Nesina®

Partnership with Takeda Pharmaceuticals

Diabetes is a chronic illness of epidemic proportions, affecting 270 million people worldwide.  By 2013, it is estimated that 552 million people worldwide will have diabetes [1].  Alogliptin is a member of an important class of oral drugs known as DPP-4 inhibitors that are used to treat type 2 diabetes (T2D) in conjunction with diet and exercise.  DPP-4 inhibitors slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), which play a major role in regulating blood glucose levels and have the potential to improve pancreatic beta-cell function.

Alogliptin is approved for once-daily treatment of T2D in a number of major markets including the US, Japan, China, Korea (Nesina®) and in the EU (Vipidia™).  Alogliptin is the only DPP-4 inhibitor that is available in fixed-dose combination with Actos® (marketed as Oseni® in the US).  It is also available as a fixed-dose combination with metformin (marketed as Kazano® in the US).  Alogliptin was developed by and is marketed by Takeda Pharmaceuticals.  As a result of our partnership with Takeda, Furiex has rights to royalties and sales-based milestones from Takeda for the sale of alogliptin and its combination products in all marketed territories.

Approximately 9,000 patients with T2D have been treated with alogliptin in 14 randomized, double-blind, controlled clinical trials.  Alogliptin has been demonstrated to be safe and effective as an add-on to diet and exercise both as monotherapy, or in combination with other diabetes therapies, including insulin, Actos, metformin, or sulfonylureas.  Alogliptin is the first and only DPP-4 inhibitor to demonstrate proven cardiovascular (CV) safety in T2D with recent acute coronary syndrome [2].

Two key studies for alogliptin were completed in 2013:

The ENDURE study (Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Subjects With Type 2 Diabetes Mellitus), which was performed to support EU registrations, demonstrated that 25 mg alogliptin in addition to metformin, offers superior durability of glycemic control, more favorable effects on glycohemoglobin, and no negative impact on weights compared to a sulphonylurea plus metformin.  There was a significantly lower incidence of hypoglycemia (including severe hypoglycemia) with patients in the alogliptin group compared to the glipizide group [3].

THE EXAMINE study (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome), which compared alogliptin to standard of care, is the first cardiovascular outcomes study of patients with T2D at high-risk for major adverse cardiac events (MACE) due to a recent acute coronary syndrome.  These data, which are published in the New England Journal of Medicine [2], demonstrate that alogliptin does not increase CV risk in T2D patients at high-risk for MACE events compared with placebo, when added to usual therapy.  The trial met its primary objective of demonstrating non-inferiority of CV risk based on a primary composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke.  Rates of hypoglycemia, malignancy, pancreatitis, serum aminotransferase elevations and of serious adverse events were similar for the alogliptin and placebo groups.

Alogliptin clinical trials can be accessed at www.clinicaltrials.gov.

References

1.  International Diabetes Federation. IDF Diabetes Atlas, 5th edition. Brussels, Belgium. Last accessed Oct 2013, available at: http://www.idf.org/diabetesatlas.

2.  White WB, Cannon CP, Heller SR, Nissen SE, et al, for the EXAMINE Investigators. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes.   New England Journal of Medicine. 2013; 369:1327-1335.     http://www.nejm.org/doi/full/10.1056/NEJMoa1305889.

3.  Del Prata S, Camisasca R, et al. Durability of the Efficacy and Safety of Alogliptin Compared to Glipizide Over 2 Years When Used in Combination with Metformin.  Abstract.  73rd Scientific Sessions, 2013 American Diabetes Association.  http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=0687e7c8-c97d-442b-92ec-ae505e051854&cKey=f9db1f36-e10e-4182-a6d5-175c4983ba21&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d.

Indications

Indications for NESINA (alogliptin) 6.25 mg, 12.5 mg, and 25 mg Tablets; KAZANO (alogliptin and metformin HCl) 12.5 mg/500 mg and 12.5 mg/1000 mg Tablets; and OSENI (alogliptin and pioglitazone) 25 mg/15 mg, 25 mg/30 mg, 25 mg/45 mg, 12.5 mg/15 mg, 12.5 mg/30 mg, and 12.5 mg/45 mg Tablets

NESINA, KAZANO, and OSENI are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

NESINA, KAZANO, and OSENI are not for treatment of type 1 diabetes or diabetic ketoacidosis.

Important Safety Information

WARNING: CONGESTIVE HEART FAILURE—for OSENI
Thiazolidinediones, including pioglitazone, which is a component of OSENI, cause or exacerbate congestive heart failure in some patients. After initiation of OSENI, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in OSENI must be considered. OSENI is not recommended in patients with symptomatic heart failure. Initiation of OSENI in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS—for KAZANO
Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, KAZANO should be discontinued and the patient hospitalized immediately.

NESINA, KAZANO, and OSENI are contraindicated in patients with a history of serious hypersensitivity reaction to any of the components of these products, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions. KAZANO is contraindicated in patients with renal impairment (e.g., serum creatinine levels ?1.5 mg/dL for men, ?1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarctions, and septicemia. KAZANO is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. Do not initiate OSENI in patients with established NYHA Class III or IV heart failure.

Warnings and Precautions—for KAZANO

Lactic acidosis: Warn against excessive alcohol intake. KAZANO is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue in patients undergoing radiologic studies with intravascular iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. Lactic acidosis due to metformin accumulation during therapy is fatal in approximately 50% of cases. The risk increases in patients with renal impairment, congestive heart failure requiring drug treatment, and with increasing age.

Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Warnings and Precautions—for OSENI

Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms.

Edema: Dose-related edema may occur. Use with caution in patients with edema.

Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health.

Bladder cancer: Data suggest an increased risk of bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Do not use OSENI in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.

Macular edema: Macular edema has been reported in some patients taking pioglitazone. Recommend regular eye exams. Instruct patients to report any visual changes promptly.

Ovulation: Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women.

Warnings and Precautions—for NESINA, KAZANO, and OSENI

Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA, KAZANO, or OSENI.

Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema or severe cutaneous adverse reactions. In such cases, promptly discontinue NESINA, KAZANO, or OSENI, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. Use caution in a patient with a history of angioedema with another DPP-4i because it is unknown whether such patients will be predisposed to angioedema.

Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended. If liver injury is detected, promptly interrupt NESINA, KAZANO, or OSENI and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA, KAZANO, or OSENI if liver injury is confirmed and no alternate etiology can be found. Use with caution in patients with liver disease.

Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with NESINA, KAZANO, or OSENI.

Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA, KAZANO, OSENI, or any other anti-diabetic drug.

Adverse Reactions

Most common adverse reactions (>4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) were nasopharyngitis (4.4%), headache (4.2%), and upper respiratory tract infection (4.2%).

Most common adverse reactions (?4% of patients treated with co-administration of alogliptin and metformin) were upper respiratory tract infection (8%), nasopharyngitis (6.8%), diarrhea (5.5%), hypertension (5.5%), headache (5.3%), back pain (4.3%), and urinary tract infection (4.2%).

Most common adverse reactions (?4% of patients treated with co-administration of alogliptin and pioglitazone) were nasopharyngitis (4.9%), back pain (4.2%), and upper respiratory tract infection (4.1%).

Drug Interactions

Use of OSENI with CYP2C8 strong inhibitors (e.g., gemfibrozil) will, or inducers (e.g., rifampin) may, require dose adjustment.

Cationic drugs eliminated by renal tubular secretion should be used with caution if taken with KAZANO.

Please see accompanying Full Prescribing Information, including Medication Guide, for NESINA.

Please see accompanying Full Prescribing Information, including Medication Guide, for KAZANO.

Please see accompanying Full Prescribing Information, including Medication Guide, for OSENI.