Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus.

Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and many patients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-ß29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that is more effective than placebo throughout the meal period; however, compared with an active comparator insulin aspart, the post-prandial control is more effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.

Comparative clinical efficacy and safety of insulin glargine 300 U/ml (Toujeo) versus insulin glargine 100 U/ml in type 2 diabetes and type 1 diabetes: A systematic literature review and meta-analysis.

AIM: To compare the clinical efficacy and safety of glargine-U100 (Lantus/Gla-100) with glargine-U300 (Toujeo/Gla-300) in adult patients with type 2 diabetes (T2D) and type 1 diabetes (T1D). MATERIALS AND METHODS: A literature search on Gla-300/Gla-100 in diabetes management was conducted using the MEDLINE/Embase/Cochrane databases from inception to 10 January 2021. Eligible studies considered for inclusion were parallel-design, randomized controlled trials (RCTs). The Cochrane risk-of-bias tool was used to evaluate the quality of the included studies. The random-effects model was applied for interpretation of the results. RESULTS: Of 5348 records screened, 592 were assessed for eligibility and 15 RCTs were considered for data extraction and meta-analysis (T2D [N = 10; n = 7082]; T1D [N = 5; n = 2222]). In patients with T1D, all safety parameters were comparable between Gla-100 and Gla-300. In T2D, statistically significant differences were observed in favour of Gla-300 over Gla-100 for nocturnal and total hypoglycaemia. For efficacy parameters, a statistically and clinically significant difference favouring Gla-100 in basal insulin dose requirement was observed for both T2D and T1D. Change in HbA1c showed a statistically but not clinically significant reduction with Gla-100 compared with Gla-300 in T1D. Statistically significant but clinically less relevant differences favoured Gla-300 for control of body weight in T1D and T2D and Gla-100 for fasting blood glucose in T2D. CONCLUSIONS: Gla-100 and Gla-300 had comparable efficacy and safety profiles in both T1D and T2D populations. Gla-300 showed a lower risk of nocturnal and total hypoglycaemia, significant in insulin-experienced/exposed patients with T2D. Patients on Gla-300 required significantly more units of insulin daily than the Gla-100 group to achieve equivalent efficacy.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar insulin N with US-licensed Humulin® N formulation in healthy subjects: Results from the RHINE-2 (Recombinant Human INsulin Equivalence-2) study.

AIM: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin-N; Biocon Biologics Ltd., Bangalore, India) and US-licensed Humulin® N (Humulin-N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects. MATERIALS AND METHODS: This was a phase-1, single-centre, double-blind, randomized, three-period, six-sequence, partially replicated, crossover, 24-h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin-N and a single dose of Humulin-N or two single doses of Humulin-N and a single dose of Biocon's Insulin-N subcutaneously at a dose of 0.4 IU/kg. The primary PK endpoints were the area under the insulin concentration-time curve from 0 to 24 h (AUCins.0-24h ) and the maximum insulin concentration (Cins.max ). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUCGIR.0-24h ) and the maximum GIR (GIRmax ). RESULTS: Biocon's Insulin-N was found to be equivalent to Humulin-N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUCins.0-24h , 100.98%-115.66% and Cins.max , 95.91%-110.16%) and PD endpoints (intra-subject variability ≥0.294; 95% upper confidence interval [(µT - µR)2 - θσ2 WR] <0; point estimates of geometric least squares mean ratio: AUCGIR.0-24h , 104.61% and GIRmax , 100.81%). The safety profile of Biocon's Insulin-N was similar to that of Humulin-N, and no serious adverse events were reported. CONCLUSION: PK and PD equivalence was shown between Biocon's Insulin-N and Humulin-N in healthy subjects, and both treatments were well tolerated and considered safe.

Biosimilars and interchangeable biosimilars: facts every prescriber, payor, and patient should know. Insulins perspective.

INTRODUCTION: For many of the 537 million adults living now with diabetes, the cost of insulin is becoming prohibitive as the insulin prices have tripled between 2002-2013. Globally, the direct annual cost of healthcare expenditure due to diabetes will soon be US$1 Trillion. Biosimilars provide access to high-quality, affordable biologic therapy that is otherwise inaccessible due to the high costs of original biologics. AREAS COVERED: A primer to the development of biosimilars shows comparable structural and analytical characterization to the original biologics (e.g. insulins), with no clinically significant or meaningful differences in efficacy and safety. 'Interchangeability' status, a regulatory designation by the US FDA, bestowed to some biosimilars, enables confidence in high-quality, bio-equivalent biosimilar of insulin with key global approvals. This can allow rapid uptake of biosimilars by the prescribers, formulary decision-makers, and payors. Biocon-Viatris's biosimilar Insulin Glargine (Semglee®) is the first interchangeable biosimilar insulin approved by the US FDA. EXPERT OPINION: The 'interchangeable' status can prompt faster and wider uptake of insulin biosimilars and keep the insulin expenditure under control, especially for patients who otherwise practice non-adherence or rationing of life-saving insulin. Education, support, and awareness can ensure that interchangeable biosimilars gain wider acceptance.

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).

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin 70/30 with US-licensed HUMULIN® 70/30 formulation in healthy subjects: Results from the RHINE-3 (Recombinant Human INsulin Equivalence-3) study.

AIM: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar insulin 70/30 (Biocon's Insulin-70/30) and HUMULIN® 70/30 (HUMULIN-70/30; Eli Lilly and Company, IN). MATERIALS AND METHODS: In this phase 1, automated euglycaemic glucose clamp study, 78 healthy subjects were randomized (1:1) to receive a single dose of 0.4 IU/kg of Biocon's Insulin-70/30 and HUMULIN-70/30. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 24 hours. Primary PK endpoints were area under the insulin concentration-time curve from 0 to 24 hours - AUCins.0-24h - and maximum insulin concentration - Cins.max . Primary PD endpoints were area under the GIR time curve from 0 to 24 hours - AUCGIR.0-24h - and maximum GIR - GIRmax . RESULTS: Equivalence was shown between Biocon's Insulin-70/30 and HUMULIN-70/30 for the primary PK/PD endpoints. The 90% confidence intervals of the treatment ratios were entirely within the acceptance range of 80.00%-125.00%. The secondary PK/PD profiles were also comparable. There were no clinically relevant differences in the safety profiles of the two treatments and no serious adverse events were reported. CONCLUSION: PK/PD equivalence was demonstrated between Biocon's Insulin-70/30 and HUMULIN-70/30 in healthy subjects. Treatment with Biocon's Insulin-70/30 and HUMULIN-70/30 was well tolerated.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar Insulin-R with the US-licensed Humulin® R formulation in healthy subjects: Results from the RHINE-1 (Recombinant Human INsulin Equivalence-1) study.

AIM: To establish equivalence in the pharmacokinetic (PK) and pharmacodynamic (PD) endpoints between proposed biosimilar Insulin-R (Biocon's Insulin-R) and Humulin® R using the euglycaemic clamp technique in healthy subjects. MATERIALS AND METHODS: In this phase-1 automated euglycaemic glucose clamp study, 42 healthy subjects were randomized (1:1) to receive a single dose of 0.3 IU/kg of Biocon's Insulin-R and Humulin-R. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 12 hours. Primary PK endpoints were area under the insulin concentration-time curve from 0 to 12 hours (AUCins.0-12h ) and maximum insulin concentration (Cins.max ). Primary PD endpoints were area under the GIR time curve from 0 to 12 hours (AUCGIR.0-12h ) and maximum GIR (GIRmax ). RESULTS: Equivalence was demonstrated between Biocon's Insulin-R and Humulin-R for the primary PK and PD endpoints. The 90% confidence intervals were within 80.00% to 125.00% limits. The PK and PD profiles were comparable. There were no significant differences in the safety profiles of the two treatments, and no serious adverse events were reported. CONCLUSION: PK and PD equivalence was demonstrated between Biocon's Insulin-R and Humulin-R in healthy subjects. Treatment with Biocon's Insulin-R and Humulin-R was well tolerated.

A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19.

Objective: Efficacy and safety of Itolizumab, an immunomodulatory mAb, in treating moderate-to-severe acute respiratory distress syndrome (ARDS) due to cytokine release in COVID-19 patients was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase-2 study.Methods: Patients were randomized (2:1) to Arm-A (best supportive care [BSC]+Itolizumab) and Arm-B (BSC). Primary outcome of interest was reduction in mortality 30-days after enrollment.Results: Thirty-six patients were screened, five treated as first-dose-sentinels and rest randomized, while four patients were screen-failures. Two patients in Arm-A discontinued prior to receiving one complete infusion and were replaced. At end of 1-month, there were three deaths in Arm-B, and none in Arm-A (p = 0.0296; 95% CI = -0.3 [-0.61, -0.08]). At end of study, more patients in Arm-A had improved SpO2 without increasing FiO2 (p = 0.0296), improved PaO2 (p = 0.0296), and reduction in IL-6 (43 vs 212 pg/ml; p = 0.0296) and tumor necrotic factor-α (9 vs 39 pg/ml; p = 0.0253) levels. Transient lymphopenia (Arm-A: 11 patients) and infusion reactions (7 patients) were commonly reported treatment-related safety events.Conclusion: Itolizumab is a promising, safe and effective immunomodulatory therapy for treatment of ARDS due to cytokine release in COVID-19 patients, with survival and recovery-benefit.

Itolizumab, an anti-CD6 monoclonal antibody, as a potential treatment for COVID-19 complications.

INTRODUCTION: The globally rampant SARS CoV-2 pandemic requires novel medical strategies to control the severity of disease and death due to complications. Of the 15-20% patients that develop pulmonary symptoms, a sub-set develops an acute respiratory distress syndrome (ARDS) rapidly progressing into a critical condition. Marked elevation of cytokines/chemokines is observed with elevation of additional markers of inflammation, coagulation, and organ damage such as CRP, D-dimer, LDH, Ferritin and Troponin-I. This hyperinflammation leads to worsening of oxygen saturation due to pulmonary infiltration and exudation, organ damage, and dysfunction of coagulation pathway and may lead to multi-organ failure. AREAS COVERED: The role of anti-inflammatory monoclonal antibodies such as Itolizumab, in cytokine storm. EXPERT OPINION: Itolizumab, an anti-CD6 humanized IgG1 mAb, binds to domain-1 of CD-6 that is responsible for priming, activation, and differentiation of T-cells. Itolizumab significantly reduces T-cell proliferation along with substantial downregulation of the production of cytokines/chemokines. Approved for moderate to severe chronic plaque psoriasis in 2013 it is currently being studied for addressing COVID-19 related cytokine storm and its complications. This article reviews its use in COVID-19 infections; its dose, administration protocol, contra-indications, and safety in treating moderate-to-severe ARDS by preventing and treating the cytokine storm and its complications.

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.