Edoxaban (Savaysa) should be approved for stroke and systemic embolism prevention in nonvalvular atrial fibrillation, an FDA advisory panel recommended Thursday.

The panel voted 9-1 in favor of approval for that indication despite dissension over what doses to approve and for which patient populations.

While the FDA usually follows the recommendation of its advisory committees, it doesn’t have to do so, and there were clear rifts in opinion within the agency over the drug.

“No FDA speaker has argued for non-approval,” said Martin Rose, MD, JD, cross-discipline team leader in the FDA’s Division of Cardiovascular and Renal Products, in presenting the discussion issues to the panel.

However, almost every other option was proposed.

The Controversy

Drugmaker Daiichi Sankyo requested approval of a 60-mg, once-daily dose as well as a 30-mg, once-daily dose for patients with moderate to severe renal impairment (creatinine clearance 15 to 50 mL/min), body weight under 132 lbs, or on P-glycoprotein inhibitors except amiodarone (Cordarone) as was used in the pivotal ENGAGE-AF trial.

None of the speakers or panelists questioned the main results of the trial, which showed noninferiority of both doses of edoxaban versus well-managed warfarin (Coumadin, median time in therapeutic range 66%).

But differences in efficacy when patients were stratified according to renal function in a post-hoc analysis complicated the assessment and were a major topic of discussion at the committee meeting.

And, for once, it was normal renal function rather than renal impairment being discussed as a potential contraindication.

In ENGAGE-AF, the overall stroke hazard ratio with edoxaban at the higher 60-mg dose versus warfarin was 1.41 (95% confidence interval 0.97-2.05) with normal kidney function but 0.51 (95% CI 0.38-0.69) in the mildly-impaired renal subpopulation.

The same pattern was seen for ischemic stroke: the hazard ratio for stroke was “markedly superior” with 60-mg edoxaban versus warfarin in the mildly impaired renal function group (HR 0.62, 95% 0.43-0.87) but worse with the factor Xa inhibitor in normal renal function (HR 1.58, 95% 1.02-2.45).

The entire trial was likely under-dosed, suggested Melanie Blank, MD, a medical officer, Division of Cardiovascular and Renal Products.

Bumping the dose up to 75 mg for normal renal function patients would have cut the event hazard ratio to an estimated 1.26, and 90 mg was projected to have a hazard ratio of 1.15, Justin Earp, PhD, an FDA pharmacometrics reviewer, reported.

Because about one-third of the study population had normal renal function, “you can imagine the public health impact of approving a dose that’s ineffective,” Blank said.

Mahmoud Ghazzi, MD, PhD, executive vice president and global head of development for Daiichi Sankyo, argued for the company’s perspective that the difference by renal subgroup was not due to inadequate exposure in the renal sufficient group but driven by warfarin variability.

The event rate was nearly identical with 60-mg edoxaban between the renally sufficient and impaired subgroups, at about 1%; whereas warfarin showed a lower rate that varied by renal function and was lower than average in other NOAC trials, company presenters noted.

The slope of the curve for major bleeding versus edoxaban exposure is steeper than the one for event prevention, Glenn Gormley, MD, PhD, global head of research and development at Daiichi Sankyo, pointed out.

Increasing edoxaban exposure by considering a dose over 60 mg will not increase efficacy but will result in more significant bleeds, he argued.

The Options for Approval

The FDA statistical reviewer supported approval with dosing based on the high exposure regimen used in the pivotal ENGAGE-AF trial plus approval of a 15-mg dose for those with severe renal impairment, although not studied.

The FDA clinical reviewer recommended an indication only for patients with renal impairment, 60-mg once daily for those with mild renal impairment. The company should establish the benefits and risks of a higher dose for those with normal renal function in a postmarketing clinical trial.

The FDA pharmacometrics reviewer also proposed approving the 60-mg dose for those with mild renal impairment but also a higher never-tested dose, projected as between 75 and 90 mg based on exposure matching, for those with normal renal function.

The 30-mg tablet seemed off the table as a starting dose, perhaps just to be used for dose reduction.

FDA reviewers pointed out that the lower dose trended toward inferiority, with a hazard ratio of 1.13 for stroke or systemic embolism versus warfarin (P=0.10).

“As there was no marked bleeding excess and bleeding rates were still well below warfarin, it seems hard to support use of a dose less than 60 mg,” the briefing documents noted.

Linda Fried, MD, MPH, a nephrologist and chief of peritoneal dialysis for the VA Pittsburgh Healthcare System, said clinicians use estimated glomerular filtration rate (eGFR), not creatinine clearance.

“None of us use creatinine clearance clinically any more,” she said.

Some FDA staffers called the two well-correlated, suggesting that clinicians could get eGFR on labs to guide the initial dose determination.

However, John Lawrence, PhD, senior statistical reviewer in the FDA’s Division of Biometrics I, argued for approval of only the 60-mg dose in part because of the potential for confusing eGFR and estimated creatinine clearance.

If a higher untested dose is approved, there is a possibility of dosing errors such that people who should be getting the 60 mg dose would get the higher, untested dose instead, he posited.

Involvement of a cross-discipline team leader in an FDA advisory panel meeting is a highly uncommon move, highlighting the discord within the agency.

Norman Stockbridge, MD, PhD, director of the FDA’s Division of Cardiovascular and Renal Products, had predicted from the outset that it would be a tough panel.

“Our internal discussions [at FDA] have been spirited and divergent,” he said in opening the meeting.

If it were not for the proposal by the FDA to increase the dose of edoxaban for patients with normal renal function, “we probably would not be taking the fifth NOAC [novel oral anticoagulant] to committee,” Stockbridge noted.

The Vote

Discussion among the advisory panel members about their “yes” votes on approval of edoxaban largely (five of nine) supported approval of the 60-mg dose for both patients with normal renal function and those with mild renal impairment.

Two favored approval of a dose greater than 60 mg for patients with normal renal function — one saying she would chose non-approval if this was not an option.

Two suggested approval of edoxaban only for patients with mild or moderate renal impairment.

“Most are concerned and very cautious about the idea of using a higher dose empirically based on pharmacokinetics … but it has been pointed out that we could assure we achieved the levels we intended with a relatively [short] study,” said the panel chair, A. Michael Lincoff, MD, of the Cleveland Clinic.

Most of the panelists said they felt some sort of patient education beyond the label regarding a higher than 60-mg dose was feasible but likely to be challenging. A range of dose adjustments could be put in the label, they suggested.

Half of the 10 voting members on the panel said they thought the finding of lower efficacy in the normal renal function group was real, whereas two said it was likely a play of chance.

“There is some division,” the panel chair summarized. “Given the size of the subgroup, the biological plausibility, …and the fact that other NOACs exist, the potential clinical impact if this is real is important.”

Putting an untested higher dose on the market, Stockbridge added, “is not without some precedent. Marketed Pradaxa [dabigatran] results in ~10% higher exposure than you got with the formulation used in the RE-LY study. For at least some of us, the proposal to adjust the dose of edoxaban is not unprecedented.”