Lupus and lupus nephritis update

The title includes the word “update” but that may be a bit generous. A dive into the American College of Rheumatology (ACR) abstracts shows that there is not much to update (http://acrannualmeeting.org/). Progress with new therapeutics remains slow.

Most patients are treated with various combinations of cytotoxic agents and immunosuppressants. These include prednisolone, mycophenolate mofetil, tacrolimus, cyclophosphamide, and azathioprine among others. Unlike the situation in RA, we do not have a new suite of drugs for systemic lupus erythrmatosis (SLE) and lupus nephritis (LN) patients.

Newer therapies can be grouped into 2 classes. The most effective class includes the B-cell depleting antibodies rituximab (anti-CD20, aka Rituxan) and epratuzumab (anti-CD22). Clinical trials report consistent and durable improvement in patient symptoms and perhaps even rate of flares. In 2012 the ACR included Rituxan use in its treatment guidelines for patients with advanced diseases (grades III-IV). Rituxan in combination with cyclophosphamide or other standard of care is currently in clinical trials for use in SLE and LN. Epratuzumab is being developed by UCB and Immunomedics and is currently in phase 3 for SLE, with data due in 2015. Certainly the available clinical data indicate that this drug will find use in the treatment of lupus.

The second class consists of the BAFF/Blys and April antagonists. Belimumab (brand name Benlysta), developed by HGS and then acquired by GSK, is an antibody to Blys, a B cell growth and survival factor. Belimumab continues to report long term benefit for patients with generally mild to moderate SLE. There is consistently improvement in patient symptoms by the SLEDAI and BILAG outcome scores, reduction in proteinuria, and in some cases a reduction in the dose of steroids required to control diseases flares. Blisibimod, a peptibody inhibitor of Blys, had updated results from SLE trials, showing reduced proteinuria and Ig levels from the PEARL-SC trial. However, outcome data from that trial was lacking. This drug from Anthera has had a mixed track record in terms of efficacy and so the jury will remain out until the phase 3 data are reported. Other drugs in the space have failed outright, including atacicept, a TACI receptor fusion protein that antagonizes both Blys and April. Toxicity associated with this drug, and lack of efficacy, halted development.

Following the outright failure of the Interferon alpha antagonists a year or more ago, new drugs are few and far between. One of these reported at ACR is AMG811, an anti-interferon gamma antibody from Amgen. This drug appears to have significant adverse event issues, and no sign of efficacy in an early clinical trial. However Amgen is still recruiting for phase 2 trials in cutaneous lupus and SLE with renal involvement. Another Amgen drug, AMG557, is an anti-B7RP-1 (aka ICOSL) antibody which will be interesting to track.

Again, this is an underserved area in terms of new and effective drug development, and it may be we have to rely of the B cell inhibitors and Bly inhibitors for the foreseeable future. Following the failure of many therapeutics over the past few years, we appear to be in a slow period for clinical development. The question we can ask for 2014 and beyond is pretty simple: what will be the new therapeutic hypotheses for lupus and lupus nephritis?