La Jolla Pharmaceutical Company posted positive 12-month interim antibody data from its ongoing double-blind, placebo-controlled, randomised phase III study of Riquent (abetimus sodium), its drug candidate for systemic lupus erythematosus (SLE or lupus).
Analyses of 12-month interim antibody data in the first 125 patients randomized in the study indicate that for all patients treated with 900 mg, 300 mg, or 100 mg of Riquent per week compared with placebo, there were significantly greater reductions in antibodies to double-stranded DNA.
The data show a dose-response curve for antibody reduction and also show that the 300 mg and 900 mg doses appear to be near the top of the antibody-related dose-response curve, thus supporting the choice of doses for this study. Antibody levels in the placebo-treated group remained around baseline levels throughout the 12 months. The rate at which antibody levels were maximally reduced appeared to be more rapid in the 900 mg dose group than in the 300 mg or the 100 mg dose groups.
"Treatment with all doses of Riquent resulted in significant and sustained reductions in antibodies to dsDNA during the entire one-year treatment period," said Michael Tansey, MD, executive vice president and chief medical officer, La Jolla Pharmaceutical Company. "Equally important, antibody levels observed in the placebo-treated patients remained around or above baseline and did not drift lower over time as occurred in the previous Phase 3 study. These data, which were generated in patients already receiving background immunosuppressive therapy, suggest that the appropriate doses were chosen for the current study and that overall, the 300 mg and 900 mg doses appear to be more effective than the 100 mg dose in the sustained reduction of antibodies to dsDNA".
Each individual dose group was significantly different from placebo. An area under the curve (AUC) analysis, which reflects the effect of the drug on antibody levels over time, showed significantly greater antibody-lowering effects for the 300 mg and 900 mg dose groups compared with the placebo group.
"The 12-month interim antibody data confirm that over the dose range being studied, treatment with Riquent resulted in significant reductions in antibodies to dsDNA," said Richard Furie, MD, chief of Rheumatology, North Shore-Long Island Jewish Health System, and an investigator in the study. "These antibodies are strongly implicated as a primary cause of lupus renal disease, and prior studies have demonstrated that reductions in these antibodies strongly correlate with a reduction in the risk of renal flare."
The AUC analysis provides additional evidence that the higher doses of Riquent suppressed antibodies further than the 100 mg dose group. The proportion of patients achieving a 50 per cent or greater AUC reduction was 0.0 per cent in the placebo and 100 mg groups, 23 per cent in the 300 mg group, and 30 per cent in the 900 mg group.
The 12-month antibody analysis assessed the impact of treatment with Riquent or placebo on antibodies to dsDNA. Antibody levels were measured every two weeks for the first 16 weeks of the study and then monthly for the remaining 36 weeks. All demographics and baseline characteristics were comparable across dosing groups.
The phase III ASPEN trial ("Abetimus Sodium in Patients with a History of Lupus Nephritis") appears to be progressing well; more than 140 sites are active and more than 670 patients have been enrolled. Compliance with weekly visits has been high and the drop-out rate remains low. The Independent Data Monitoring Board (DMB) has completed three reviews of the safety data and has not indicated any safety issues.
The study is an event-driven trial designed to be completed when 128 renal flares have occurred. The current overall renal flare rate is lower than the original trial assumption. As a result, in an effort to shorten the time to achieve the required number of renal flares, the company will continue enrolment beyond the initially targeted 740 patients and extend the treatment period beyond 12 months until the required number of renal flares is achieved. The company now estimates that at least 800 patients will be enrolled in the study. Based on these changes, the company expects the trial to complete in the second half of 2009.
The phase III trial includes two interim efficacy analyses, each with target p values of p < 0.001 and a final p value of p < 0.05. The company has added a futility analysis to each interim efficacy analysis. The interim efficacy analyses have been moved to occur later in the study when a greater number of renal flares will have been observed. As a result, the first interim efficacy analysis is expected to occur around the fourth quarter of 2008, and the second interim efficacy analysis is expected to occur about midway between the first analysis and the expected end of the study.
These modifications to the trial have been discussed with the FDA, and the trial continues to be conducted under the FDA's Special Protocol Assessment.
"The interim results from the ASPEN trial are very encouraging," said Deirdre Gillespie MD, president and CEO of La Jolla Pharmaceutical Company. "At this point in the trial enrolment remains strong, the overall renal flare rate is lower than the original trial assumption, and the safety data appear to be consistent with data from our previous trials. These new data appear to show that the 300 mg and 900 mg doses of Riquent reduce antibodies to dsDNA more than the previously studied 100 mg dose."
Dr. Gillespie added, "We continue to make great progress and believe that the additional refinements to the study will hasten its completion and possibly enable us to observe a definitive outcome earlier."
The phase III study is designed to assess the ability of Riquent treatment to prevent or delay the time to renal flare in lupus patients with a history of renal disease and with antibodies to dsDNA. Equal numbers of patients are being treated with 300 mg per week, 900 mg per week, or placebo. A small number of patients are receiving 100 mg per week. All patients continue to receive standard of care which can include background immunosuppressive therapies.
A lupus renal flare is a potentially life-threatening increase in inflammation of the kidney due to lupus. A renal flare often requires treatment with immunosuppressive agents which can have severe side effects. Riquent is also being studied to assess whether drug treatment decreases proteinuria, as was observed in previous clinical trials. Proteinuria, or protein in the urine, is a common problem for patients with renal disease and is an indicator of renal damage.
Riquent has received an Approvable Letter and Fast Track status from the Food and Drug Administration, and has Orphan Drug designation in the United States and Europe.
Riquent is being developed to specifically treat lupus renal disease by preventing or delaying renal flares, a leading cause of sickness and death in lupus patients.