Washington Editor

Shares of Savient Pharmaceuticals Inc. skyrocketed 56 percent Friday after FDA drug reviewers said in briefing documents that the firm's gout drug Krystexxa (pegloticase) was effective.

However, regulators raised concerns about serious adverse events, including deaths, in patients treated with the drug.

Nonetheless, Wall Street analysts said they expected the FDA Arthritis Drugs Advisory Committee to be swayed at Tuesday's meeting more by Krystexxa's ability to fill an unmet medical need for refractory gout than by its safety issues.

Shares of the East Brunswick, N.J.-based company (NASDAQ:SVNT) closed at $9.26 Friday, a gain of $3.33.

Savient is seeking approval of Krystexxa as a therapy for treatment-failure gout (TFG), an uncommon but severe outcome of progressive gout resulting from demonstrated intolerance of or refractoriness to available therapy to prevent urate crystal deposition by reducing and maintaining serum urate levels in a subsaturating range. TFG is characterized by painful arthritis, chronic arthropathy and destructive deposits of uric acid in tissues, a condition known as tophi.

The disease affects about 50,000 people in the U.S., or about 1 percent of the overall population of patients with gout.

Savient submitted its biologics license application for Krystexxa last October, which was granted a priority review. The FDA also granted it orphan drug designation.

However, the firm submitted a major amendment to its application in February with additional analyses to address adverse cardiovascular events among Krystexxa-treated patients in the firm's Phase III studies, which extended the review time by about three months.

If approved, Krystexxa would be the first uricase product marketed in the U.S. The drug is intended to be infused in doctors' offices, likely by rheumatologists and a subset of nephrologists.

The efficacy of Krystexxa in controlling hyperuricemia and managing the signs and symptoms of TFG was assessed in two randomized, placebo-controlled replicate Phase III trials, known as 405 and 406. The drug was studied at two dosages: 8 mg every two weeks or 8 mg every four weeks.

The primary endpoint of the Phase III trials, which was achieved in both studies, was the proportion of subjects who maintained a plasma uric acid (PUA) concentration below 6 mg/dL for at least 80 percent of the time during months three and six vs. placebo.

The FDA reviewers noted that the magnitude of the decrease in mean PUA levels was greater in both Krystexxa treatment groups compared with placebo. In addition to lower plasma urate levels, patients treated with Krystexxa had a significant reduction in tophi.

The FDA said it is not disputing the efficacy of Krystexxa at the studied dosages, but wants its advisers Tuesday to address the safety concerns identified in the drug's clinical trial program, including adverse cardiovascular events and allergic reactions.

In addition to the 24-week, randomized, blinded safety data generated from studies 405 and 406, Savient submitted safety data generated from the ongoing 48-week open-label extension trial, known as Study 407, and single-dose and 12-week multiple-dosing data from the company's Phase I and Phase II trials.

There were a total of nine deaths reported in the Krystexxa clinical development program, which included three deaths in the placebo group and two deaths that occurred more than 30 days after the last dose of Krystexxa was administered.

Two of the three deaths that occurred in patients receiving Krystexxa every two weeks were due to sudden death in patients with histories of extensive cardiovascular disease, including end-stage cardiomyopathy, congestive heart failure, coronary atherosclerotic heart disease and coronary artery bypass.

Both of those patients had multiple comorbid conditions that increased their risk for developing a fatal cardiovascular event, the FDA reviewers noted. The third subject who died in the Krystexxa every two weeks group was an 89-year-old male nursing home resident who developed an infected perianal decubitus ulcer from sleeping in a chair. Subsequently, he died of sepsis secondary to methicillin-resistant Staphylococcus aureus after refusing additional invasive medical treatment for his infection after failing extensive antibiotic therapy.

Two of the three deaths in the Krystexxa every four weeks group that occurred in patients during the open-label extension also were due to sepsis, the FDA said.

The FDA reviewers noted that most of the patients who developed the serious cardiovascular events had other cardiac risk factors. Therefore, regulators said they were uncertain about whether the adverse events identified during the studies represented a genuine safety signal or were expected adverse events related to underlying risk factors.

It is those concerns that the FDA wants its panel of outside experts to deliberate on at Tuesday's meeting.

Drug regulators said they are seeking advice about whether Savient's studies are sufficient or if further studies are needed before or after approval to evaluate the cardiovascular risks associated with the drug. The agency also wants its advisers to help the FDA identify the appropriate patient population and frequency of patient monitoring if Krystexxa is approved.

Cowen & Co. analyst Eric Schmidt said he believed the latter question was "perhaps key to Krystexxa's approval." Savient's management, he said, "has conveyed to us that they are willing to do what it takes to get Krystexxa approved."

While predicting the ultimate outcome of Tuesday's panel remains difficult, Schmidt said the "relatively benign nature" of the review documents made him "modestly more optimistic" for a recommendation for approval with a stringent risk evaluation and mitigation strategy program.

Leerink Swann analyst Joseph Schwartz said he was encouraged by the roster of the voting members, which is dominated by many of the same rheumatologists who also had voted in favor of Takeda Pharmaceutical Co. Ltd.'s gout drug Uloric (febuxostat).

Due to the rheumatologists' understanding of the unmet medical need in TFG, he surmised that they were likely to vote in favor of Krystexxa.

Should Krystexxa be approved by the FDA, Cowen's Schmidt said, the orphan drug pricing could support a "multi-hundred million dollar opportunity in the U.S."

Published  June 15, 2009