Taking another step down the long and often bumpy road of lupus drug development, Human Genome Sciences Inc. and partner GlaxoSmithKline plc initiated the first of two pivotal Phase III trials with LymphoStat-B (belimumab).

Rockville, Md.-based HGS had planned to start the trial in the fourth quarter of 2006, but UBS Securities LLC analyst Annabel Samimy said in a report that the delay was "not meaningful," especially given the lengthy timelines projected for the Phase III program.

HGS' vice president of corporate communications, Jerry Parrott, declined to speculate how long the trial would take to enroll or when data would be available other than to say that the company expects to enroll "throughout 2007 and into 2008." Samimy predicts a late 2009/early 2010 regulatory filing based on the initiation of the second trial in the first half of 2007 and completion of enrollment in both trials in 2008.

The double-blind, placebo-controlled, multicenter Phase III trials will each enroll about 810 systemic lupus erythematosus (SLE) patients, all of whom are serologically active as determined by a standard set of blood tests used in lupus diagnosis. Patients will receive the best available care plus 1 mg/kg of LymphoStat-B, 10 mg/kg of LymphoStat-B, or placebo for 76 weeks in the ongoing trial and 52 weeks in the second trial. The primary endpoint of the current trial is patient response rate at week 52 as defined by a composite of various measures, and secondary endpoints include patient response rate at week 76, quality-of-life data and other factors. (See BioWorld Today, Aug. 10, 2006.)

The design was agreed to under a special protocol assessment by the FDA and reviewed by the European Agency for the Evaluation of Medicinal Products. It incorporates several lessons learned during a previous Phase II trial. That trial missed its primary endpoints of reducing lupus signs and symptoms at week 24 and increasing the time to first lupus flare over a 52-week period. (See BioWorld Today, Oct. 6, 2005.)

Yet a closer look at the Phase II data revealed a statistically significant improvement in lupus signs and symptoms at week 52 for serologically active patients. Those three factors - a primary endpoint of improving lupus signs and symptoms, analysis at week 52 and inclusion of only serologically active patients - form the basis for the Phase III design.

To measure the improvement in lupus signs and symptoms, HGS will use a composite endpoint comprised of measures that worked well in the Phase II trial including: 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. The SELENA SLEDAI test measures multiple factors associated with lupus, while the PGA assesses disease worsening, and the BILAG monitors organ involvement.

As for the timeline, analysis of the primary endpoint in the Phase III trial will occur at week 52. The 52-week data could support the filing of a biologic license application, Parrott said, but the trial will continue on to week 76 to determine any extended benefits resulting from LymphoStat-B's "durable clinical and biological effects." That aspect of the trial is based on results of a 24-week extension to the Phase II study, in which the percentage of serologically active patients who achieved the composite response rate increased from 46 percent to 56 percent.

And regarding the patient population, 72 percent of patients in the Phase II trial were classified as serologically active, but that figure will increase to 100 percent in the Phase III due to the change in inclusion criteria.

As evidenced by the complexity of the trial, lupus is a difficult indication for drug developers. Despite the fact that the disease affects an estimated 1.5 million Americans, no new drugs have been approved by the FDA in nearly 40 years. The current treatments include "heavy steroids, anticancer drugs, antimalarial compounds and many other drugs with very difficult side effects," Parrott said.

The lack of approvals is not for lack of trying, but setbacks are an all too common occurrence.

Last fall, the FDA placed a clinical hold on a Phase III trial of epratuzumab (UCB SA and Immunomedics Inc.) in lupus. And both Genelabs Technologies Inc.'s Prestara (prasterone) and La Jolla Pharmaceuticals Co.'s Riquent (abetimus sodium) have suffered through Phase III disappointments and approvable letters.

But "everyone is learning from everyone else," Parrott said. He added that although there is not an established regulatory pathway in lupus, pharmaceutical companies are starting to understand how to apply tests that were "designed for use in a clinical setting" to determine whether or not a drug is having an effect.

Moving forward in the field, La Jolla is back on track with another Phase III Riquent trial, and Aspreva Pharmaceuticals Corp. also is conducting a Phase III with CellCept (mycophenolate mofetil) in lupus nephritis. Additionally, Rituxan (rituximab, Genentech Inc. and Biogen Idec Inc.) is in Phase III for lupus.

In addition to the now-ongoing Phase III trial with LymphoStat-B, HGS is conducting the first of two planned pivotal Phase III trials with Albuferon (albumin-interferon alpha 2b), its hepatitis C virus drug partnered with Basel, Switzerland-based Novartis AG. (See BioWorld Today, Oct. 5, 2006.)

Shares of HGS (NASDAQ:HGSI) closed at $11.58 on Tuesday, up 4 cents.