La Jolla Pharmaceutical Co. is moving ahead with a post-marketing study of Riquent, though the lupus drug has yet to receive approval.

The San Diego-based company expects to receive a regulatory decision on or about Oct. 16. But in the meantime, it reached a written agreement with the FDA's Cardio-Renal Division to fully conduct a Phase IV trial if Riquent (abetimus sodium) is authorized under the agency's accelerated approval regulation, also called Subpart H. The trial protocol was evaluated and agreed to under the special protocol assessment process, and La Jolla expects to screen the first patient this month.

"This is an important step forward for us," Andrew Wiseman, the company's senior director of business development, told BioWorld Today. "Our decision to move forward with the trial, based on our discussions with the division, shows a strong commitment from the company that we're serious about this trial, prepared to move forward aggressively and meet the FDA halfway, so to speak."

The company stressed that though it began the trial, there can be no guarantee that the FDA will approve Riquent, under Subpart H or otherwise. Under Subpart H, a post-marketing trial to confirm clinical benefit may begin prior to approval, but would not need to be completed until after approval.

The Phase IV study is designed to address shortcomings in two Phase III studies on which Riquent's new drug application is based. La Jolla filed the NDA in December, about seven months after receiving FDA guidance to submit the application despite missed endpoints. (See BioWorld Today, May 6, 2003.)

Those data, reported a year and a half ago, revealed that Riquent did not demonstrate a statistically significant increase in time to renal flare, the studies' primary endpoint. While reaction to the news resulted in a 72.5 percent stock drop, the company noted that there were fewer renal flares and major systemic lupus erythematosus flares in Riquent-treated patients, compared to placebo-treated patients, suggesting a benefit to patients if antibodies to double-stranded DNA are reduced, as such antibodies are associated with renal flares. (See BioWorld Today, Feb. 19, 2003.)

"We got what we thought were very compelling data from the last trial," said Wiseman, who also co-founded the company. "The antibodies were reduced by the drug, [while the presence of] antibodies strongly correlated with the risk of renal flare. Patients with sustained reductions had much better outcomes."

To be eligible for the Phase IV study, patients must have antibodies to double-stranded DNA and a history of renal flare within the last four years, and must not be receiving high doses of immunosuppressive agents. The trial's primary endpoint also is time to renal flare, and it is expected to take several years to complete.

"There are a variety of enhancements in this trial compared to the previous ones," Wiseman said. "These are a variety of things we are doing to try to maximize and increase our chances for success."

In testing lupus patients with a history of renal disease, the double-blinded study will assess a higher dose of Riquent, 300 mg, in addition to further evaluating the 100-mg dose studied in the Phase III trials. Patients will be randomized to receive either placebo, 100 mg of Riquent per week, 300 mg of the drug per week, or 100 mg of Riquent per week shifting to 300 mg at week 12.

It will include about twice as many patients, as enrollment will increase to between 500 and 600 patients. The study also will last longer, providing a 12-month treatment duration for each patient, and offer more control of immunosuppressive drugs at baseline.

Immunosuppressive treatment is common in the estimated 1 million lupus patients in the U.S. and Europe. Wiseman said about 90 percent are women, and half of all lupus patients have active renal disease that leads to death. Therapy through off-label use of high-dose prednisone, an immunosuppressant agent, and cyclophosphamide, a chemotherapy agent, can lead to equally troubling side effects.

But Riquent, which is designed to solely target immune system cells that produce double-stranded DNA, appears to avoid such problems. Delivered weekly via intravenous infusion, it has a one-hour half-life.

"Given where we are to date in our clinical development, there are no side effects at all attributed to the drug," Wiseman said. "It has been very well tolerated in all clinical studies."

Should the FDA approve Riquent in two months, he said La Jolla probably would launch the drug about six months later. The company is not yet building inventory or a sales force, though Wiseman noted that its pilot manufacturing facility would be sufficient to produce doses for 20,000 patients per year. It plans to sell the drug through an internal sales force in the U.S., while likely seeking a marketing partner in Europe. Near the end of the year, Wiseman said, La Jolla expects to submit an application for the drug's approval in Europe.

Outside of its Riquent drug development activities, the company has a Phase I/II program to test the use of LJP 1082 for antibody-mediated thrombosis. But Wiseman said its development remains at a bit of a standstill, as nearly all resources are focused on Riquent.

On Monday, La Jolla Pharmaceutical's stock (NASDAQ:LJPC) jumped 20.7 percent, a gain of 44 cents, to close at $2.57.