FDA Wants Controlled tQT Study of Long-Acting Exenatide

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.

Emily Hayes is with “The Pink Sheet” which, along with this newspaper, is published by Elsevier.

A long-acting formulation of exenatide has failed to pass muster with the Food and Drug Administration, which is asking the manufacturer Amylin for its most recent clinical trial results and a new QT prolongation analysis.

The FDA issued a complete response letter for the formulation, called Bydureon, the company announced last month. This is the agency's second complete response letter for Bydureon. The first, issued in March, had straightforward requirements, and Amylin responded within a month. However, the new request for a thorough QT prolongation study, which assesses effects on cardiac repolarization, could push the resubmission back by more than a year.

Complete response letters are not made public by the agency, and only the company can reveal contents at its discretion.

The FDA is also asking for results of a recently completed clinical trial, known as DURATION-5, which can be pulled together rapidly.

Amylin initially submitted the Bydureon new drug application (NDA) in May 2009, supported by the DURATION-1 head-to-head study of Bydureon vs. exenatide twice daily (Byetta), safety data from the DURATION-2 trial, and more than 7 years of clinical data.

DURATION-1 comprised 295 patients who did not achieve adequate glucose control either with use of diet and exercise or with oral glucose-lowering drugs. Exenatide once-weekly showed a statistically significant improvement in hemoglobin A_1c of approximately 1.9% from baseline, compared with an improvement of 1.5% for Byetta. About three-fourths of the study subjects who were treated with the long-acting drug achieved a hemoglobin A_1c level of 7% or less.

Regulatory requirements for diabetes drugs have tightened since the Byetta program began, however. In 2008, the FDA issued guidelines requiring manufacturers to monitor potential for cardiovascular events in new diabetes drugs, but this was not an issue for the Bydureon application.

Since 2005, the FDA has required thorough QT prolongation studies to support all NDAs – for all therapeutic categories – and this was at the heart of the FDA's complete response letter. Prolongation of the QT interval may signify increased risk of cardiac arrhythmia, a recurrent safety concern for new drugs.

Amylin executives said that they conducted extensive preclinical and clinical QT prolongation studies on Byetta, but did not find any signs of risk. A QT prolongation study was also conducted to support the Bydureon filing. But the study consisted of administration of a single 10-mcg dose of Byetta in healthy volunteers, and did not have a control arm.

In addition, a QT assessment had been done for Bydureon as part of the DURATION-1 study, including patients with mild to moderate renal impairment, and showed no signs of QT prolongation.

The FDA now wants Amylin to analyze exposures higher than typical therapeutic levels of Bydureon in a controlled thorough QT (tQT) study.

“The complete response letter was the first indication that this was an approvability issue,” Amylin CEO Daniel Bradbury asserted during a conference call with investors and press.

Exenatide is cleared through the kidneys and the chief issue with Bydureon, which underlies regulators' concerns, appears to be that the drug persists in elevated levels in patients with renal impairment.

The agency has requested that the new tQT study include patients with pharmacokinetic concentrations consistent with levels seen in patients with renal impairment.