTS: The observed mean HbA1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69). CONCLUSIONS: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil's early postprandial effects were comparable to IAsp, its late postprandial effects were inferior. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer.

PURPOSE: This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks). RESULTS: A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was -1.6 (CI -9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%). CONCLUSIONS: MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints. TRIAL REGISTRY INFORMATION: EU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32. PLAIN LANGUAGE SUMMARY: Previous studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O (n = 337) demonstrated comparable efficacy to bevacizumab (n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was -1.6 (95% CI -9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months (p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus.

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between-meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo-controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose-lowering effect (glucose area under concentration-time curve [AUC]) compared to the 30-minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between-meal interval. The 6-hour between-meal interval resulted in better absorption of insulin tregopil in comparison to 4- and 5-hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0-180min in the insulin tregopil 4-hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high-fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high-fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5-hour between-meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study.

Oral insulin tregopil (IN-105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN-105 on pharmacokinetics (PKs) of metformin. In this randomized, open-label, cross-over study, metformin was administered to healthy volunteers receiving IN-105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0-inf ; fasting and fed) and peak plasma concentration (Cmax ; fed) of metformin were within 0.80-1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN-105 on PKs of metformin under fasting/fed conditions, and it was safe.