Washington Editor

Late-stage lupus drug development is moving forward for Human Genome Sciences Inc. and La Jolla Pharmaceutical Co., both of which unveiled Phase III plans Wednesday.

HGS will begin patient enrollment over the next few months in a two-trial pivotal program to test systemic lupus erythematosus patients' response to LymphoStat-B (belimumab), a drug designed to treat an underlying cause of the chronic, life-threatening disease. Already the Rockville, Md.-based company has received positive feedback on the studies' major components from U.S. and European regulatory authorities, including a primary efficacy endpoint based on an innovative composite measure, and plans are in the works to soon submit the final Phase III designs to the FDA for a special protocol assessment.

"We are really breaking new ground here," HGS President and CEO H. Thomas Watkins said in a conference call. "There's not been a lot of work done successfully in the lupus field."

Indeed, the Lupus Foundation of America said no new drug has been approved by the FDA for nearly 40 years, even though estimates indicate that about 1.5 million Americans suffer from various forms of the disease. Of that total, between 200,000 and 500,000 have systemic lupus erythematosus.

The company has proposed two double-blind, multicenter superiority trials to compare LymphoStat-B plus standard of care, to placebo plus standard of care.

The studies' primary efficacy endpoint is patient response rate after a year based on multiple components: at least a four-point reduction from baseline in a score of the Safety of Estrogen in Lupus Erythematosus National Assessment Trial (SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), no worsening in Physician's Global Assessment, no new British Isles Lupus Assessment Group (BILAG) disease activity index A organ domain score and no more than one new BILAG B organ domain score from baseline.

"They're blazing a new path here, using this new composite primary endpoint," said Christopher Raymond, an analyst with Robert W. Baird & Co. in Chicago. "But you would expect that, given how difficult lupus has been."

HGS designed the program in collaboration with GlaxoSmithKline plc, its partner for the program, and will receive a $24 million payment this quarter in consideration of GSK's rights to LymphoStat-B. That money will help defray some of the Phase III costs, which HGS is shouldering.

One study will last a year and the other for six more months, but aside from their different durations, they have similar protocols. Each will enroll about 810 patients and randomize them to one of three treatment groups: 1 mg/kg LymphoStat-B, 10 mg/kg LymphoStat-B or placebo. That design, Raymond told BioWorld Today, "nails it." The data are "going to be robust."

They will be dosed intravenously three times in the first four weeks, then once every four weeks thereafter. Secondary endpoints include patient response rate at week 76, the SF-36 Health Survey physical component summary score, fatigue measures and the percentage of patients with reduction from baseline in average prednisone dose between the 40th and 52nd weeks. An independent data monitoring committee will evaluate safety and tolerability throughout both studies.

LymphoStat-B, a human monoclonal antibody, inhibits the biological activity of B-lymphocyte stimulator, or BLyS, a naturally occurring protein required for B-lymphocyte cells to develop into mature plasma B cells and produce antibodies. In lupus and other autoimmune diseases, elevated BLyS levels are believed to contribute to the production of autoantibodies, and their presence appears to correlate with disease severity.

Should LymphoStat-B receive approval down the road, HGS and London-based GSK would share equally in Phase III/IV costs, sales and marketing expenses, as well as profits.

Raymond pointed to LymphoStat-B's importance to HGS' future, labeling it "their second major" product, along with Albuferon (albumin-interferon alpha 2b) for chronic hepatitis C, the centerpiece of a potential $550 million deal with Basel, Switzerland-based Novartis AG. But LymphoStat-B remains some distance from market - Raymond estimated that enrollment could last into early 2008, after which follow-up evaluations and regulatory filings could take more than another year. Approval might not come until 2010.

HGS created LymphoStat-B in collaboration with Cambridge Antibody Technology plc, of Cambridge, UK. It has since received fast-track designation from the FDA for lupus and also is part of the agency's Continuous Marketing Application Pilot 2 program.

Simultaneous with its drug development news, HGS reported a $61.3 million net loss for the quarter ended June 30, or 47 cents per share, in accordance with GAAP. Raymond indicated that the company's earnings were in line with expectations, and offered "kudos" for its recent deals and real estate maneuverings that expanded cash and investments to $784.7 million, including $59.1 million of restricted investments. "Their ability to work within the asset base that they have is impressive," he said.

On Wednesday, shares in HGS (NASDAQ:HGSI) gained 6 cents to close at $9.78.

Phase III Riquent Trial Running Again

La Jolla Pharmaceutical reactivated enrollment in its latest study of Riquent (abetimus sodium), designed to treat a symptom of lupus, with recruitment expected to wrap up in the second half of next year.

The global trial has been tailored to better demonstrate Riquent's ability to treat renal flares, an indication for which the product received an approvable letter requesting better efficacy than a prior Phase III study showed. The expanding trial would appear to satisfy that requirement. (See BioWorld Today, Oct. 18, 2004.)

To date, the San Diego company has activated 30 sites: 21 in the U.S. and nine in Asia. It is being expanded to Europe and Mexico to include a total of nearly 600 patients, double the number included in the previous Phase III to increase the likelihood of seeing a statistically significant difference between the Riquent- and placebo-treated groups. Also, twice as many patients will be treated with Riquent as placebo.

A double-blind study, it will employ two doses of Riquent that are higher than those used in past studies, 300 mg and 900 mg. The previously used 100-mg dose also will be used, although research indicates that higher Riquent doses might further reduce levels of antibodies to double-stranded DNA that are believed to cause renal flares, potentially increasing the drug's clinical benefit.

Its primary endpoint, a measure of time to renal flare, no longer includes hematuria as a component because it can be less specific and occur due to conditions other than a renal flare. Also, the current trial will evaluate treatment for a year, less time than the previous Phase III trial's length of up to 22 months.

In addition, study entry criteria will further restrict the use of immunosuppressive agents, which previously could have reduced the renal flare rate, especially in placebo patients. Lastly, the trial will involve more nephrology clinics to increase the number of patients with impaired renal function, the group that showed increased benefit from Riquent treatment.

On Wednesday, La Jolla's stock (NASDAQ:LJPC) gained 9 cents to close at $3.61.