Erythropoiesis-stimulating agents marketed by Amgen and Johnson & Johnson now confront possible restrictions on use in patients with anemia due to chronic kidney disease, as FDA and CMS gear up for separate advisory panel reviews of emerging safety data on such treatment.

Use of ESAs, which include Amgen's Aranesp (darbepoetin alfa) and Procrit (epoetin alfa) , marketed by J&J but produced by Amgen, in oncology patients has already been sharply curtailed by FDA and CMS due to safety concerns. After more than two years of dealing with the oncology setting, the focus has shifted to how to manage the risks in the renal disease market.

The present situation underscores the question of whether Amgen and J&J could have mitigated these setbacks if they had already closed with FDA on a Risk Evaluation and Mitigation Strategy, the post-marketing drug safety program authorized by the FDA Amendments Act of 2007.

FDA and CMS do not work in tandem on post-marketing safety issues, but the presence of a REMS might have helped protect public perceptions of the company in the midst of adverse safety findings. And in fact, in the context of its platelet producer Nplate , (romiplostim), Amgen has previously argued a REMS should help preclude the need for Medicare coverage restrictions (¹ Also see "Nplate REMS Precludes Need For Medicare Coverage Restrictions – Amgen" - Pink Sheet, 13 October, 2008.).

FDA has been in negotiations with Amgen and J&J over a REMS program for the drugs in oncology and non-oncology uses for about two years. An Amgen spokesperson says "we anticipate our discussions with the FDA will be brought to a close in the near future."

March Could Be Rough Month For ESAs

FDA announced plans for an advisory committee review to reevaluate the use of ESAs in CKD in an editorial posted online by the New England Journal of Medicine Jan. 7.

The article was authored by Office of Drug Evaluation I Deputy Director Ellis Unger and three other agency officials, including Robert Temple, now deputy director for clinical science in the Center for Drug Evaluation and Research.

The meeting is expected to focus on labeling and dosing in the pre-dialysis setting, but may also refer to use of ESAs in dialysis patients. Amgen markets epoetin alfa as Epogen exclusively for those patients.

The agency did not release a specific date for the meeting. However, the next meeting of its Cardiovascular and Renal Drugs Advisory Committee, which will handle the review, is March 1, according to a tentative agency schedule.

That same month - on March 24 - CMS has asked its Medicare Evidence Development and Coverage Advisory Commission to review the extent and appropriateness of use of the drugs in CKD.

FDA's disclosure that it plans an advisory panel review is a new development. However, CMS started down the road toward reconsidering its Medicare Part B payment policy for ESAs in CKD some time ago.

CMS announced the MedCAC meeting last summer ² Also see "MedCAC To Examine ESAs In Chronic Kidney Disease, Pharmacogenomic Testing In Cancer" - Pink Sheet, 21 August, 2009.). And the summer before, the agency signaled its concern with the issue when it proposed opening a national coverage determination for ESAs in CKD and end-stage renal disease ³ Also see "As Amgen Drops Some ESA “Overhangs,” New Payment Threat Appears" - Pink Sheet, 4 August, 2008.).

FDA's NEJM editorial followed the late October release of negative clinical trial results from Amgen. Amgen's Trial to Reduce Cardiovascular Events with Aranesp Therapy, known as TREAT, was originally aimed at broadening the indications for Aranesp to include a reduction in cardiovascular disease in diabetics with chronic kidney disease.

The study also aimed to establish the benefit in pre-dialysis patients. Results were announced Oct. 30 at the American Society for Nephrology annual meeting in San Diego, and simultaneously published in the New England Journal of Medicine.

However, the trial instead found an increased rate of stroke and thromboembolic events in treated patients, and limited benefits in terms of quality of life and reduced rates of transfusions. The study also found a higher incidence of cancer recurrence among some patients.

The TREAT results support earlier findings that using ESAs in renal patients to attain hemoglobin levels of 13 g per deciliter or more is harmful, Unger et. al state. "Clearly more conservative hemoglobin targets - well below 12 g per deciliter - should be evaluated."

Updated Label Warnings For ESAs

Following the release of the TREAT study in December Amgen and J&J updated the warnings sections in labeling for Aranesp and Epogen/Procrit to reinforce the currently approved recommendation that the drug be used to maintain hemoglobin levels within the range of 10 to 12 g/dL.

Current professional recommendations have been more permissive. In 2007, National Kidney Foundation guidelines for treating anemia in chronic kidney disease set hemoglobin targets at 11 to 12 g/dL. And the guidelines warned physicians to begin cutting back on treatment only when hemoglobin levels exceeded 13 g/dL.

Limitations On Use In CKD

FDA raises the possibility that it may bar use of the drugs in renal disease except to avoid the need for transfusions, generally when hemoglobin levels drop below 10 g/dL.

The article states the accumulated safety data raise "major concerns regarding the use of ESAs to increase hemoglobin concentrations in patients with chronic kidney disease above a level intended solely to avert the need for erythrocyte transfusions."

The impact of limiting ESA use to only avoiding transfusions is unclear. A recent analysis by Medco found that, while use of the drugs in the renal and "non-renal" populations declined from 2006 through 2008 as safety concerns arose, there was no corresponding increase in the need for transfusions.

Medco noted that further study is planned to assess the impact of reduced ESA usage on emergency room visits and hospitalizations for these patients. The analysis was based on drug and medical claims data in the pharmacy benefit manager's national integrated database.

In its NEJM article, FDA acknowledges there may be some benefit in raising hemoglobin slightly. However, the agency emphasizes that randomized clinical trials are needed to establish the optimal hemoglobin target.

The agency also discusses the need for clinical data to establish an ESA dosing algorithm and monitoring approach in chronic kidney disease patients.

FDA says it has long been concerned that "the risk of cardiovascular events is related to the rapidity of the increase in hemoglobin concentration, as well as to oscillations in hemoglobin levels and overshoots of the target concentration; aggressive dosing can cause all these effects."

Renal expert Daniel Coyne, Washington University, St. Louis, Mo., noted in an e-mail that "the editorial makes a strong case [that] the risk may be about doses of ESA and partly or entirely unrelated to" hemoglobin level or changes.

He suggests that a "subtext" of the editorial is that "the doses of ESA approved for use should be evaluated and possibly rolled back." Coyne also pointed out that in both Europe and Japan, mean ESA doses are well below those used in the U.S.

Challenges For ESA Competitors

In an investor note on the TREAT study, Bernstein analyst Geoffrey Porges suggests the results may create obstacles for upcoming branded competitors to Amgen.

"It is clear that these findings will lead experts, regulators and companies to endorse tighter monitoring of [hemoglobin] levels, and frequent adjustments to ESA dose to avoid high dosing and rapid fluctuations in [hemoglobin] level," he writes.

"Such close titration will probably only be achievable with short-acting ESA products, such as Epogen, Porges said.

In contrast, longer acting products, such as Roche's Mircera (eopetin beta) and Takeda/Affymax's investigational Hematide, are more difficult to titrate and "could cause [hemoglobin] levels to rise faster, or more uncontrollably, than products where the dose can be increased or decreased once or twice weekly." Mircera is scheduled to launch in 2013 (⁴ 'The Pink Sheet,' Dec. 23, 2009). Hematide is in Phase III.

- Cathy Kelly ( ⁵ c.kelly@elsevier.com )

ESAs In Renal Use May Face New FDA, CMS Constraints; REMS Still In Progress

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