In the midst of increased regulatory scrutiny involving erythropoiesis-stimulating agents (ESAs), Affymax Inc. is forging ahead with a Phase III program of its anemia drug, Hematide, in chronic renal failure patients.
The Palo Alto, Calif.-based firm expects to begin enrolling patients, both those on dialysis and those who are not, later this year in four concurrent, open-label, randomized trials to evaluate Hematide's safety and efficacy in comparison to marketed ESAs including Amgen Inc.'s top-selling anemia products Aranesp and Epogen. Designed as non-inferiority studies, all four trials will assess safety and the mean change in hemoglobin levels from baseline as the primary endpoints. Though Affymax opted not to proceed with the pivotal program under a special protocol assessment, executives said the company has been in discussions with the FDA and expects to submit finalized study protocols to the agency within the next few weeks.
"We believed our development program [for Hematide] meets the FDA requirements now proposed for new ESAs," Affymax President and CEO Arlene Morris told investors during a conference call, adding that the company's plan is "poised to take advantage of the most current thinking on ESA usage."
A multibillion supportive-care market, the ESA landscape has been under a regulatory microscope for the past several months - particularly the use of ESAs in treating chemotherapy-induced anemia, though the chronic renal failure indication is under close inspection as well - after several studies revealed potential safety concerns, such as thrombosis, cardiovascular events, tumor progression and reduced survival. Earlier this year, an FDA advisory committee recommended curbing the use of ESAs, the Center for Medicare & Medicaid Services (CMS) issued a proposal limiting coverage for ESAs in certain cancers and related neoplastic conditions and Congress continued a long-standing probe into the products. (See BioWorld Today, May 16, 2007.)
It's a market that's "clearly in transition," Morris said, "with questions being raised related to safety, usage and reimbursement of these agents."
In spite of those challenges, Affymax's management said it is confident that, pending successful Phase III data, Hematide could be submitted for approval in 2010 and could hit the market as an ESA product with significant advantages over existing agents. Unlike Aranesp (darbepoetin alfa), Epogen (epoetin alpha) and Procrit (epoetin alfa, marketed by Johnson & Johnson), Affymax's Hematide is not an erythropoietin, or EPO, product. Instead, it's a synthetic peptide-based EPO receptor agonist that is not related to EPO, which might prove to be a safer approach than existing drugs. Hematide also requires less frequent dosing and allows for room-temperature storage.
The company anticipates patient dosing to begin in the fourth quarter, after the FDA's pending cardiorenal panel meeting on ESAs in October. But it's unlikely any recommendations from that panel will affect Hematide's Phase III program, said Robert Naso, executive vice president of research and development. It is expected that the panel meeting will involve recommendations regarding "Phase IV studies for currently marketed products and general safety discussions."
Affymax will remain flexible with its plans, Naso added, though "we've been able to get clear direction" from the FDA on navigating Hematide through the "murky" ESA development process.
Overall, the Phase III program will involve about 2,200 patients. Two trials will include chronic renal failure patients who are not on dialysis to compare Hematide against Aranesp in correcting anemia and maintaining hemoglobin in a corrected range over time, with a hemoglobin target range of 11 g/dL to 12 g/dL. The other two studies will enroll dialysis patients previously treated with EPO and compare Hematide to Epogen or epoetin beta when patients are switched from either of those products to Hematide. The hemoglobin target range for those trials will be 10 g/dL to 12 g/dL. In all four studies, Hematide will be dosed once every four weeks, and each study will continue until all patients have been treated for one year. The program's safety endpoint will be assessed using a composite cardiovascular endpoint from pooled study data.
Concurrent with the Phase III program, Affymax also is testing Hematide in a Phase II study in hemodialysis patients who previously have not received ESA treatment. The company believes, based on discussions with the FDA, that those data would be sufficient for an additional label in ESA-naïve patients, said Anne-Marie Duliege, vice president of clinical, medical and regulatory affairs.
Affymax considers itself fortunate that its business strategy called for pursuing anemia due to chronic renal failure as the lead indication for Hematide, a "somewhat less controversial" indication compared to oncology, Morris said. The drug's development in chemotherapy-induced anemia falls to Affymax's partner, Osaka, Japan-based Takeda Pharmaceutical Co. Ltd., which is in discussions with the FDA and is expected to begin mid-stage trials "as soon as possible." The companies signed the potential $535 million collaboration in June 2006 to co-develop and co-commercialize Hematide in the U.S. Takeda licensed exclusive rights in the rest of the world. (See BioWorld Today, June 28, 2006.)
Anemia due to renal failure makes up about 45 percent of existing ESA sales, while anemia in oncology comprises about 50 percent of the market, Morris said.
To date, Thousand Oaks, Calif.-based Amgen has dominated the ESA market, with worldwide sales of Aranesp in 2006 totaling more than $4 billion, and full-year Epogen sales totaling $661 million. But a number of other products are in development, such as Mircera, a CERA (continuous erythropoietin receptor activator) from Swiss pharma firm F. Hoffmann-La Roche Ltd., which could be close to entering the market. Other drugs in the pipeline include NE-180, a GlycoPEGylated erythropoietin agent from Horsham, Pa.-based Neose Technologies that is in Phase II testing in chemotherapy-induced anemia, and Montreal-based ProMetic Life Science Inc.'s PBI-1402, an oral, synthetic compound that showed positive preliminary results earlier this month in chemotherapy-induced anemia.
Affymax should have sufficient cash to get through the Phase III studies of Hematide in chronic renal failure. The company, which reported a net loss of $7.2 million for the first quarter, had $226.7 million in cash as of March 31. Morris said the firm will provide updated financial guidance once all the final details of the Phase III program are worked out.
Shares of Affymax (NASDAQ:AFFY), which traded as high as $31.48 Monday, closed at $28.04, up $1.15.