News Release

SAN FRANCISCO, June 14, 2014 /PRNewswire/ -- For the first time today, Eli Lilly and Company (NYSE:LLY) and Boehringer Ingelheim Pharmaceuticals Inc. presented data showing that LY2963016, the alliance's investigational new insulin glargine product, has a similar safety and efficacy profile to currently marketed insulin glargine (Lantus^®).^1,2,3,4,5,6 Results from these Phase I and Phase III studies were presented at the 74^th American Diabetes Association Scientific Sessions in San Francisco.

"Results from six completed clinical trials for this new insulin glargine product showed that it works similarly in the body and produces clinical results similar to Lantus," said Tom Blevins, M.D., endocrinologist with Texas Diabetes & Endocrinology, Austin, TX. "These data are important because Lilly/BI's insulin glargine could serve as an important treatment option in the future when physicians are deciding on an insulin glargine product to help patients meet their treatment goals."

LY2963016 insulin glargine is an investigational basal insulin that is intended to provide long-lasting blood sugar control between meals and at night, an integral part of glycemic control.⁷ It has the same amino acid sequence as Lantus^® and, in most geographic regions, will be submitted for approval as a biosimilar. As the term 'biosimilar' is a regulatory designation, LY2963016 insulin glargine is considered a biosimilar in some regions but not in others, including the United States.

"Lilly and BI are pleased to share our new insulin glargine data with the medical community," said Gwen Krivi, Ph.D., vice president, Lilly Diabetes Development. "Our LY2963016 insulin glargine data package has been submitted for review to several global regulatory agencies, including the U.S., Europe and Japan.  This is one step closer to providing an important insulin glargine option to physicians and patients."

Phase III Study Results
In patients with type 1 and type 2 diabetes, LY2963016 insulin glargine was compared to currently marketed insulin glargine, and both products led to significant decreases in average blood glucose levels (HbA1c). LY2963016 insulin glargine demonstrated non-inferiority compared to marketed insulin glargine, and marketed insulin glargine demonstrated non-inferiority to LY2963016 insulin glargine.^4,5

• Patients with type 1 diabetes had HbA1c reductions of -0.4 percent (LY2963016 insulin glargine) and -0.5 percent (marketed insulin glargine) at 24 weeks, with similar results at 52 weeks (-0.3 percent for both insulin glargine treatments).⁴
• Patients with type 2 diabetes had HbA1c reductions of -1.3 percent in both insulin glargine treatment groups at 24 weeks.⁵

Approximately one-third of patients with type 1 diabetes reached target HbA1c levels of less than 7 percent at 24 weeks with LY2963016 insulin glargine (35 percent) and marketed insulin glargine (32 percent) treatment.⁴ In patients with type 2 diabetes, about half of patients reached these target levels with LY2963016 insulin glargine (49 percent) and marketed insulin glargine (53 percent) treatment.⁵

In patients with type 1 diabetes, the incidence of adverse events at 52 weeks was the same between the two insulin treatments (62 percent). The total average hypoglycemia rate (having symptoms attributable to a low blood sugar level and/or blood glucose less than or equal to 70 mg/dL) at 24 weeks was also similar between LY2963016 insulin glargine and marketed insulin glargine (87 and 89 events/patient/year, respectively).⁴

The frequency of adverse events was similar between the two treatments in patients with type 2 diabetes (52 percent and 48 percent, LY2963016 insulin glargine and marketed insulin glargine, respectively), including the total average hypoglycemia rate (21 vs. 22 events/patient/year, LY2963016 insulin glargine and marketed insulin glargine, respectively).⁵

The Phase III studies also evaluated whether LY2963016 insulin glargine and marketed insulin glargine led to similar development of insulin antibodies and similar effects of immune responses on clinical outcomes. Results showed a similar immunogenicity profile of LY2963016 insulin glargine to marketed insulin glargine.

• The proportion of patients with type 1 diabetes with detectable anti-insulin antibodies was similar between LY2963016 insulin glargine and marketed insulin glargine at baseline (17 percent and 21 percent, respectively) and throughout treatment to 52 weeks (40 percent and 39 percent, respectively).
• The proportion of patients with type 2 diabetes with detectable insulin antibodies was similar between LY2963016 insulin glargine and marketed insulin glargine at baseline (6 percent and 4 percent, respectively) and throughout treatment to 24 weeks (15 percent and 11 percent, respectively).
• Clinical outcomes, including HbA1c levels, basal insulin dose and total hypoglycemia levels, were not affected by whether or not patients developed antibodies response during the study.⁶

Phase I Study Results
Results from Phase I studies showed that LY2963016 insulin glargine and marketed insulin glargine have similar pharmacokinetic (PK) and pharmacodynamic (PD) profiles, meaning that LY2963016 insulin glargine, when injected under the skin, provided similar amounts of insulin in the blood, with similar characteristics and insulin action (how insulin works to control blood glucose levels), compared to marketed insulin glargine.^1,2

• The PK and PD of LY2963016 insulin glargine and the EU- and US-approved versions of insulin glargine were compared in three studies of healthy participants who received 0.5U/kg doses of two different insulin glargine products on two separate occasions. Results showed similar PK and PD properties of LY2963016 insulin glargine and marketed insulin glargine.¹
• The PK and PD properties were similar between LY2963016 insulin glargine and marketed insulin glargine and were consistent across both administered doses in a study comparing the two insulin treatments at two different doses (0.3 and 0.6 U/kg) in healthy participants.²

In these Phase I studies, LY2963016 insulin glargine was well-tolerated, with no safety concerns noted in adverse events, clinical laboratory tests, vital signs or ECG data. The frequency of adverse events reported was similar between the two treatments.^1,2

A further Phase 1 study assessed LY2963016 insulin glargine's duration of action (how long the insulin works to control blood glucose levels) in patients with type 1 diabetes. Results showed that the average duration of action was 24 and 26 hours for LY2963016 insulin glargine and marketed insulin glargine, respectively. LY2963016 insulin glargine was well-tolerated, with no safety concerns noted in adverse events, clinical laboratory tests, vital signs or ECG data. The frequency of adverse events reported was similar between the two treatments.³

About the Phase III Studies
ELEMENT-1 was a 52-week Phase III, randomized, open-label study of 535 patients with type 1 diabetes. The primary objective was to evaluate whether LY2963016 insulin glargine was non-inferior to currently marketed insulin glargine in reducing average blood sugar levels (HbA1c) from baseline at 24 weeks. Patients in the study were also treated with mealtime insulin. Anti-insulin glargine antibodies were also measured to determine the immunogenicity profile of LY2963016 insulin glargine.^4,6

ELEMENT-2 was a 24-week Phase III, randomized, double-blind study of 756 patients with type 2 diabetes. The primary objective was to evaluate whether LY2963016 insulin glargine was non-inferior to currently marketed insulin glargine in reducing average blood sugar levels (HbA1c) from baseline at 24 weeks in patients inadequately controlled on two or more oral diabetes medicines. Anti-insulin glargine antibodies were also measured to determine the immunogenicity profile of LY2963016 insulin glargine.^5,6

About the Phase I Studies
The pharmacokinetics (PK) and pharmacodynamics (PD) of LY2963016 insulin glargine and the EU- and US-approved versions of insulin glargine were evaluated in three Phase I, randomized, double-blind, cross-over replicate euglycemic clamp studies in healthy participants. There was a minimum washout period of one week to separate the doses. Blood samples were collected pre-dose and up to 24 hours post-dose to assess PK, and a euglycemic clamp lasting up to 24 hours was used to assess PD after administration of study insulin at 0.5 U/kg.¹

The PK and PD of two other doses of LY2963016 insulin glargine and currently marketed insulin glargine (0.3 and 0.6 U/kg) were also assessed in a Phase I, randomized, subject- and investigator-blinded study. Twenty-four healthy participants randomly received one of four dosing sequences, receiving a total of two doses each of LY2963016 insulin glargine and currently marketed insulin glargine. There was a minimum washout period of six days to separate the doses. Blood samples were collected pre-dose and up to 24 hours post-dose to assess PK, and a euglycemic clamp lasting up to 24 hours was used to assess PD.²

A Phase I randomized, double-blind, crossover glucose clamp study assessed the duration of action of LY2963016 insulin glargine and currently marketed insulin glargine in 20 fasted males with type 1 diabetes. Patients received single administered doses of 0.3 U/kg of both insulin treatments, with a minimum washout period of one week to separate the doses. Duration of action was assessed with a euglycemic clamp lasting up to 42 hours post-dose.³

About Diabetes
Approximately 24.4 million Americans and an estimated 382 million people worldwide have type 1 or type 2 diabetes. Type 2 diabetes is the most common type, accounting for an estimated 85 to 95 percent of all diabetes cases. Diabetes is a chronic condition that occurs when the body either does not properly produce, or use, the hormone insulin.⁸

Boehringer Ingelheim and Eli Lilly and Company
In January 2011, Boehringer Ingelheim and Eli Lilly and Company announced an alliance in diabetes that centers on compounds representing several of the largest diabetes treatment classes. The alliance leverages the strengths of two of the world's leading pharmaceutical companies. By joining forces, the companies demonstrate commitment in the care of patients with diabetes and stand together to focus on patient needs. Find out more about the alliance at www.boehringer-ingelheim.com or www.lilly.com.

About Boehringer Ingelheim Pharmaceuticals Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates and more than 47,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales.

For more information please visit http://www.us.boehringer-ingelheim.com  

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 http://newsroom.lilly.com/social-channels.

P-LLY

This press release contains forward-looking statements about LY2963016 (new insulin glargine product) an investigational compound that is being studied for type 1 and type 2 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 new insulin glargine product will receive 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.

CONTACT:

Tammy Hull 
Communications Manager
Lilly Diabetes
Email: hullta@lilly.com 
Phone: (317) 651-9116

Shirley Johnson, Public Relations
Boehringer Ingelheim Pharmaceuticals, Inc.
Email: shirley.johnson@boehringer-ingelheim.com 
Phone: (203) 448-1893

REFERENCES

1. Linnebjerg, H, Lam E, et al. Comparative Pharmacokinetics (PK) and Pharmacodynamics (PD) of LY2963016 Insulin Glargine and EU- and US-approved Versions of Lantus® Insulin Glargine in Healthy Subjects. Abstract 889-P. Presented at 74^thAmerican Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
2. Zhang, X, Lam, E, et al. Comparative Pharmacokinetics and Pharmacodynamics of Two Insulin Glargine Products, LY2963016 and Lantus®, in Healthy Subjects at Two Dose Levels. Abstract 890-P. Presented at 74th American Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
3. Heise, T, Zhang, X, et al. Duration of Action of 2 Insulin Glargine Products, LY2963016 and Lantus®, in Subjects with Type 1 Diabetes Mellitus (T1DM). Abstract 891-P. Presented at 74th American Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
4. Blevins, T, Dahl, D, et al. Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1D: the ELEMENT 1 Study. Abstract 69-OR. Presented at 74th American Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
5. Rosenstock, J, Hollander, P, et al. Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T2D: the ELEMENT 2 Study. Abstract 64-OR. Presented at 74th American Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
6. Deeg, M, Ilag, L, et al. Evaluation of Immunogenicity of LY2963016 Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1D or T2D. Abstract 70-OR. Presented at 74th American Diabetes Association (ADA) Scientific Sessions; June 13-17, 2014; San Francisco, CA.
7. Inzucchi SE, Bergenstal RM, et al. Management of Hyperglycemia inType2 Diabetes: A Patient-Centered Approach. Diabetes Care June 2012 vol. 35 no. 6 1364-1379.
8. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas.

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SOURCE Eli Lilly and Company; Boehringer Ingelheim