Lilly's Basal Insulin Peglispro Shows Superiority to Insulin Glargine in Reducing HbA1c in People with Type 2 Diabetes

Data from Phase III Clinical Trial Program Presented at the 2015 American Diabetes Association Scientific Sessions®

News provided by

Jun 06, 2015, 01:45 ET

INDIANAPOLIS, June 6, 2015 /PRNewswire/ -- Eli Lilly and Company's (NYSE: LLY) basal insulin peglispro (BIL) consistently demonstrated superior hemoglobin A1c (HbA1c) reduction in people with type 2 diabetes compared to insulin glargine across three Phase III trials. The results were presented today at the 75^th American Diabetes Association (ADA) Scientific Sessions in Boston.^1,2,3

The trials compared BIL and insulin glargine in three common type 2 patient populations: those not previously using insulin (IMAGINE-2), those using basal insulin with mealtime insulin (IMAGINE-4) and those currently using a basal insulin (IMAGINE-5).

"BIL is the first and only basal insulin to consistently demonstrate superior glycemic benefits along with a reduction in nocturnal hypoglycemia and a weight advantage compared to insulin glargine in Phase III clinical studies," said Melanie Davies, M.D., professor of diabetes medicine, University of Leicester, United Kingdom. "Further innovation in basal insulin treatments is important as many people currently being treated do not reach glycemic targets and experience nocturnal hypoglycemia or weight gain."

Additional data from IMAGINE-2, IMAGINE-4 and IMAGINE-5 showed that more patients taking BIL consistently met the ADA's recommended HbA1c target of less than 7 percent.⁴ A greater percentage of BIL-treated patients also reported less nocturnal hypoglycemia compared to those on insulin glargine. Rates of total and severe hypoglycemia did not differ significantly between treatment groups. Patients taking BIL experienced less weight gain than patients taking insulin glargine in IMAGINE-2 and IMAGINE-4.

In all three clinical trials, patients taking BIL had an increase in the liver enzyme ALT (alanine aminotransferase), and triglyceride levels were higher than in patients treated with insulin glargine.¹^,²^,³ Liver fat content was higher after treatment with BIL compared to insulin glargine in subsets of patients studied from IMAGINE-2 and IMAGINE-5.

"BIL is mechanistically different from current basal insulins. It has a hepato-preferential action, driven by its reduced effect on peripheral tissues," said David Kendall, M.D., vice president, Medical Affairs, Lilly Diabetes. "What we've seen from the Phase III trials are unprecedented results in the basal insulin space: superior glycemic control with less nocturnal hypoglycemia and reduced weight gain, all of which are important to physicians and patients. We're pleased to share these Phase III results with the scientific community this week. "

BIL Type 2 Clinical Data
In all three type 2 diabetes trials, BIL showed consistent superiority in reducing HbA1c levels from baseline to the primary endpoint compared to insulin glargine:¹^,²^,³^,⁵

IMAGINE-2 (reductions of 1.6 percent vs. 1.3 percent at 52 weeks)¹
IMAGINE-4 (reductions of 1.7 percent vs. 1.5 percent at 26 weeks)²
IMAGINE-5 (reductions of 0.82 percent vs. 0.29 percent at 26 weeks).³

More patients taking BIL reached the ADA's recommended target HbA1c of less than 7 percent compared to insulin glargine at the primary endpoint:

IMAGINE-2: 58 percent vs. 43 percent at 52 weeks¹
IMAGINE-4: 63 percent vs. 53 percent at 26 weeks²
IMAGINE-5: 73 percent vs. 52 percent at 26 weeks³

In an additional Phase III trial (IMAGINE-6), patients taking BIL experienced greater reductions in HbA1c than those taking Neutral Protamine Hagedorn (NPH) insulin (1.7 percent vs. 1.4 percent). More BIL patients also reached the ADA's recommended target of less than 7 percent (63.1 percent vs. 43.4 percent).⁵ A greater percentage of BIL-treated patients also reported less nocturnal hypoglycemia compared to those on NPH.

Hepatic (liver) safety findings:

In integrated analyses of type 2 diabetes clinical trials compared to glargine, more patients taking BIL had a mean increase from baseline in the liver enzyme ALT at 52 weeks (mean difference between treatment groups: 7.4 IU/L). Additionally, a greater proportion of BIL patients had ALT levels greater than or equal to three times the upper limit of the normal range (ALT≥3X ULN) compared to insulin glargine (2.03 percent vs. 0.62 percent). No cases of severe drug-induced liver injury (Hy's Law) occurred in these studies.
- IMAGINE-2 :
  - ALT change from baseline at 52 weeks: 4.1 IU/L vs. -2.0 IU/L
  - ALT ≥3X ULN: 2.3 percent vs. 0.6 percent¹
- IMAGINE-4:
  - ALT change from baseline at 26 weeks: 7.6 IU/L vs. -0.6 IU/L
  - ALT ≥3X ULN: 1.9 percent vs. 0.9 percent²
- IMAGINE-5:
  - ALT change from baseline at 52 weeks: 8.3 IU/L vs. 0.4 IU/L
  - ALT ≥3X ULN: 2.3 percent vs. 0.0 percent³
In IMAGINE-6, more patients taking BIL had a mean increase from baseline in the liver enzyme ALT at 52 weeks (mean difference between treatment groups: 7.4 IU/L). However, the proportion of BIL patients that had ALT levels greater than or equal to three times the upper limit of the normal range (ALT≥3X ULN) was similar to patients treated with NPH insulin.
In IMAGINE-2 and IMAGINE-5, liver fat was measured using magnetic resonance imaging (MRI) in a subset of patients. Results showed:
- In IMAGINE-2, liver fat did not change from baseline in patients treated with BIL, while patients taking insulin glargine experienced a decrease in liver fat from 12.7 percent at baseline to 10.0 percent at 52 weeks. The mean difference between treatment groups at 52 weeks was 2.6 percent.¹
- In IMAGINE-5, patients taking BIL experienced an increase in liver fat from 10.4 percent at baseline to 14.8 percent at 52 weeks, while liver fat did not change significantly in patients taking insulin glargine. The mean difference between treatment groups at 52 weeks was 5.3 percent.³

Non-hepatic safety findings:

In IMAGINE-2, IMAGINE-4 and IMAGINE-5 trials, triglycerides were higher in patients treated with BIL compared to insulin glargine. Rates of major adverse cardiac events MACE+ (cardiovascular death, non-fatal stroke, non-fatal MI and hospitalization due to unstable angina) were similar between patients treated with BIL and insulin glargine.¹^,²^,³
An analysis across all trials – including type 1—showed that the rates of major adverse cardiovascular events among patients taking BIL and those taking insulin glargine or NPH insulin were similar, with an observed hazard ratio below 1 and the upper limit of the 95 percent confidence interval below 1.4.
Injection site reactions were more common with BIL than insulin glargine.¹^,²^,³

About the Studies
IMAGINE-2
IMAGINE-2 is a Phase III, randomized, 52-week, double-blind, treat-to-target study of BIL (n=1,003) compared to insulin glargine (n=535) in insulin-naïve patients with type 2 diabetes. Patients in both groups had a baseline HbA1c of 8.5 percent. Insulin therapy was taken alone or on a background of oral antihyperglycemic medication.¹

IMAGINE-4
IMAGINE-4 is a Phase III, randomized, 26-week, double-blind, treat-to-target study designed to compare BIL (n=691; baseline HbA1c: 8.4 percent) to insulin glargine (n=678; baseline HbA1c: 8.5 percent) in combination with mealtime insulin in patients with type 2 diabetes.²

IMAGINE-5
IMAGINE-5 is a Phase III, 52-week, open-label, randomized, treat-to-target study designed to evaluate BIL (n=307) compared to insulin glargine (n=159) in patients with type 2 diabetes already taking a basal insulin. Patients in both groups had a baseline HbA1c of 7.4 percent. Insulin was administered alone or in combination with oral antihyperglycemic medications.³

IMAGINE-6
IMAGINE-6 is a Phase III, 26-week, open-label, treat-to-target, randomized study designed to determine if BIL (n=428) was non-inferior to NPH insulin (n=213) in reducing HbA1c when added to pre-study oral agents. Patients in both groups had a baseline HbA1c of 8.5 percent. Insulin was administered alone or in combination with oral antihyperglycemic medications.⁵

About Basal Insulin Peglispro
Basal insulin peglispro (BIL), which was discovered and developed in Lilly Research Laboratories, is currently in Phase III clinical trials and is being studied as a once-daily basal insulin treatment for type 1 and type 2 diabetes. BIL is a hepato-preferential basal insulin. Its activity profile is derived from its reduced effect in peripheral tissue, making it more similar to endogenous insulin compared to other exogenous insulins with a conventional activity profile.

In the clinical trial program to date, consisting of more than 6,000 patients, approximately 3,900 patients have been treated with BIL. In the core Phase III clinical trial program – consisting of seven IMAGINE trials in patients with type 1 and type 2 diabetes – superiority in HbA1c for BIL was seen in five trials conducted against insulin glargine.

About Diabetes
Approximately 29 million Americans⁶ and an estimated 387 million people worldwide have type 1 and type 2 diabetes. Type 2 diabetes is the most common type, accounting for an estimated 90 to 95 percent of all diabetes cases.Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin.⁷

About Lilly Diabetes
Lilly has been a global leader in diabetes care since 1923, when we introduced the world's first commercial insulin. Today we are building upon this heritage by working to meet the diverse needs of people with diabetes and those who care for them. Through research and collaboration, a broad and growing product portfolio and a continued determination to provide real solutions—from medicines to support programs and more—we strive to make life better for all those affected by diabetes around the world. For more information, visit www.lillydiabetes.com.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and newsroom.lilly.com/social-channels.

P-LLY

This press release contains forward-looking statements about an investigational compound basal insulin peglispro, which is currently in development for the treatment of diabetes. It reflects Lilly's current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in the process of drug development and commercialization. There is no guarantee that future study results and patient experience will be consistent with study findings to date or that basal insulin peglispro will receive required regulatory approvals or prove to be commercially successful. For further discussion of these and other risks and uncertainties, please see Lilly's latest Forms 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

¹ Davies M, Russell-Jones D, Selam J, et al. Basal Insulin Peglispro (BIL) is Superior to Insulin Glargine (GL) in Reducing HbA1c at 52 Wks in Insulin-Naïve T2D Patients (Pts) Treated with Oral Antihyperglycemic Medications (OAMs): IMAGINE 2. Abstract 93-OR. Presented at 75^th American Diabetes Association (ADA) Scientific Sessions; June 5-9, 2015; Boston, MA.
² Blevins T, Pieber T, Vega G, et al. Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs Insulin Glargine (GL) and Preprandial Insulin Lispro in a Double-blind Study in Patients (Pts) with Type 2 Diabetes (T2D): IMAGINE 4. Abstract 985-P. Presented at 75th American Diabetes Association (ADA) Scientific Sessions; June 5-9, 2015; Boston, MA.
³ Buse J, Rodbard H, Serrano C, et al. Superior HbA1c Reduction with Basal Insulin Peglispro (BIL) vs Insulin Glargine (GL) Alone or with Oral Antihyperglycemic Medications (OAMs) in T2D Patients (Pts) Previously Treated with Basal Insulin: IMAGINE 5. Abstract 984-P. Presented at 75th American Diabetes Association (ADA) Scientific Sessions; June 5-9, 2015; Boston, MA.
⁴ Standards of Medical Care in Diabetes. Diabetes Care. January 2014. 37:1. Accessed at: http://care.diabetesjournals.org/content/37/Supplement_1/S14.full.
⁵ Grunberger G, Chen L, Rodriguez Á, et al. Basal Insulin Peglispro (BIL) Provides Clinically and Significantly Better HbA1c Control with Less Nocturnal Hypoglycemia than NPH When Used in Combination with Oral Agents in Insulin-Naïve T2D Patients (Pts): IMAGINE 6. Abstract 1004-P. Presented at 75th American Diabetes Association (ADA) Scientific Sessions; June 5-9, 2015; Boston, MA.
⁶ Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014. Available at: http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. October 2014.
⁷ International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, 2014. http://www.idf.org/diabetesatlas/update-2014.