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SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.
At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.
The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).
However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m2); but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m2), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.
FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.
The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.
They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function
“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”
The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”
Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.
The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.
The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.
If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe.
SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.
At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.
The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).
However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m2); but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m2), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.
FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.
The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.
They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function
“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”
The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”
Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.
The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.
The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.
If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe.
SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.
At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.
The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).
However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m2); but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m2), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.
FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.
The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.
They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function
“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”
The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”
Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.
The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.
The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.
If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe.
AT AN FDA ADVISORY COMMITTEE MEETING
