Washington Editor

The FDA rejected Savient Pharmaceuticals Inc.'s Krystexxa (pegloticase), a pegylated porcine uricase enzyme, as a therapy for treatment-failure gout, despite an overwhelming recommendation from the agency's panel of outside advisers, sending the firm's shares spiraling 18 percent Monday.

The East Brunswick, N.J.-based company's shares (NASDAQ:SVNT) had lost as much as $5.59 Monday before regaining some ground to close at $12.80, a loss of $2.79.

In a complete response letter, the FDA said the company's comparability data submitted for the material produced using the firm's commercial manufacturing process, which had been changed from that used for its Phase III trial and open-label extension study, was not adequate.

While preparing for the validation of its manufacturing process, Savient made a process modification, altering the PEG concentration in the pegylation process to "provide a higher level of assurance that the final product would target the middle of the proposed range of that product's specification," Savient President Paul Hamelin explained Monday during a conference call with investors and analysts.

The company pursued a chemistry, manufacturing and controls comparability program designed to demonstrate that the validation batches manufactured for the process change were comparable to the Phase III trial material, Hamelin said.

But the FDA concluded that there were insufficient data for regulators to determine that the material produced with the process change was representative of the Phase III material that Savient used to establish efficacy and safety in its trials, he said.

Regulators gave the company two options: revert to and validate the manufacturing process used to produce Krystexxa for the Phase III trials, or conduct additional comparability trials to support the use of the drug manufactured using the proposed commercial manufacturing process.

Hamelin told investors and analysts that the company plans to revert to its earlier manufacturing process, with revalidation of three batches, which it expects to have completed by October.

"We believe that this will take significantly less time than generating the additional comparability clinical study required by the other alternative," he said.

Hamelin said the company anticipates resubmitting its application in early 2010.

The complete response letter also stated that the FDA has determined that a risk evaluation and mitigation strategy plan was necessary for Krystexxa, including a patient-friendly medication guide and a communication plan directed to health care providers likely to prescribe the drug.

In addition, the REMS must include an assessment plan to monitor and assess the effectiveness of the medication guide and communication plan in communicating to patients and physicians an understanding of the risks of Krystexxa treatment.

The lack of a requirement for a registration program, which was recommended by several panelists at the June 16 meeting of the FDA's Arthritis Drugs Advisory Committee, is a "significant positive factor," with "fewer hoops to jump through" for patients and prescribers, said Leerink Swann analyst Joseph Schwartz.

Panelists at the June meeting voted 14 to 1 in favor of approval of Krystexxa, despite concerns about adverse cardiovascular events identified during clinical testing and the prevalence of underlying cardiac disease in gout patients. (See BioWorld Today, June 17, 2009.)

Savient plans to seek a "Type A" meeting with the FDA, which would gain the firm a face-to-face discussion within 30 days of the agency's receipt of the company's request, Hamelin said.

"We have every intention to work closely and collaboratively" with the FDA, he said.

Hamelin said his company was not waiting for the FDA meeting to begin action on addressing some of the concerns regulators raised in the complete response letter.

"We have already begun addressing a number of the outstanding issues contained in the complete response letter, and several of these issues were previously discussed and identified by the FDA as potential post-approval commitments, if we had been approved by the Aug. 1 PDUFA date," Hamelin said.

In light of Krystexxa's delay to market, Savient plans to "significantly slow down or virtually stop" its prelaunch commercialization activities to conserve cash and to focus its efforts on addressing the remaining open issues identified in the complete response letter, Hamelin explained.

"We feel very comfortable that we can be able to efficiently and quickly resume these activities at the appropriate time after addressing the issues raised by the FDA in the complete response letter," he said.

Krystexxa was anticipated to be the second new drug approved in 45 years for gout before Savient's hopes were dashed by the FDA complete response letter.

Takeda Pharmaceutical Co. Ltd.'s Uloric (febuxostat), a xanthine oxidase inhibitor, was approved in February.

Before that, the mainstay of gout treatment was allopurinol, which is used to lower uric acid. However, that drug has several adverse events associated with it, including gastrointestinal, hepatic, renal, hematological and skin toxicities, which occur in about 20 percent of patients on the drug.

Other firms, such as San Diego-based Ardea Biosciences Inc., also are working in the gout space.

Ardea recently entered a Phase IIb trial of its gout small molecule RDEA594, which it expects to complete by the end of this year and move into Phase III by mid-2010, said CEO Barry Quart.

Theoretically, Quart told BioWorld Today, Ardea's entire Phase III program could be concluded by the end of 2011 if all goes smoothly.

RDEA594 was discovered more as a fluke than by intent.

During the development of its HIV infection drug, RDEA806, the company noticed that the only side effect was that the compound lowered uric acid levels.

"So we didn't set out to identify a uric acid lowering agent, biology designed it for us," Quart said.