The results confirm a prior analysis of the trial showing that treatment with Rituxan failed to reach its primary endpoint, a superior clinical response compared to placebo.
Now, a reanalysis of the results, using newly developed tools to measure patients’ clinical response, confirms that a 52-week treatment with Rituxan is not effective in SLE patients without kidney disease.
The study, “Rituximab in moderate to severe non-renal systemic lupus erythematosus: a reanalysis of the EXPLORER study,” was published in the journal Annals of the Rheumatic Diseases.
Rituxan (also sold under the brand MabThera and as the biosimilars Truxima and Zytux) is an antibody that targets B-cells, a subtype of immune cells that play a primary role in the progression of lupus.
In people with lupus, B-cells produce auto-reactive antibodies, which target the body’s own cells rather than protect against disease-causing organisms such as bacteria or viruses.
Given its inhibitory effect over B-cells, Rituxan has been investigated as a possible treatment for SLE patients. However, while observational and open-label clinical trials have reported a positive effect for the drug, two large Phase 2 and 3 trials — the EXPLORER (NCT00137969) and LUNAR (NCT00282347) studies — failed to demonstrate its benefit over placebo.
A possible explanation for these latter failures was the poor sensitivity of the criteria used at the time to assess patients’ clinical response.
In the EXPLORER study, SLE patients’ response was measured using the British Isles Lupus Assessment Group (BILAG) scores.
With the availability of new SLE clinical response criteria, researchers sought to reanalyze the EXPLORER study using four new scores: the SLE Response Index-4 (SRI-4), a modified SRI-4 (including reduction of corticosteroid to 10 mg a day or less), a modified BILAG-based Clinical Lupus Assessment (mBICLA), and a modified Lupus Low Disease Activity Score (mLLDAS).
The EXPLORER trial was a randomized, double-blind, placebo-controlled trial that took place at centers in the U.S. and Canada. It was sponsored by Genentech, a member of the Roche Group and the manufacturer of Rituxan.
The study included 257 patients with moderate to severe active SLE, without kidney involvement.
Patients were randomized to receive either intravenous Rituxan (1,000 mg), or placebo, in addition to a maintenance regimen with immunosuppressants and oral prednisone (a corticosteroid).
The reanalysis showed that at 52 weeks, Rituxan failed to show a statistically significant efficacy over placebo for all four recently developed response criteria. Consistent with this observation, there was no difference in corticosteroid use between the Rituxan- and placebo-treated groups.
Data also was analyzed in groups for each of the four response criteria.
If the clinical response was measured by SRI-4 only, patients without mucocutaneous involvement (no manifestations in the skin or mucus membranes) at the study’s start were more likely to benefit from Rituxan — 10.2 times the chance of those who received placebo.
In addition, there was a trend, although not statistically significant, for people with blood involvement under treatment with Rituxan to have a better response in terms of SRI-4.
It was not possible to determine the magnitude of Rituxan’s effect — how much it improved the clinical responses compared with placebo — in patients with inflammation of the blood vessels (vasculitis). But it was possible to determine that at week 52, Rituxan improved SRI-4 response to some degree in 39.3% of those patients.
Other clinically relevant patient groups, such as those under treatment with the antimalarial hydroxychloroquine or immunosuppressant medications, with prior corticosteroid use, or smokers did not show any significant improvements under Rituxan.
Many theories have been proposed as to why Rituxan failed to demonstrate significant efficacy in randomized controlled trials.
Possible explanations include the use of “high-dose corticosteroids, associated immunosuppressive medication, inappropriate endpoints and patient heterogeneity,” researchers stated.
“In the current reanalysis, we retrospectively took into account these factors but failed to demonstrate [Rituxan] superiority over placebo,” investigators said.
“Future SLE trials might need to better select their patients [e.g., using gene activity profile], reduce or avoid steroid bursts at inclusion and concomitant immunosuppressive medications to overcome the difficulties of demonstrating efficacy in SLE,” they said.
Nevertheless, an important observation of the study was the consistency between old and new SLE response criteria, the team noted.