Staff Writer

Full rejoicing must wait until November, when the second - and somewhat riskier - lupus trial will report data, but Human Genome Sciences Inc. meanwhile has wowed investors with positive top-line results from a Phase III study with Benlysta (belimumab).

The Rockville, Md.-based firm's stock (NASDAQ:HGSI) closed Monday at $12.51, up $9.19, or 277 percent.

"I wouldn't say we were not expecting it, but we were pleased," said Gary Gilkeson, lupus researcher at the Medical University of South Carolina. "We've all had patients who have done well [on Benlysta]." Gilkeson is the principal investigator at MUSC in the second Phase III trial.

Known as BLISS-52, the trial met its primary endpoint with statistical significance, 57.6 percent (p = 0.0006), at the 10 mg/kg dose vs. placebo. The 1 mg/kg dose gained a 51.7 percent patient response rate (p = 0.011), while the placebo's response rate was 43.6 percent.

The composite endpoint was fairly complicated, which is one element that had given analysts pause regarding BLISS-52's probable outcome. Combined in the endpoint are four measures: a reduction from baseline in the SELENA SLEDAI score of at least four points; no worsening in PGA; no new BILAG-A organ domain score; and no more than one new BILAG-B organ domain score from baseline. SELENA SLEDAI measures multiple factors associated with lupus, while the PGA assesses disease worsening, and the BILAG monitors organ involvement.

HGS said full results will be unveiled later this year at the American College of Rheumatology meeting, slated for mid-October in Philadelphia. The solid numbers from BLISS-52 (conducted under a special protocol assessment) are bolstered by four-year follow-up data disclosed in June from a Phase II study. BLISS-52 - the largest lupus trial in history, with 867 subjects - enrolled in Asia, South America and Eastern Europe. (See BioWorld Today, June 12, 2009.)

Certain to pique interest as well are the data due in November from the second, identically designed Phase III study, BLISS-76, which enrolled 826 patients in North America and Europe. The failed Phase II trial with Benlysta (formerly known as LymphoStat-B) also drew its patient base from North America. (See BioWorld Today, Oct. 6, 2005.)

Gilkeson said conductors of the Phase II trial were not stringent enough about patients allowed into the study. There's no single diagnostic test for lupus, but the anti-nuclear antibody test often is used to screen patients, and 25 percent of those let into the Phase II trial did not test positive for ANAs, he said.

The BLISS trials should do better, "based on cleaning it up and bigger numbers" of patients, Gilkeson said.

Favorable results from BLISS-76 could position HGS to file a biologics license application in the first half of 2010, with approval possible late that year. Even without the BLISS-76 results, BLISS-52's outcome along with encouraging, four-year follow-up data from the Phase II trial may be sufficient for the FDA to grant approval, at least in the view of Leerink Swann analyst Joseph P. Schwartz.

HGS' partnership with GSK, which provided $26 million up front, calls for the pair to split development costs, marketing expenses and profits from Benlysta, and does not include milestone payments. Long-sought success with the lupus drug could inspire takeover talks by GSK. (See BioWorld Today, July 8, 2005.)

Analyst Christopher J. Raymond with Robert Baird & Co. conceded in a Monday research report that his firm "missed the opportunity" and did not upgrade the rating on HGS' shares before the trading surge on BLISS-52's data, but Raymond was hardly alone. Not many on Wall Street had given Benlysta better than a 50-50 chance of success, and some guesses were even more pessimistic.

Benlysta, if approved, could garner global sales of $2.3 billion by 2012 and peak sales of $5.4 billion, estimated Piper Jaffray analyst Edward A. Tenthoff in a July 20 research report.

The trial names for Benlysta derive from the mechanism of action of the compound, which antagonizes BLyS, a protein involved in maturation of B lymphocytes. High BLyS levels apparently boost autoantibodies that attack healthy tissues in lupus.

Validation of that approach could mean good things for Darmstadt, Germany-based Merck KGaA's late-stage lupus candidate atacicept, also a binding antagonist of BLyS, though the Merck drug also inhibits other B cell growth factors and cytokines. Atacicept, a soluble receptor that links the extracellular domain of the TACI receptor to the Fc portion of human immunoglobulin, came to Merck by way of a licensing deal with Zymogenetics Inc., due for royalties on atacicept.

Shares of Seattle-based Zymogenetics (NASDAQ:ZGEN) rose 19.5 percent Monday, or 85 cents, to close at $5.22. But huge investor enthusiasm may not be warranted, given the somewhat different mechanism of action, and difference in study designs between the composite-endpoint BLISS trials and the Phase II/III trials with atacicept, which simply measure the occurrence of disease flares.

"Atacicept actually is a more potent inhibitor of the pathway than [Benlysta]," Gilkeson said. "This is one of the things we've been curious about - if you block too much, is that worse than blocking it a little bit? By blocking the pathway completely you may have more side effects, more infections," the primary bane of lupus candidates thus far.

Many have failed. The field of recent casualties includes La Jolla Pharmaceutical Co.'s Riquent (abetimus), along with Rituxan (rituximab, Genentech Inc. and Biogen Idec Inc.), Prestara (prasterone, Genelabs Technologies Inc.) and CellCept (oral mycophenolate mofetil, Aspreva Pharmaceuticals Corp.).

"The challenge has been the heterogeneity of the disease," Gilkeson said. "You're looking at people with arthritis, skin rash and kidney disease." Plus, lupus waxes and wanes. "All the trial results are a one-time assessment comparing the baseline to six months or one year," so they depend on the patient's condition at a specific, limited time, he noted.

Published  July 21, 2009