Biologicals for the treatment of SLE – new hope or expensive drugs without benefit?
Steffen Frese, Nov 2014
Belimumab (trade name Benlysta®) is a monoclonal antibody directed against the cytokine BLyS (B-lymphocyte stimulator; also known as BAFF, TALL-1; THANK). The cytokine BLyS is necessary for the activation and the survival of certain white blood cells which themselves are responsible for the production of auto-antibodies. On the basis of a large (so called phase III) clinical trial belimumab was the first new drug after 50 years to be approved by the FDA (Food and Drug Administration) for the treatment of SLE. FDA approval was issued in March 2011 based on the BLISS-52 trial. This study recruited 865 patients with SLE; whereby patients with severe lupus nephritis were excluded. The study protocol of BLISS-52 defined three groups to which patients were randomly allocated. Two groups of patients received different concentrations of belimumab, patients in the third group a placebo. The study medication was given in parallel to the standard SLE medication. The primary end point of the study was the improvement in a complex clinical score for SLE in week 52. Using this study protocol, the following results were obtained: 44 % of patients in the control group showed an improvement in the SLE score compared to 53 % in the group treated with 1 mg/kg belimumab and 58 % in the group treated with 10 mg/kg belimumab. The difference between the placebo group and the belimumab groups was statistically significant resulting in FDA approval of the drug. Although it demonstrated statistically significant data, the BLISS-52 trial also showed that 11 patients had to be treated to achieve an improvement in SLE in one patient (the so called Number Needed to Treat was 10.7). Additional costs associated with belimumab are estimated at US$ 35,000 per year for one patient.
The data of a second phase III clinical trial with belimumab were published in December 2011. The BLISS-76 trial had a similar design to the BLISS-52 trial. The only difference was that patients in the BLISS-76 trial were treated for longer, and the clinical effects of belimumab were evaluated at week 76 in addition to week 52. The following results shown as the percentage of SLE improvement were obtained:
|week 52||week 76|
|belimumab 1 mg/kg||40.6 % (p=0.089)||38.5 % (p=0.13)|
|belimumab 10 mg/kg||43.2 % (p=0.017)||39.1 % (p=0.11)|
|placebo||33.5 %||32.4 %|
When the p value is higher than 0.05, the results are not statistically significant, i.e. there is no effect when compared with the placebo group. These values are marked in red demonstrating that beliumumab at a concentration of 1 mg/kg did not improve the course of SLE. Belimumab at the higher concentration showed a significant effect only at week 52 but not at week 76 despite continuing treatment of the patients.
Rituximab (trade name MabThera®) is a monoclonal antibody directed against the B lymphocyte surface protein CD20. Application of rituximab was shown to destroy B cells in terms of B cell depletion from the blood. In previous trials rituximab was successfully applied for the treatment of lymphomas and severe forms of the autoimmune disease rheumatoid arthritis. Several non-randomized reports exist which demonstrated beneficial effects of rituximab in SLE. To evaluate these effects, al large randomized phase III clinical trial in patients with lupus nephritis was conducted. The LUNAR (Lupus Nephritis Assessment With Rituximab) trial recruited 144 patients with refractory lupus nephritis (e.i. the patients are afflicted with active lupus nephritis despite treatment with standard SLE medication) who were randomly allocated to either the rituximab or the placebo group. Treatment with rituximab or a placebo was performed concomitant with SLE standard medication. Compared with the placebo group, the addition of rituximab to SLE standard medication demonstrated no improvement in existing lupus nephritis (p=0.55).  However, irrespective of these negative results, rituximab continues to be widely used for the treatment of SLE.
Ocrelizumab is a monoclonal antibody similar to rituximab which induces B cell depletion from the blood. A phase III trial recruiting 378 patients with active lupus nephritis was stopped early due to a high rate of serious infections. The data acquired before the premature termination of the study showed no statistically significant amelioration of lupus nephritis.
Atacicept represents a genetically engineered protein inhibiting both the B cell-activating factors BLyS (see above) and APRIL (a proliferation-inducing ligand). It was suggested that dual blockage of BLyS and APRIL might produce better results than demonstrated for the inhibition of BLyS alone by belimumab (see above). To verify this, 455 patients with SLE, but not with active lupus nephritis, were recruited. The trial was enrolled with three groups; two different concentrations of atacicept and a placebo were applied. Unfortunately, the group receiving the higher atacicept concentration had to be prematurely stopped owing to severe side effects (pneumonia with hemorrhage in two patients). The lower atacicept dose demonstrated no beneficial effects on SLE compared with the placebo group.
Abatacept (trade name Orencia®) is a recombinant fusion protein involving the protein CTLA-4. This biological was genetically engineered to block the CD28-CD80/86 signaling pathway known to activate co-stimulating T lymphocytes. Abatacept is currently used for the treatment of the autoimmune diseases rheumatoid arthritis and polyarticular juvenile idiopathic arthritis providing other therapeutic options have failed. In a first phase IIb clinical trial with 175 patients suffering from less severe forms of SLE (patients with active lupus nephritis were excluded), the treatment with abatacept yielded no therapeutic benefit. A subsequent phase III clinical study recruited 298 patients with active lupus nephritis. Treatment with abatacept in combination with steroids and mycophenolat mofetil did not improve existing lupus nephritis. In another, very recently published phase III trial 134 patients with active lupus nephritis were enrolled. Abatacept was given in combination with cyclophosphamide or azathioprine and steroids. Similar to the previous trial, no beneficial effect of abatacept on lupus nephritis was observed.
- ↑ Mackay, F. & Browning, J.L. BAFF: a fundamental survival factor for B cells. Nature reviews. Immunology 2, 465-475 (2002).
- ↑ Navarra, S.V., et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721-731 (2011).
- ↑ Furie, R., et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 63, 3918-3930 (2011).
- ↑ Rovin, B.H., et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64, 1215-1226 (2012).
- ↑ Mysler, E.F., et al. Efficacy and Safety of Ocrelizumab in Active Proliferative Lupus Nephritis: Results from the Randomized, Double-Blind Phase III BELONG Study. Arthritis Rheum (2013).
- ↑ Isenberg, D., et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis (2014).
- ↑ Merrill, J.T., et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62, 3077-3087 (2010).
- ↑ Furie, R., et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol 66, 379-389 (2014).
- ↑ Treatment of lupus nephritis with abatacept: the abatacept and cyclophosphamide combination efficacy and safety study. Arthritis Rheumatol 66, 3096-3104 (2014).