Eli Lilly and Company recently reported that its IMAGINE-1 and IMAGINE-3 Phase III clinical trials showed that basal insulin peglispro (BIL) treatment induces a statistically significant lower hemoglobin A1c (HbA1c, glycated haemoglobin), a measure of average blood sugar levels, compared with insulin glargine (Lantus, a registered trademark of Sanofi), respectively, at 26 and 52 weeks, in patients with type 1 diabetes.
Lilly Diabetes introduced the world’s first commercial insulin in 1923 and has since been a global leader in diabetes care. Basal insulin peglispro (BIL), discovered and developed in Lilly Research Laboratories (www.lilly.com), is currently in Phase III clinical trials and is among several diabetes molecules candidates in the Lilly late-stage pipeline. BIL is being studied as a once-daily treatment for type 1 and type 2 diabetes.
“These data are promising and give us further confidence in the clinical profile of BIL,” said Enrique Conterno, president of Lilly Diabetes.
The Phase III Clinical Trial Program is consists of seven IMAGINE trials, IMAGINE-1 to IMAGINE-7, in patients with type 1 and type 2 diabetes.
In trials of both type 1 and type 2 diabetes, BIL showed consistent superiority of HbA1c when compared with standard treatments.
“Lilly is committed to meeting the diverse needs of people living with diabetes who need therapies that will help them meet their individual goals. If approved, we believe BIL will be an important new basal insulin option for people with diabetes,” added Conterno.
IMAGINE-1 is a Phase III, 78-week, open-label study designed to compare BIL (n=295) with insulin glargine (n=160) in combination with mealtime insulin in patients with type 1 diabetes.
IMAGINE-3 is a Phase III, 52-week, double-blind randomized study designed to compare BIL (n=664) with insulin glargine (n=450) in combination with mealtime insulin in patients with type 1 diabetes.
The results obtain from IMAGINE-1 and IMAGINE-3 trials show, in the primary study endpoint, that significantly more BIL-treated patients had an HbA1c of less than 7 percent than those taking insulin, a target value for glycemic control established by the American Diabetes Association.
Moreover, in both trials, in which patients were taking both mealtime and basal insulin, it was shown that the rate of nocturnal hypoglycemia was significantly lower in patients taking BIL when compared with those taking insulin glargine. There was a statistically significant increase in the rate of total hypoglycemia for patients taking BIL compared with those taking insulin glargine due to a higher rate of daytime hypoglycemic events.
In the open-label IMAGINE-1 trial and double-blind IMAGINE-3 trial, a larger study, it was shown, respectively, that patients taking BIL have a statistically significant higher rate of severe hypoglycemic events and the rate of severe hypoglycemic events was numerically lower compared with insulin glargine but was not statistically significant. In addition, patients taking BIL show loss of weight (lower HbA1c) contrary to the patients taking insulin glargine that gain weight (higher HbA1c).
“All patients with type 1 diabetes depend on insulin to achieve and maintain their target blood glucose levels. For a number of those patients, current insulin options may not be optimal — particularly in those who experience nocturnal hypoglycemia or weight gain,” said David Kendall, M.D., vice president, Medical Affairs, Lilly Diabetes.
“Basal insulin peglispro may offer a useful option to help address these challenges,” added David Kendall.
In IMAGINE-1 and IMAGINE-3 trials, patients taking BIL had changes in lipid parameters, including a small but statistically significant increase in triglycerides. In IMAGINE-3, there were significant decreases and increases, respectively, in HDL (high-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol in patients. There was small but statistically significant increases in systolic and diastolic blood pressure in patients taking BIL when compared to insulin glargine (less than 2 mmHg mean difference at 52 weeks). In IMAGINE-1 there were no statistically significant differences in HDL and LDL cholesterol and blood pressure. Also, there were no major adverse cardiac events (MACE) in IMAGINE-1, and in IMAGINE-3, the MACE+ (cardiovascular death, non-fatal stroke, non-fatal MI and hospitalization due to unstable angina) event rate was lower for patients taking BIL compared with those taking insulin glargine.
In both trials, treatment with BIL was associated with a statistically significant higher incidence of patients with more than three times the upper limit of normal range in the liver enzyme ALT (alanine aminotransferase) compared with patients taking insulin glargine. There were no cases of severe liver injury (Hy’s Law) occurring in either of the trials. Using MRI imaging, to measure liver fate, it was shown that a subset of patients treated with BIL had a statistically significant increase in liver fat compared to insulin glargine-treated patients. In both trials, there were significantly more injection site reactions observed in patients taking BIL compared to those taking insulin glargine.
Concerning IMAGINE-7, a Phase III, 36-week, randomized, cross-over study designed to compare BIL (n=182) administered once daily at a fixed time with BIL administered at a variable time of day in patients with type 1 diabetes. The IMAGINE-7 trial—a flexible dosing study of BIL in patients with type 1 diabetes—and the IMAGINE-6 trial, evaluating BIL compared to Neutral Protamine Hagedorn (NPH) insulin, an intermediate-acting insulin given to diabetes patients to control the blood sugar level, in patients with type 2 diabetes, are both completed. In this trial, there was no statistically significant difference in HbA1c between BIL dosed at the same time every day versus BIL dosed at variable times.
IMAGINE-6, a Phase III, 26-week, open-label study designed to compare BIL (n=428) with (NPH) insulin (n=213) in insulin naïve patients with type 2 diabetes, met its primary efficacy endpoint of non-inferior reduction in HbA1c compared with NPH insulin at 26 weeks and also demonstrated HbA1c superiority of BIL compared to NPH insulin. There were no new safety signals in both trials and the adverse events were similar to those seen in the other IMAGINE trials.
An analysis across all clinical trials in patients with type 1 and type 2 diabetes showed that the rates of major adverse cardiovascular events were similar between patients treated with BIL, insulin glargine or NPH insulin.
The Phase III Clinical Trial Program is complete and in all six of the Phase III trials performed it was shown superiority for HbA1c in the treatment with BIL when compared with active standard-therapies. The results of the detailed study for all Phase III trials are expected to be revealed in 2015.
Importantly, Lilly plans to submit BIL for regulatory review to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) by the end of March 2015.