The first drug ever developed specifically to treat systemic lupus erythematosus, the monoclonal antibody benlimumab, was approved four years ago, and the disease remains a serious unmet medical need
Systemic lupus erythematosus remains a serious unmet medical need. The first new treatment for the disease in half a century, the monoclonal antibody benlimumab, was approved four years ago, and this represented the first drug ever developed specifically to treat lupus; prior to this, the last drug to be given an FDA licence for the disease – back in the 1950s – was the antimalarial plaquenil.
Lupus is a systemic B-cell mediated autoimmune disease, characterised by the body raising antibodies against its own tissues. The result is inflammation. Systemic lupus erythematosus (SLE) damages a number of internal organs, including the heart, liver, kidneys and lungs, as well as the nervous system and blood vessels, plus the characteristic effects it causes in the skin.
The typical course of the disease involves flare-ups and remissions, and those with the disease are at increased risk of heart problems resulting from atherosclerosis.
A new potential treatment, blisibimod, is currently undergoing clinical trials. It was initially developed by Amgen, and is now being progressed through the development process by Anthera Pharmaceuticals.
The peptibody is a fusion protein constructed from four B-cell activating factor (BAFF) domains, fused to a human antibody Fc region. BAFF, also known as B-lymphocyte stimulator, is important in the survival, activation and differentiation of B-cells, and lupus patients typically have elevated levels of BAFF.
Blisibimod binds to soluble and cell surface BAFF, and in preclinical mouse studies it reduced B-cell numbers, and improved lupus development.1
A dose ranging Phase II trial has been carried out in 547 patients with SLE. Subjects were given subcutaneous blisibimod in one of three doses or placebo for 24 weeks.2 The primary endpoint was a significant improvement on the SLE responder index-5, which represents a greater than or equal to five point improvement in the safety of estrogens in lupus erythematosus national assessment – SLE disease activity index, or SELENA-SLEDAI.
While SRI-5 response rates were not significantly better than placebo for the blisibimod treated patients when all pooled together, at the highest dose, 200mg once a week, the improvement reached statistical significance at week 20. Significant changes in anti-double stranded DNA antibodies, complement C3 and C4, and reduction in B-cell count were seen in the treated group.
The rates of serious adverse events, infections, deaths, and malignancies were not significantly different between the treated group and those given placebo.
An interim analysis of a Phase III trial has recently been released, ahead of expected final data in late 2016. An independent statistician advised that, after carrying out an interim futility analysis for the trial by analysing the SRI-6 response after 24 weeks, the trial should continue to completion. The primary endpoint has been shifted from SRI-8 to SRI-6, in response to other studies on BAFF inhibitors in lupus patients.
In addition, blisibimod is being investigated in the treatment of IgA nephropathy, and a Phase II trial is underway for this indication.
1. H. Hsu et al. Clin. Exp. Rheumatol. 2012, 30, 197
2. R.A. Furie et al. Ann. Rheum. Dis. 2014, doi:10.1136/annrheumdis-2013-205144