Epratuzumab a new drug in development for SLE shows promising results in EMBLEM study

Epratuzumab, a new humanised IgG1 monoclonal antibody that acts on CD22 (a molecule preventing over-activation of the immune system and emergence of auto-immune diseases) has shown promise as a potential treatment of moderate to severe systemic lupus erythematosus (SLE) according to results of a new study EMBLEM. Data from the phase IIB study involving 227 patients who received epratuzumab in a range of doses or placebo, were presented at the annual American Congress of Rheumatology meeting in Atlanta.

EMBLEM was primarily designed to identify optimal dose levels and treatment schedules but also to confirm safety and efficacy findings from previous preliminary studies. Results of EMBLEM exceeded expectations however, said investigators who say they are excited by what they observed.

Data from the 12-week double-blind randomised placebo-controlled study showed patients in four of the five arms who received active treatment rather than placebo had already responded well to treatment within a short time span of four to eight weeks, reducing their disease activity according to assessments on the BILAG-2004 (British Isles Lupus Assessment Group) index and the SLEDAI (SLE disease activity index). Patients who received one particular cumulative dose did particularly well.

EMBLEM is the first study to use the BILAG-2004 index as a composite endpoint and as a means of identifying optimal thresholds for dosing. The BILAG index allocates alphabetic ratings to different organ-based systems assessing each system individually, eg, cardiovascular and respiratory, musculoskeletal, mucocutaneous and neurological, after taking account of a patient’s disease history, clinical examination findings and results of laboratory investigations. An ‘A’ rating indicates active disease severity or a flare while a ‘D’ rating suggests freedom from symptoms in an organ system previously known to be affected by SLE. A change in BILAG ratings is considered a sensitive and reliable way of monitoring improvement or deterioration in a patient’s condition. The SLEDAI is also a means of assessing disease and response to treatment but is based more on clinicians’ global impressions.

Presenting the data from EMBLEM in Atlanta, lead investigator Dr Daniel Wallace of Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, USA, said the study population comprised patients with fairly severe disease. Over 70 per cent of patients included in the trial had a BILAG A score at baseline and most had BILAG A and B ratings before treatment. If patients improved their BILAG scores, showed no worsening of disease activity and needed no increase in their background therapy, they were considered responders.

“What we found was very very interesting,” he told rheumatologists who packed the meeting room at ACR where the results were announced. There was a bell-shaped curve in responses from the five treatment arms with responses increasing with dose up to an optimal level of 600mg weekly but showing no improvement over placebo at the highest dose tested. The highest dose was thought to affect a cellular mechanism that cancelled out the response, he suggested. “However, patients who received a cumulative dose of 2400mg (either 600mg weekly or 1200mg every other week) clearly showed a statistically significant (p=0.02) and clinically meaningful improvement on the responder index that was more than double the response seen in the placebo arm (45.9% and 43.2% vs 21.1%).”

By week 12 significantly more patients receiving epratuzumab 600mg weekly had improved their baseline BILAG A/B scores to BILAG D in all six body systems (indicating no active disease) than patients receiving placebo. “A high proportion (62.1 per cent) improved by two categories in BILAG ratings,” he noted.

“The degree of improvement was substantial. These were sick patients and I’m very excited about the results we saw from epratuzumab.”

Epratuzumab acts on CD22 but also reduces B cells although only by a modest amount (30-40 per cent), said Dr Wallace. Benefit started to be apparent quickly, within four to eight weeks. This is faster-acting than drugs with a larger B-cell depleting effect, he commented.

With regard to safety, epratuzumab was well tolerated, he reported. The discontinuation rate was no higher than 3 per cent in any treatment arm and there were no increases in infusion reactions over placebo. Adverse events including infections and injection site reactions, and serious adverse events in the treatment arms were comparable to those seen in the placebo arm. “There were no new safety signals,” he added

Co-investigator, Dr Ken Kalunion, UCSD School of Medicine, La Jolla, USA, said within specific body systems, notably CNS and cardio-respiratory, most patients had symptom reduction or absence of active disease after treatment. All patients receiving the 600mg dose improved their rating to BILAG D in the cardio-respiratory system by the 12-week endpoint. And in the neuropsychiatric system, 5 out of 6 patients in the 600mg weekly group went from BILAG B to D. “These are small numbers but the results are very encouraging”, he said.

Another co-investigator Dr Vibeke Strand of Stanford University, Palo Alto, USA, commented: “It is terrific to see improvement within three months that is clinically meaningful. I am very excited about epratuzumab. I think it’s a great drug that may have potential to be an induction therapy. I’m eager to see where it goes in phase III.”

SLE affects about 50 per 100,000 population in the US and the condition is currently regarded as having an unmet clinical need. Although there are several symptomatic treatments there are none that tackle the underlying pathology of SLE. New treatments are eagerly awaited.

Epratuzumab is in development by Immunomedics Inc and the Belgian pharmaceutical company UCB. Phase III clinical trials investigating epratuzumab are expected to begin early in 2011, Dr Wallace said.