Will ESA Spectre Haunt Affymax Anemia Drug?
By Mari Serebrov
The ghost of anemia drugs present could haunt Affymax Inc.'s peginesatide injection when it comes up for discussion Wednesday at a meeting of the FDA's Oncologic Drugs Advisory Committee (ODAC).
Raising the spectre of older erythropoiesis-stimulating agents (ESA) with their risks of serious cardiac events, the FDA is asking the committee to consider those safety issues in determining whether peginesatide (formerly Hematide) has a favorable benefit/risk profile.
Once-monthly peginesatide demonstrated noninferiority to approved ESAs, dosed one to three times a week, in four clinical trials involving anemic patients with chronic kidney disease, but questions about safety materialized in the two trials that evaluated the drug in those patients who weren't on dialysis.
"The major concern raised by these trials is the uncertainty about the evidence for the safety of peginesatide," the FDA said in its briefing document for the ODAC meeting.
Because of the trial results, which are shaded by the broader safety concerns of ESAs in general, Affymax is requesting an indication in dialysis patients only. It also is proposing a risk management plan that would limit distribution of its synthetic peptide-based ESA to dialysis centers to minimize the potential for off-label use.
The Palo Alto, Calif.-based company and its Japanese partner Takeda Pharmaceutical Co. Ltd. had originally hoped to file for approval in dialysis and nondialysis patients simultaneously, but those plans changed upon evaluating the data from the two PEARL studies that compared peginesatide with Amgen Inc.'s Aranesp (darbepoetin alfa) in nondialysis patients. (See BioWorld Today, June 22, 2010, and June 1, 2011.)
While the trials hit their primary endpoints by establishing noninferiority in maintaining hemoglobin levels, the PEARL data revealed a higher incidence of cardiovascular death, unstable angina and arrhythmia, as well as more peginesatide patients requiring red blood cell transfusions.
Investors were spooked by the results – shares of Affymax (NASDAQ:AFFY) took a beating when the data were released in June 2010, dropping from $23.90 to $7.08 in one day.
But the FDA is uncertain about their significance. Subsequently, it's asking ODAC to weigh in on whether peginesatide has a favorable benefit/risk profile for use in nondialysis, as well as dialysis, patients.
The agency noted that the PEARL trials "had an imbalance in safety outcomes that was significantly different by the applicant's planned analysis" of the composite safety endpoint, defined as the first occurrence of death, stroke or a variety of major cardiac events.
When assessed by major adverse cardiac events and with a 95 percent confidence interval, the FDA said, the difference, "while still numerically unfavorable to peginesatide, was not significantly different in these two trials.
"There were baseline imbalances unfavorable to peginesatide in the proportion of patients with diabetes, peripheral vascular disease and coronary heart disease," the agency added. "Whether the difference in safety outcomes can be attributed to the baseline demographic imbalances is uncertain."
However, the agency didn't see an imbalance in the proportion of patients with abnormal laboratory results, such as leukocytosis or thrombocytosis, which could potentially increase the risk of thrombosis.
The only ESAs approved in the U.S. – epoetin alfa (Epogen and Procrit) and darbepoetin alfa – are indicated for patients with and without dialysis. Their safety profiles have changed significantly over the years.
In pushing for approval of peginesatide, Affymax builds a case for another ESA option, noting that the FDA-approved ESAs are all manufactured by one company. (Although Procrit is marketed by Janssen Products LP, it's manufactured by Amgen.)
It also touted the benefits of a monthly injection as opposed to multiple injections each week and peginesatide's potential to avoid pure red cell aplasia, a rare, life-threatening complication of protein-based ESAs.
Recognizing the ESA apparitions that will hover over the meeting, Piper Jaffray analyst M. Ian Somaiya expects ODAC to recommend approval. But ultimately, "the key question is if the FDA believes another anemia drug is necessary given the prior safety risk in the category," he said. He set a $10 price target for Affymax.
The company's shares soared more than 25 percent Monday morning, to $6.59, after the FDA released its briefing documents for the meeting.
By closing Monday, they had settled at $6.26, up $1.01, or 19.2 percent. Volume also was up, with 4.2 million shares traded, the second highest level since the week the disappointing PEARL results were released.
In addition to peginesatide, the FDA is asking ODAC to discuss the safety profile for Pfizer Inc.'s Inlyta (axitinib) tablets, intended as a second-line treatment of patients with advanced renal cell carcinoma.
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