Tradjenta - Treatment for Type II Diabetes
Linagliptin (BI-1356), which is being marketed under the trade name Tradjenta, is an orally medicated drug for the treatment of type 2 diabetes. It reduces the blood glucose levels in diabetic patients. The drug is being manufactured by Boehringer Ingelhiem in partnership with Eli Lilly.
A marketing authorisation application for the drug was submitted in the US, EU and Japan in the second half of 2010. Tradjenta was approved by the US Food and Drug Administration (FDA) in May 2011 for the treatment of type 2 diabetic patients in the US. It can be used as a single monotherapy or in combination with other drugs like metformin, sulphonylurea and thiazolidinediones.
A regulatory application for the use of the drug in fixed-dose combination with metformin will be submitted in the US, EU and Japan. The company also plans to file regulatory submission for the use of the drug in combination with pioglitazone.
The drug has received a positive response from the European medicine agency (EMA). It was approved by the EMA in August 2011, and will be manufactured and launched under the trade name Trajenta in the EU.
In 2011, linagliptin obtained approval in Japan, where it will be marketed under the trade name Trazenta. The drug has also been approved in Mexico and Brazil under the trade name Trayenta.
Linagliptin was approved by Health Canada in October 2011.
Type 2 diabetes
Diabetes is a chronic illness which results in very high amounts of sugar in the blood. It is usually caused due to lower secretion of insulin in the human body and in people with low activity, poor diet, and obesity. It may also occur due to genetic inheritance.
Type 2 diabetes is the most common type of diabetes. Its symptoms include fatigue, blurred vision, increased appetite and increased thirst.
Tradjenta mechanism of action
Gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the intestine and accumulated in the blood. These hormones enhance the production of insulin from the pancreas and therefore are involved in reducing the sugar levels in the blood. GLP-1 also inhibits the secretion of glucagon, a hormone which increases the glucose secretion in the liver.
Dipeptidyl peptidase-4 (DPP-4), a protein, plays a major role in the degradation of GLP-1 and GIP.
Linagliptin, a DPP-4 inhibitor, has unique properties with high affinity to the DPP-4. It binds to DPP-4 and inhibits its action, thereby increasing the levels and activity of GLP-1 and GIP.
Early clinical trials
Phase I clinical trials were initiated in August 2010 to evaluate the bioavailability of linagliptin in 42 type 2 diabetics. The study was completed by November 2010.
The Phase II trial was initiated in April 2006 to evaluate the safety and efficacy of the drug when taken in combination with metformin.
The study enrolled 336 patients and was completed by August 2007.
Around 112 paediatric type 2I diabetes patients were enrolled in a Phase II trial to determine the safe and effective dose for the treatment. The primary endpoint for the trial is a change in baseline of HbA1c after 12 weeks of treatment. The trial was initiated in April 2011 and will be completed by July 2013.
Phase III trials
Out of the planned 19 Phase III studies, seven have been completed and four have finished the enrolment.
Phase III trials to evaluate linagliptin as a monotherapy were initiated in August 2008 and completed by August 2010. The trials were conducted on 227 type 2 diabetes patients in whom metformin therapy did not show positive effects. It was observed that Linagliptin enhances the glycaemic control in type 2 diabetes patients. The trial data also supports the safety and efficacy of the drug which was already observed in Phase II trials.
Phase III trials were also conducted to evaluate the safety and efficacy of the drug as an add-on therapy to sulphonylurea in patients with uncontrollable type 2 diabetes. A smaller group of patients was enrolled and administered either 5mg of Tradjenta or placebo.
Reduction in HbA 1c from baseline was observed and the drug was found to be safe and efficient, apart from a few side effects that also occurred in the placebo group. Hyperglycemia was not observed.
Phase III trials to evaluate the safety and efficacy of the drug in patients undergoing metformin therapy and yet having lower glycaemic control began in October 2010 and was completed by March 2010.
A Phase III trial was initiated in August 2008 to evaluate the safety and efficacy of the drug as a monotherapy or in combination with pioglitazone.
A total of 2,122 patients were enrolled and were administered either 5mg of linagliptin or 5mg of linagliptin and pioglitazone 30mg.
The trial data was released in December 2010 and the safety and efficacy of the drug was observed.
Phase III trials were also conducted to study the safety and efficacy of the drug in type 2 diabetes patients with severe renal impairments and in those with or without renal impairments.
A Phase III trial named CAROLINA began enrolment in October 2010 and will recruit approximately 6,000 type 2 diabetics. It is being conducted to evaluate the safety and efficacy of the drug on the cardiovascular system. It is expected to be completed by September 2018.
A Phase III trial to compare the effects of linagliptin to those of pioglitazone was initiated in August 2010 and is expected to be completed by August 2013. It is a 30-week study and will enrol 896 patients.
Results from a 102-week Phase III trial were announced in September 2011. The trial established the long-term safety and efficacy of linagliptin and the drug's ability to reduce blood glucose levels in adults with type 2 diabetes.
Around 680 patients are being enrolled for a Phase IV trial to be initiated in November 2011. The trial will evaluate the safety and efficacy of Tradjenta in combination with metformin. The primary endpoint is to achieve a change in baseline in HbA1c after 14 weeks of treatment.
In December 2011, results from a 24-week Phase III trial of linagliptin in combination with metformin were announced. Data from the trial indicated that linagliptin was able to achieve stable glucose control with a low risk of hypoglycaemia.