New data analysis reduces some of the concerns over upcoming Systemic Lupus Erythematosus (SLE) treatment, Benlysta (belimumab)

Related report: Pipeline Insight: Systemic Lupus Erythematosus - Turning a corner in drug development click here

A gradual improvement has been seen over recent decades in the treatment of Systemic Lupus Erythematosus (SLE) through the use of non-biologics. Emerging data describing Benlysta (belimumab), an anti-BLyS (BAFF) monoclonal antibody developed by Human Genome Science and GSK is increasingly underlining the central role that biologics may play in the next era of lupus treatments.

Data from the pivotal studies, BLISS-52 and BLISS-76 highlighted two recent meetings, EULAR in Rome and LUPUS2010 in Vancouver.

Systemic Lupus Erythematosus (SLE) is a multiorgan autoimmune disease which is particularly common in women. Prevalence varies between different ethnic groups; in African-American women of child-bearing age the prevalence may be as high as 1 in 200 but overall prevalence rates across USA and Europe vary from 14-70/100 000 and the annual incidence is between 3 and 5 new cases per 100 000 population.

The past quarter of a century has seen a remarkable improvement in the treatment of lupus even though there has not been a new drug approval for the disease for at least 50 years. The improvement has come from a better understanding of the disease and the use of pre-existent treatments and as a result 5 year survival rates have improved from 50% to 95%.

Mild to moderate disease is treated with low dose steroids, NSAIDs, methotrexate and antimalarial treatments. More severe disease is treated with higher doses of steroids, cyclophosphamide (Cytoxan) and mycophenolate (Cellcept). Despite the improvements that such treatments have brought, significant needs remain. Notably the treatments carry considerable adverse events, significant mortality remains and, according to a recent survey, up to 30% of sufferers report that they are unemployed as a result of their disease.

To fill the unmet needs a number of companies are developing biologics. The most advanced of these include Benlysta (belimumab), epratuzumab, sifalimumab, atacicept, abatacept and rontalizumab. As described in our recent feature Pipeline Insight: Systemic Lupus Erythematosus - Turning a corner in drug development [learn more about this report here], the pipeline is relatively complex, targeting a variety of different immune proteins and exhibiting a range of profiles. Successful development of the pipeline is however likely to bring significant rewards, not only for patients but also for companies developing lupus candidates.

The commercial potential of biologics is clear. The pipeline insight report described above estimates that 2008 lupus sales were approximately $1.1 billion in the seven major markets. This report forecasts that four late-stage pipeline products could inject $2.9 billion into the market by 2019.

Most clinicians expect Benlysta (belimumab) to reach the market first and are excited about the potential it will offer. Human Genome Sciences and GSK will therefore likely benefit from rapid uptake, with peak sales of $1.9 billion expected by 2013. Market potential will remain for pipeline products through both further patient penetration and patient switching. Critical questions will include: which patients will receive Benlysta (belimumab) and how will the drug be used? Closer inspection of data released from Phase 3 studies offers some clues.

Two Phase 3 studies of Benlysta (belimumab) have been completed forming the basis of IND and MAA filings in June 2010: BLISS-52 and BLISS-76. Both studies randomized patients to three arms (placebo, belimumab 1mg/kg and belimumab 10mg/kg). The primary end-point was a composite measure designed for the study known as the SLE responder index (improvement in SELENA SLEDAI score of 4 points or greater, with no clinically significant BILAG worsening and no clinically significant worsening in Physician’s Global Assessment). The primary end-point was measured at 52 weeks and improved with 10mg/kg belimumab compared to placebo from 44% to 58% in BLISS-52 and 34% to 43% in BLISS-76.

There are two key differences between BLISS-52 and BLISS-76. The former was conducted outside of the US, while BLISS-76 was conducted in the US. Other than the geographical differences, the studies are distinguished by the fact that BLISS-52 continued for 76 weeks, 24 weeks longer than BLISS-56. This difference has given rise to some degree of confusion around Benlysta (belimumab).

Although both trials met their primary end-point with an increase in patient response rates at 52 weeks, significance was lost at week 76 in BLISS-76. Some clinicians believe that non-biological immunosupressants should be used initially in lupus patients with biologics reserved for maintenance therapy. With this paradigm the BLISS-76 data may limit Benlysta (belimumab) use to just 1 year thus reducing the potential revenue for the drug. A recent re-cut of the data presented at LUPUS2010 suggests otherwise however.

A press release from Human Genome Sciences at the time of LUPUS2010 describes a reanalysis of the effect of Benlysta (belimumab) on the SLE Responder Index at 76 weeks iusing different SELENA SLENDAI definitions. Consequently, if an improvement of 5 instead of 4 points on the scale is employed, Benlysta (belimumab) is seen to have a significant effect at 76 weeks – the scores in placebo and 10mg/kg groups were 20% vs 33% at 52 weeks and 22% vs 31% at 76 weeks. In short this reanalysis may dramatically modify how the drug is used.

The next question is which patients would most benefit from Benlysta (belimumab)? One criticism of the BLISS studies is that patients have been recruited on relatively high levels of background therapy. This is a potential problem as it may mask efficacy under a trial setting. However this issue may also have revealed a particular benefit for Benlysta (belimumab). Specifically, a significant number of patients become “stuck” on medium to high levels of steroids and data presented from the BLISS studies suggests that Benlysta (belimumab) is able to reduce steroid use.

At entry into the BLISS-76 study, approximately 46% of patients were receiving steroids at a prednisone-equivalent dose of at least 7.5 mg per day. Among these patients, the percentage of patients who had their average steroid dose reduced from baseline to 7.5 mg per day or less by Week 76 was 25.8% for Benlysta (belimumab) 10 mg/kg, 27.7% for Benlysta (belimumab) 1 mg/kg, and 17.5%% for placebo. Although this was statistically significant for just the lower dose, we believe that clinicians will view Benlysta (belimumab) as being a particularly good steroid sparing strategy while at the same time improving response.

Overall therefore, as Benlysta (belimumab) approaches the market, clinicians are gaining a better understanding on how to use the drug. This understanding will improve as we move closer to approval although it is only after approval and real world experience is gained that matters will really become clear.