Product
Tradjenta

Approval Date
May 2, 2011

Release Date
May 23, 2011

Company
Boehringer Ingelheim /Eli Lilly

Class
Dipeptidyl peptidase-4 (DPP-4) inhibitor

Indication
Used along with diet and exercise to lower blood sugar in adults with type 2 diabetes

Active Ingredient
Linagliptin

Agency Roster
Torre Lazur McCann

Marketing Strategy/Execution
Tradjenta was set to be promoted through a shared Lilly-Boehringer sales force, but a court order issued just after launch threatens that plan. Amylin Pharmaceuticals sued Lilly, obtaining a temporary restraining order that bars Lilly from proceeding with its scheme to use the same sales force to sell both Amylin’s Byetta (exanatide)—which the two have been co-promoting under an older pact—and now Tradjenta. The court also enjoined Lilly from disclosing any confidential information about exenatide to any of its sales reps or employees participating in the marketing, promotion or sale of Tradjenta. Lilly said it’s “taking the appropriate steps to comply with the Court’s order, including as it relates to the activities of its sales force, while working to mitigate the impact of any temporary modifications to its diabetes business.” The lawsuit doesn’t make Tradjenta’s climb any easier. BI and Lilly need to differentiate it from competitors (Merck’s Januvia and Bristol-Myers Squibb/AstraZeneca’s Onglyza) by emphasizing the once-daily pill’s profile: single dosage strength for all patients, regardless of kidney or liver impairment, and high potency and selectivity, with only 5% excretion via the kidneys. The companies say that this may translate into potentially important benefits for patients with renal-impairment, which is relatively common among diabetics.

Physician Outlook
BI/Lilly’s Tradjenta will be the third-in-class entry in the DPP-4 category. It remains to be seen if Tradjenta’s unique features are sufficiently compelling benefits for both patients and doctors, and if the brand contributes significantly to overall usage of the class, which has been growing since its introduction in late 2006. At the same time, Tradjenta marks the debut of Lilly and BI in the diabetes oral medications space. It is also one more sign that the insulin manufacturers are moving toward becoming broader “diabetes companies,” offering oral medications, non-insulin injectables, or blood glucose meters, thus serving an even wider range of patients, especially the large Type 2 non-insulin segment.

-Dave Jacobson, Practice Leader, Roper Global Diabetes Group, GfK HealthCare

Recent MM&M Coverage
For Tradjenta, a tough climb, and for Lilly, a vital one

Also in the Pipeline (courtesy of Adis R&D Insight)
No competitor DPP-4 compounds in phase III or pre-registration.

Source: Wolters Kluwer Pharma Solutions

Pharmacology
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.

Clinical Trials
Linagliptin was studied in approximately 3800 patients with type 2 diabetes in 8 double-blind, placebo-controlled safety and efficacy trials.

A total of 730 patients participated in two studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of linagliptin monotherapy. Treatment with linagliptin 5mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo.

A total of 701 patients participated in a 24-week study designed to assess the efficacy of linagliptin in combination with metformin. In combination with metformin, linagliptin provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo.

The efficacy of linagliptin is being evaluated in a 104-week double-blind, glimepiride-¬controlled non-inferiority study in type 2 diabetic patients with insufficient glycemic control despite metformin therapy. After 52 weeks, ¬linagliptin and glimepiride both had reductions from baseline in A1C (-0.4% for linagliptin, -0.6% for glimepiride) from a baseline mean of 7.7%.

A total of 389 patients participated in a 24-week study designed to assess the efficacy of linagliptin in combination with pioglitazone. In initial combination with pioglitazone 30mg, linagliptin 5mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone.

A total of 245 patients participated in an 18-week study designed to assess the efficacy of linagliptin in combination with a sulfonylurea. In combination with a sulfonylurea, linagliptin provided statistically significant improvements in A1C compared with placebo following 18 weeks treatment; the improvements in FPG observed with linagliptin were not statistically significant compared with placebo.

A total of 1058 patients participated in a 24-week study designed to assess the efficacy of linagliptin in combination with a sulfonylurea and metformin. In combination with a sulfonylurea and metformin, linagliptin provided statistically significant improvements in A1C and FPG compared with placebo.

Adverse Reactions
Nasopharyngitis, hypoglycemia, arthralgia, back pain, headache; hypersensitivity reactions (eg, urticaria, angioedema, localized skin exfoliation, bronchial hyperreactivity), myalgia, pancreatitis.

Adults
5mg once daily.

Children
Not Recommended.

Precautions
Not for the treatment of type 1 diabetes or diabetic ketoacidosis. Pregnancy (Cat. B). Nursing mothers.

Interactions
Antagonized by strong P-gp or CYP3A4 inducers (eg, rifampin); consider alternatives to linagliptin if used in combination. Concomitant sulfonylurea: may need lower dose of sulfonylurea to reduce risk of hypoglycemia. Concomitant insulin: not studied.