Human Genome Sciences, Inc. (HGSI) has received a special protocol assessment from the US Food and Drug Administration (FDA), agreeing to the company's phase 3 clinical development programme for LymphoStat-B (belimumab) in patients with active Systemic Lupus Erythematosus (SLE).
"We expect to initiate phase 3 trials of LymphoStat-B before the end of 2006, and we look forward to moving ahead with site activation and patient enrolment," said H. Thomas Watkins, president and chief executive officer, HGSI. "We believe that this novel antibody drug will become an important therapeutic option for patients suffering from SLE. For HGSI, advancing LymphoStat-B to late-stage clinical study is a critically important step in our evolution into a commercial organization."
The design of the LymphoStat-B phase 3 development programme includes a primary efficacy endpoint that emerged directly from the previously reported results of a phase 2 clinical trials. The endpoint is a combined patient response rate that includes elements of the Selena Sledai And Bilag disease activity indices, as well as the physician's global assessment index. These measures are well known to clinical investigators with experience in SLE. The phase 2 results show that LymphoStat-B, as measured by this combined response rate, significantly reduced disease activity in serologically active patients, the population in which the drug will be studied in phase 3.
"The positive special protocol assessment received from the FDA leaves no issues outstanding, and provides HGSI with confidence that the design of the phase 3 development program and clinical trials for LymphoStat-B is suitable to support regulatory approval," said Sally D. Bolmer, Ph.D., R.A.C., senior vice president, regulatory affairs. "The SPA agreement is the latest example of the positive and productive interactions HGSI has had with the FDA throughout the development of this product, including its designation as a fast track product, its selection for participation in the pilot 2 program, and the excellent guidance we received during our end-of-phase 2 meeting."
HGSI previously disclosed that it has met with the European Agency for the Evaluation of Medicinal Products (EMEA), and has received agreement on the major components of the phase 3 clinical development programs, including the primary efficacy endpoint, target patient population, and dose selection. HGSI designed the program in collaboration with GSK and leading international SLE experts.
Under the terms of the special protocol assessment, and as proposed by HGSI, the phase 3 development program for LymphoStat-B will include two double-blind, placebo-controlled, multi-centre phase 3 superiority trials, Bliss-52 and Bliss-76, which will 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 primary efficacy endpoint of both studies is the patient response rate at Week 52, as defined by: a reduction from baseline in the Selena Sledai score of at least 4 points; no worsening in physician's global assessment (with worsening defined as an increase in PGA of more than 0.30 points from baseline); no new Bilag A organ domain score and no more than 1 new Bilag B organ domain score from baseline.
The total duration of the two studies will differ, at 52 weeks (Bliss-52) and 76 weeks (Bliss-76), respectively. Aside from duration, the two studies will have similar protocols. In each of the two-phase 3 trials, approximately 810 patients will be enrolled and randomised to 1 of 3 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. To be eligible for enrolment in the phase 3 trials, patients must be serologically active, with unequivocal antinuclear antibody (ANA) test results assessed at 2 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.
Important secondary endpoints will include the patient response rate at weeks 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 40-52. Safety and tolerability will be evaluated by an independent data monitoring committee throughout both studies.
Improved response rate among seropositive patients at weeks 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 per cent for LymphoStat-B versus 29 per cent for placebo). This combination of measures is the primary efficacy endpoint in the phase 3 program design.
LymphoStat-B is a human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein discovered by HGSI that is required for the development of B-lymphocyte cells into mature plasma B cells. Plasma B cells produce antibodies, the body's first line of defence against infection. In lupus, rheumatoid arthritis, and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies - antibodies that attack and destroy the bodies own healthy tissues. The presence of autoantibodies appears to correlate with disease severity. Pre clinical and clinical studies demonstrate that B-cell antagonists can reduce auto antibody levels and help control autoimmune disease activity.
LymphoStat-B is a HGSI drug, created through a collaboration with Cambridge antibody technology. It has received a fast track product designation from the FDA for its potential use in treating SLE and has been selected for participation in the FDA's continuous marketing application pilot 2 program.
Systemic lupus erythematosus (SLE) is a chronic, life-threatening disease. The Lupus Foundation of America estimates that approximately 1.5 million Americans suffer from various forms of lupus, including SLE. More than 300,000 people are afflicted with SLE in the United States alone. Lupus can occur at any age, but appears mostly in young people between the ages of fifteen and forty-five. About 90 per cent of the individuals diagnosed with lupus are women. African-American women are about three times more likely to develop lupus, and it is also more common in Hispanic, Asian and American Indian women. Symptoms may include extreme fatigue, painful and swollen joints, unexplained fever, skin rash, and kidney problems. Lupus can lead to arthritis, kidney failure, heart and lung inflammation, central nervous system abnormalities, inflammation of the blood vessels, and blood disorders.