Many type 2 diabetes patients in clinical practice are treated with pre-mixed insulins, such as Humalog® Mix 75/25, in order to receive both basal and prandial insulin in a single injection. Pre-mixed insulin is commonly dosed before breakfast and before dinner and is usually used in patients who are not candidates for an intensive basal-bolus insulin regimen that would require four or more injections per day. Humulin® R U-500 is the only concentrated insulin available in the U.S. and is usually used to treat type 2 diabetes patients with severe insulin resistance who require very high doses of insulin -- typically greater than 200 units per day.
BIOD-531 is an ultra-rapid-acting formulation of recombinant human insulin (RHI) at a concentration of 400 units/ml (U-400) combined with EDTA, citrate and magnesium sulfate. In the Phase 1 Study 3-150, the results of which were released in
The recently completed Study 3-152 was designed to test the hypothesis that a single dose of BIOD-531 would confer better postprandial glucose control for two consecutive meals compared to Humalog® Mix 75/25 when administered to type 2 diabetes patients with moderate insulin resistance.
In Study 3-152, glucose profiles were assessed after single subcutaneous injection of 0.6 U/kg doses of the study drugs administered with a standardized breakfast on separate days in a randomized four arm cross-over sequence in which subjects received pre-meal BIOD-531, pre-meal Humalog® Mix 75/25, pre-meal Humulin® R U-500 and post meal BIOD-531. In order to assess the duration of glucose lowering, subjects received a standardized lunch at 330 minutes (5.5 hours) after breakfast dosing with no insulin administered at that time. Glucose levels were measured every five minutes during the 720 minutes (12 hours) after test insulin dosing at breakfast.
The results of the current study demonstrate that the ultra-rapid-acting profile with an extended duration of action of BIOD-531 seen in Study 3-150 may translate into clinically meaningful benefits of superior mealtime and basal coverage for type 2 diabetes patients with moderate insulin resistance.
BIOD-531 was associated with superior glucose control compared to Humalog® Mix 75/25 throughout the day of observation. A single dose of BIOD-531 administered immediately before breakfast (pre-meal) achieved significantly lower mean glucose concentrations than did Humalog® Mix 75/25 administered immediately before breakfast. The mean glucose concentration after breakfast was 167.8 ± 10.4 mg/dl with BIOD-531 treatment compared to 205.1 ± 8.3 mg/dl with Humalog® Mix 75/25 treatment (p < 0.001). Mean glucose concentrations were also significantly improved after lunch with pre-meal BIOD-531. Over the course of the entire day of observation, pre-meal BIOD-531 was associated with an average glucose concentration of 177.8 ± 11.9 mg/dl compared to 225.1± 10.7 mg/dl with Humalog® Mix 75/25 treatment (p < 0.001). The percentage of glucose readings within the target range of 70-180 mg/dl was increased more than two-fold following BIOD-531 treatment (46.3 ± 8.4%) compared to Humalog® Mix 75/25 treatment (20.6 ± 5.9 %; p=0.002). Likewise, the post-breakfast area under the curve for the glucose excursion and the mean maximal glucose concentrations after breakfast and after lunch were significantly improved with pre-meal BIOD-531 treatment compared to Humalog® Mix 75/25 treatment.
BIOD-531 was also associated with superior glucose control compared to Humulin® R U-500. Mean glucose concentrations after the standardized breakfast were 167.8 ± 10.4 mg/dl with BIOD-531 treatment compared to 193.1 ± 8.3 mg/dl with Humulin® R U-500 treatment (p=0.006). Over the entire day of observation, mean glucose concentrations were 177.8 ± 11.9 mg/dl with BIOD-531 treatment compared to 197.2 ± 8.8 mg/dl with Humulin® R U-500 treatment (p=0.042). Over the course of the entire day of observation, glucose concentrations were in the target range of 70-180 mg/dl 46.3 ± 8.4% of the time with BIOD-531 treatment compared to 29.1 ± 6.1% of the time with Humulin® R U-500 treatment (p=0.032).
BIOD-531 dosed 20 minutes after the start of the standardized breakfast also resulted in a superior glucose control compared to either Humalog® Mix 75/25 or Humulin® R U-500 dosed prior to the meal. Mean glucose concentrations over the course of the day were 178.3 ± 11.2 mg/dl for post-meal BIOD-531 treatment compared to 225.1 ± 10.7 for pre-meal Humalog® Mix 75/25 treatment (p < 0.001). The percentage of readings within the 70-180 mg/dl target range was 46.2 ± 7.6% for post-meal BIOD-531 treatment compared to 20.6 ± 5.9% for pre-meal Humalog® Mix 75/25 treatment (p=0.003) and 29.1 ± 6.1% for pre-meal Humulin® R U-500 treatment (p=0.040).
Safety and Tolerability
Mean visual analog scores and absolute severity scores were low for all participants, suggesting excellent injection site tolerability. There were no statistically significant differences in 100 mm visual analog scores among the treatment groups.
|Blood Glucose Profiles of BIOD-531 Vs. Humalog ® Mix 75/25 or Humulin ® R U-500 Following Standardized Meal Challenges|
|Meal||Efficacy Parameter||Treatment Group Comparison|
|BIOD-531 Before Meal (A)||
Before Meal (B)
Before Meal (C)
|BIOD-531 After Meal (D)||P Value|
|(A) vs. (B)||(A) vs. (C)||(B) vs. (D)||(C) vs. (D)|
|After Breakfast*||Change BG AUC0-120min (mg.min/dl)||7140 ± 962||10302 ± 1051||8160 ± 533||7319 ± 889||0.001||0.228||0.002||0.319|
|Change BG AUC0-330min (mg.min/dl)||23526 ± 3054||33751 ± 2396||30158 ± 2342||23833 ± 3846||0.003||0.036||0.004||0.051|
|Avg BG 0-330min (mg/dl)||167.8 ± 10.4||205.1 ± 8.3||193.1 ± 8.3||173.4 ± 11.6||< 0.001||0.006||0.001||0.031|
|BG Maximum0-120min (mg/dl)||192.9 ± 12.3||233.7 ± 12.5||212.8 ± 7.0||195.3 ± 10.7||< 0.001||0.050||< 0.001||0.082|
|Percent Values 5-330min Within 70- < 80 mg/dl Range (%)||52.7 ± 10.3||28.0 ± 9.1||33.5 ± 9.5||48.6 ± 10.3||0.026||0.074||0.067||0.172|
|After Lunch**||Avg BG 5-390min (mg/dl)||186.3 ± 15.0||241.9 ± 15.3||200.7 ± 11.6||176.4 ± 14.9||< 0.001||0.205||< 0.001||0.060|
|BG Maximum0-120min (mg/dl)||237.6 ± 15.5||297.3 ± 16.1||256.3 ± 13.4||230.4 ± 14.4||< 0.001||0.212||< 0.001||0.101|
|Percent Values 0-390min Within 70- < 80 mg/dl Range (%)||41.1 ± 9.1||13.6 ± 6.4||25.7 ± 6.9||43.8 ± 9.8||0.002||0.072||0.001||0.042|
|Overall Test Period||Avg Glucose 0-720min (mg/dl)||177.8 ± 11.9||225.1 ± 10.7||197.2 ± 8.8||178.3 ± 11.2||< 0.001||0.042||< 0.001||0.058|
|Percent Values 5-720min Within 70- < 80 mg/dl Range (%)||46.3 ± 8.4||20.6 ± 5.9||29.1 ± 6.1||46.2 ± 7.6||0.002||0.032||0.003||0.040|
|Data presented are the Mean ± SEM from twelve subjects randomized. One of these subjects discontinued after treatment with Humalog® Mix 75/25 and Humulin® R U-500 only. Blood glucose was measured every 5 minutes.|
|BG: Blood glucose; Change BG: Change in blood glucose from baseline; AUC: Area under the glucose response curve|
|*Test insulin was administered only for the breakfast meal|
|**No insulin treatment was administered at lunch (330 min after injection)|
Study 3-152 was a single-blinded, four-arm cross-over study. Twelve subjects were randomized and 11 patients completed the study. The patients evaluated in this study were a typical population with type 2 diabetes who used between 50-200 units of insulin per day with mean age of 55 years old, mean baseline HbA1c of 9%, mean weight of 99 kg, and mean BMI of 33.5 kg/m2. Subjects were washed out of background diabetes medications (including insulins) and admitted to the research unit the evening before study drug dosing. Overnight, blood glucose concentration was stabilized at the target range of 100 ± 20 mg/dl using intravenous insulin. The intravenous insulin was discontinued no later than 15 minutes before a standardized breakfast in the morning. Each subject came in for the following four treatments administered subcutaneously on separate days assigned in a random order: (a) BIOD-531 immediately before the meal (pre-meal); (b) Humalog® Mix 75/25 pre-meal; (c) Humulin® R U-500 pre-meal; and (d) BIOD-531 twenty minutes after the start of the meal (post-meal). The dose for each session was 0.6 U/kg. After the breakfast, glucose concentrations were measured every 5 minutes throughout the day for a total of 720 minutes (12 hours) after insulin dosing. In order to assess the duration of glucose control of the test insulins, the subject received a standardized lunch 330 minutes (5.5 hours) after breakfast dosing but did not receive a lunch-time dose of insulin. Injection site toleration was assessed with a 100 mm visual analog scale and severity scores.
The current unmet medical need for a concentrated ultra-rapid-acting insulin formulation exists among a subset of type 2 diabetes patients who demonstrate severe insulin resistance and require greater than 200 units of insulin daily to meet their insulin needs. Currently Eli Lilly's Humulin® R U-500 is the only concentrated insulin product on the U.S. market. Humulin® R U-500 concentrated insulin has a suboptimal pharmacokinetic and pharmacodynamic profile for prandial coverage, with a more delayed onset than U-100 regular human insulin or rapid-acting insulin analog formulations.
Eli Lilly and Novo Nordisk market preparations of human insulin or rapid-acting analog prandial insulins pre-mixed with intermediate-acting basal neutral protamine insulins in a variety of ratios such as 70/30, 75/25 and 50/50. Pre-mixes provide basal and bolus therapy with fewer injections per day. Pre-mixed prandial/basal insulins have a suboptimal pharmacokinetic and pharmacodynamic profile with a more delayed onset than prandial U-100 regular human insulin or rapid-acting insulin analog formulations. Pre-mixes represent approximately thirty percent of the more than $8 billion global rapid-acting prandial insulin market.
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