GlaxoSmithKline (GSK) is recruiting participants for a Phase 3 clinical trial to evaluate the effectiveness and safety of Benlysta (belimumab) in combination with rituximab for treating patients with active systemic lupus erythematosus (SLE).
The study will evaluate if the treatment combo is better at sustaining low disease activity or remission than Benlysta alone, while also addressing its safety and tolerability.
It employs a new therapy combination regimen, different from other ongoing trials testing the same combination, and is one of the first assessing efficacy in terms of long-term disease control and remission, after the treatment is stopped for 52 weeks. This could shift the current paradigm of SLE treatment, researchers say.
The trial’s protocol, which describes the design of the study, treatment doses and schedules, and the measures used to assess efficacy and safety, has been published in the report “Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol” in the journal BMJ Open.
Benlysta, the first biological medication approved for SLE, is used as an add-on therapy to standard treatment in patients with active SLE. It is an antibody that blocks the action of the B lymphocyte stimulator (BLyS), a protein essential for the survival of autoantibody-producing B-cells. Consequently, Benlysta reduces B-cell autoimmune responses in people with SLE.
Rituximab (sold under the brand names Rituxan, Truxima, and MabThera) is also an antibody, but it targets the CD20 protein present at the surface of B-cells, leading to their destruction. It has been used to treat some types of cancer involving B-cells and certain autoimmune diseases, but two trials indicate that rituximab alone is ineffective against SLE and lupus nephritis.
Thus, researchers hope the combination of both may be more effective for the treatment of SLE. “The residual disease activity that many patients with SLE experience despite current therapies further justifies the exploration of this novel combination treatment,” they wrote.
To test this hypothesis, GSK — the seller of Benlysta — launched the pivotal Phase 3 trial (NCT03312907), called BLISS-BELIEVE, last year. The study is aimed at determining the superiority of the Benlysta-rituximab combo over Benlysta alone at sustaining disease control or remission in patients with active SLE.
Researchers plan to enroll at least 200 patients at multiple sites worldwide, including in the U.S., Canada, Argentina, Brazil, France, Germany, Russia, Spain, the Netherlands, and Korea.
Patients must be 18 or older, have a clinical diagnosis of SLE according to the American College or Rheumatology criteria, and an SLE Disease Activity Index (SLEDAI-2K) score of six or higher at screening. Patients with severe lupus nephritis or severe active central nervous system lupus will be excluded.
Participants will be randomized into three groups: Benlysta plus placebo for 52 weeks; Benlysta plus a cycle of rituximab (at four and six weeks only) for 52 weeks; or just Benlysta plus standard of care for the total duration of the study, which is 104 weeks.
Benlysta will be administered through under-the-skin injections at 200 mg/week, and rituximab will be given into the vein (intravenous infusions) at a dose of 1,000 mg. Placebo will be matched to rituximab and also given intravenously.
In the first two groups (Benlysta-placebo and Benlysta-rituximab), treatment will be stopped at 52 weeks, after which patients will be followed for another 52 weeks.
In those groups, no immunosuppressant medications will be allowed after four weeks, aside from rituximab. But therapy with antimalarials or non-steroidal anti-inflammatory drugs (NSAIDs) may be used for all participants.
After the first 12 weeks of treatment, corticosteroids will be tapered off in all three groups to reach a prednisone equivalent dose of 5 mg per day or less by 26 weeks.
Patients who don’t respond adequately to the study treatment, fail to taper off corticosteroids or tolerate immunosuppressants, or who require additional therapy will be considered treatment failures. But they may remain in the study if they wish to receive all safety and efficacy assessments through the 104-week period.
The primary objective of the study is the proportion of patients with disease control at 52 weeks. This is defined as a SLEDAI-2K score of two or less, without immunosuppressants and with a low dose of corticosteroids (prednisone equivalent dose of 5 mg per day or less).
Main secondary goals are the proportion of patients with a state of clinical remission at 64 weeks — defined as a SLEDAI-2K score of zero, without immunosuppressants and corticosteroids — and a durable maintenance of disease control, that is, the proportion of patients with disease control at 104 weeks.
Safety will also be assessed, and adverse events will be monitored by physical examination, electrocardiograms (ECG), laboratory tests, neurological assessment, and suicidal risk monitoring.
If the study confirms the researchers’ hypothesis that Benlysta-rituximab therapy is more effective than standard Benlysta care, “this may transform the current treatment paradigm, allowing patients with SLE to discontinue conventional, often toxic medications,” according to them.
Two other Phase 2 trials are evaluating the combo for SLE and lupus nephritis — BEAT Lupus (ISRCTN47873003) and CALIBRATE (NCT02260934) — but use different treatment schedules and different efficacy objectives.
“The 52-week observational, treatment-free phase provides an opportunity to observe if a true disease remission occurs, and allows for the assessment of the durability of any such remission or low disease activity,” the researchers wrote.
“In the treatment of SLE, it is important to balance clinical efficacy and therapy-related toxicity. The unique design of BLISS-BELIEVE will ensure this is assessed through the use of rigorous endpoints (such as clinical remission), and by enabling the termination of belimumab if toxicity is an issue,” they concluded.
Recruitment for BLISS-BELIEVE started in March 2018 and is still open. The study is expected to be completed in June 2021. More information on contacts and locations is available here.