Savient has made a clever anticipatory move that could help avoid a "complete response" letter for its BLA for pegloticase, a therapy for treatment-failure gout. The firm submitted major amendments just one month prior to its scheduled advisory committee hearing, including a revised proposed Risk Evaluation and Mitigation Strategy that adds a certification program.

In addition, the amendments change the dosing regimen and provide results of an independent adjudication of cardiovascular data to mitigate concerns about excess CV risk.

FDA is rescheduling the March 5 advisory committee meeting and has extended the user fee date by three months to July 30 in light of those amendments, Savient announced Feb. 12. The BLA, submitted Nov. 30, received priority review for the orphan drug. Savient is also submitting a new brand name, replacing Puricase with Krystexxa .

Increasing The Chance Of A Positive Agency Action

Though the major amendments mean a delay, they also increase the chance of a positive action from FDA once an action comes.

Further evidence of Savient's savvy approach is that the company set up a "BLA Oversight Committee" to address review-related questions from FDA and hired Lee Simon, a former director of the Analgesic, Anti-Inflammatory and Ophthalmologic Drug Products Division, to chair the group. The committee coordinated these steps to save pegloticase.

"We believe the steps we have taken further clarify the favorable risk to benefit profile of pegloticase," Savient President Paul Hamelin noted in a Feb. 12 call with investors. "Securing FDA approval remains our number one priority and we believe making these amendments is an important step toward achieving that goal."

One of the most drastic aspects of the amendments is a revised REMS, which takes the risk management plan beyond the basic levels to include elements to assure safe use. Savient is proposing a performance-linked access program for prescribers, infusion sites and patients. As with Biogen Idec's Tysabri REMS program, TOUCH, Kristexxa providers and patients would have to enroll and get certified in the access program in order to prescribe, administer or receive the drug.

Under the new REMS proposal, a 1,000-patient observational study would be expanded to a voluntary registry of up to 3,000 patients.

While Savient's move certainly postpones FDA action, it could very well give the firm more control over the outcome and perhaps reduce the delay that sponsors of recent BLAs have experienced while coming to an agreement with the agency on a REMS. In the first nine months of the REMS era, several products with extensive REMS have received "complete response" letters at their user fee deadline, giving FDA and sponsors more time to negotiate and fine-tune the REMS proposals (¹ [A#00710020003], p. 14). Centocor's ustekinumab and Ipsen's Dysport are examples.

Amendments Aim To Eliminate Concerns About Fatal CV Events

Savient is also using the major amendments to address a safety concern that could have derailed an approval. Early on, there had been some question whether patients on the drug experienced more cardiovascular events leading to death.

Under the guidance of Simon's BLA Oversight Committee, Savient turned to a panel of external experts to conduct a review of cardiovascular events.

The independent physician panel used APTC (Antiplatelet Trialists' Collaborative) assessment criteria, a standardized approach accepted by FDA as a method of evaluating cardiovascular risk using deaths and non-fatal myocardial infarction or non-fatal stroke events.

The panel's post hoc adjudication of all CV events included in all reports of serious adverse events, infusion reactions and severe infusion reactions from the Phase III trials suggested no imbalance in ischemic events or deaths between the drug-treated and placebo groups.

The post-hoc blinded adjudication and unblinded review of serious infusion reactions found three APTC cardiovascular events in the pegloticase treatment arms and zero in the placebo arms. There were 10 non-APTC cardiovascular events in the treatment arms.

An unblinded adjudication of the open-label extension study found two APTC cardiovascular events and seven non-APTC events.

In addition, a separate external panel of experts performed an all-cause mortality analysis of the Phase III trials and open-label extension study, which confirmed the initial report from October 2008 that there were five deaths in the pegloticase treatment arms of the Phase III trials and open-label extension study compared to three deaths in the placebo arm of the Phase III trials. The analysis found one additional death in the extension study as of Feb. 6, which was of infectious origin.

"Significantly, the data ... confirms that a death imbalance of pegloticase does not exist," according to Simon.

Cleaning Up Dosing, Futility Guidance

While two dosing regimens used in the pivotal trials met their primary endpoints, the firm is now focusing exclusively on an every-two-week dose rather than every four weeks. This dose regimen "presents a much clearer path toward FDA approval due to the significant medically and clinically relevant benefit demonstrated as early as week 13," the firm said in a statement.

Updated immunogenicity analyses included in the amendments came up with new guidance for treatment. The additional review determined that a clinically important immune response in pegloticase can be detected within the first four months of treatment, through monitoring serum uric acid in normal medical practice patterns. A lack of response correlates with high levels of antibody production, which should "enable physicians to more quickly identify patients who should discontinue treatment."

Cowen and Company said that while it was pleased that Savient's amendments provide a better BLA package than what was originally submitted, it still views a positive first-cycle approval as a "toss up." Analyst Rachel McMinn wrote in a Feb. 13 research note: "We continue to view the market opportunity for Krystexxa as small.

Takeda's investigational first-line treatment for gout, febuxostat ( Uloric ) was given a positive recommendation from an FDA advisory committee. The application, however, is still pending; the agency missed its Jan. 18 user fee date (² 'The Pink Sheet' Jan. 26, 2009, In Brief).

If Uloric or Kristexxa is approved, it would be the first gout drug to win FDA approval in more than 40 years. Cardiome's Oxyprim (oxypurinol) never made it past the Arthritis advisory committee and Merck's COX-2 inhibitor Arcoxia' s (etoricoxib) increased cardiovascular risk led FDA to reject the application (³ Also see "Takeda Febuxostat Benefits Outweigh CV Risk; Will Other Gout Drugs Follow?" - Pink Sheet, 1 December, 2008., p. 5).

Savient has the financial wherewithal to bring the investigational drug to market in the U.S., and says it is still open to partnerships, Hamelin noted. The firm has a $65 million burn rate. Hamelin said during the third quarter earnings call that the firm would end the year with about $80 million in cash. Savient reports its year-end earnings in early March.

- Pamela Taulbee (p.taulbee@elsevier.com)

Savient Suggests More Restrictive REMS Plan For Pegloticase In BLA Amendment

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