Human Genome Sciences, Inc (ROCKVILLE, Maryland) and GlaxoSmithKline PLC (LONDON, UK) announced the initiation of dosing in BLISS-76, one of two pivotal phase III clinical trials of LymphoStat-B® (belimumab, a human monoclonal antibody that blocks the biological activity of B-lymphocyte stimulator, or BLyS®) in patients with active systemic lupus erythematosus (SLE). LymphoStat-B is being developed by HGS and GSK; the two companies entered into a definitive development and commercialization agreement in August 2006.

The LymphoStat-B phase III development program includes two double-blind, placebo-controlled, multicenter superiority trials to evaluate the efficacy and safety of LymphoStat-B plus standard of care versus placebo plus standard of care in the treatment of patients with active SLE. The duration of therapy in BLISS-76 will be 76 weeks, but the data from this first phase III trial will be analyzed after 52 weeks in support of a potential biologics license application (BLA). The second phase III trial, BLISS-52, is expected to begin in the first half of 2007 and will have a 52-week duration.

The primary efficacy endpoint of both studies is the patient response rate at week 52, defined by a reduction from baseline in the SELENA SLEDAI score of at least four points, no worsening in Physician's Global Assessment (with worsening defined as an increase of more than .30 points from baseline), no new BILAG A organ domain score, and no more than 1 new BILAG B organ domain score from baseline. Important secondary endpoints will include the 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 at weeks 40 through 52. Safety and tolerability will be evaluated by an independent data monitoring committee throughout both studies.

In each of the two phase III trials, approximately 810 patients will be enrolled and randomized to one of three treatment groups (1 mg/kg LymphoStat-B, 10 mg/kg LymphoStat-B, or placebo). Patients will be dosed intravenously on days 0, 14, and 28, then every 28 days for the duration of the study. To be eligible for enrollment in the trials, patients must be serologically active with unequivocally positive antinuclear antibody test results assessed at two independent time points (HEp-2 ANA >1:80 and/or anti-dsDNA >30 IU/mL). Background SLE medications must be stable for a period of at least 30 days prior to day 0.

The results of a phase II trial of LymphoStat-B in 449 patients with active SLE showed that LymphoStat-B produced statistically significant reductions in disease activity versus placebo, exhibited clinically relevant biological activity, and appeared generally safe and well tolerated. Findings included a significantly improved response rate among serologically active patients at week 52, as defined by an improvement in SELENA SLEDAI score of 4 points or greater, no BILAG worsening, and no worsening in Physician's Global Assessment (46% for LymphoStat-B versus 29% for placebo, P <.01). This combination of measures is the primary efficacy endpoint in the phase III trials. Among LymphoStat-B patients who chose to participate in an optional 24-week extension phase of the phase II study, the percentage of serologically active SLE patients who achieved the combined response rate increased from 46% at week 52 to 56% at week 76, with no increase in infections or infectious events.

In August 2006, HGS and GSK entered into a definitive codevelopment and cocommercialization agreement under which HGS has responsibility for conducting the LymphoStat-B phase III trials, with assistance from GSK. The companies will share equally in phase III/IV development costs, sales and marketing expenses, and profits of any product commercialized under the agreement.

BLyS is a naturally occurring protein discovered by HGS that is required for the development of B-lymphocyte cells into mature plasma B cells. In lupus, rheumatoid arthritis, and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies. LymphoStat-B was generated by HGS through collaboration with Cambridge Antibody Technology. The agent has received a fast track product designation from the US FDA for its potential use in treating SLE and has been selected for participation in the FDA's Continuous Marketing Application Pilot 2 Program. The FDA has provided a Special Protocol Assessment agreeing to the LymphoStat-B phase III clinical development program in patients with active SLE. Agreement has also been received from the European Agency for the Evaluation of Medicinal Products on the major components of the LymphoStat-B phase III clinical development program, including the primary efficacy endpoint measures, target patient population, and dose selection.

—A. Techman