At the 2013 European League Against Rheumatism (EULAR) Annual Congress, held from 12th to 15th June, in Madrid, Spain, new data were presented from an open-label extension (SL0008) of the EMBLEM Phase IIb dose-ranging study evaluating the long-term effects of UCB's epratuzumab treatment in adult patients with moderate-to-severe systemic lupus erythematosus (SLE). The primary outcome of the open-label extension (OLE) was to assess the safety of epratuzumab in patients with this disorder. Epratuzumab, licensed from Immunomedics, is the first monoclonal antibody that targets CD22. It is the first CD-22/B-cell receptor targeted monoclonal antibody to be evaluated in clinical studies for the treatment of SLE.
Relative to the 12-week, double-blind, placebo-controlled EMBLEM study, data from the long-term OLE identified no new safety or tolerability signals. In addition, relative to EMBLEM baseline values, secondary outcome data indicated that the efficacy of epratuzumab, as measured by reduction in disease activity, was maintained over two years. Secondary outcome data also indicated that relative to EMBLEM baseline values, treatment over two years with epratuzumab was associated with decreases in corticosteroid use in patients receiving >7.5mg/day.
EMBLEM was designed to identify a suitable dosing regimen for epratuzumab. A total of 227 patients with moderate-to-severe SLE received either: placebo, epratuzumab cumulative dose of 200mg (100mg every other week), 800mg (400mg every other week), 2,400mg (600mg weekly), 2,400mg (1,200mg every other week) or 3,600mg (1,800mg every other week). In the OLE, 203 patients from any arm of the EMBELM study received epratuzumab 1,200mg at weeks zero and two of 12-week cycles. Safety variables were primary outcome measures in SL0008 and included duration of exposure, adverse events (AEs), infusion reactions and infections.
Exposure to epratuzumab was a median 845 days over a median ten treatment cycles. AEs caused discontinuation in 29 (14.3 per cent) patients. The most common serious AEs were SLE flare (3.4 per cent), lupus nephritis (2 per cent) and symptomatic cholelithiasis (1.5 per cent). The most common infections/infestations were urinary tract infection (24.6 per cent) and upper respiratory tract infection (23.2 per cent). There were no opportunistic infections and no patterns of specific serious or severe infections.
Secondary outcome measures in SL0008 included efficacy, as measured by reduction in disease activity, and assessed by: BILAG improvement, SLE disease activity index (SLEDAI) score, Physician Global Assessment (PGA) score and combined treatment response defined as BILAG improvement without worsening, no SLEDAI worsening and no PGA worsening, relative to EMBLEM baseline. The median BILAG total score was 25.0 at EMBLEM baseline and 9.0 at week 108. The score was 14.0 at SL0008 screening. Median SLEDAI score was 12.0 at EMBLEM baseline and 4.0 at week 108. The score was 10.0 at SL0008 screening. The median PGA score was 50.0 at EMBLEM baseline and 17.5 at week 108 with a score of 31.0 at SL0008 screening. The proportion of patients achieving the combined treatment response was 32.5 per cent at SL0008 screening (n=203) and 60.3 per cent at week 108 (n=116).
Corticosteroid doses were monitored throughout SL0008 and this was a secondary outcome measure. Median corticosteroid dose at EMBLEM baseline and SL0008 screening was 10.0mg/day. At week 116, this was 5mg/day (n=112). Data indicated that treatment over two years with epratuzumab was associated with decreases in corticosteroid use in patients receiving >7.5mg/day with a corresponding increase in the proportion of patients receiving lower doses or no longer receiving corticosteroids.
The proportion of patients requiring 7.5 to 20mg/day and >20mg/day decreased (49.8 and 10.8 per cent at baseline and 33.9 and 8.0 per cent, respectively, at week 116) and the proportion of patients receiving >0 to 7.5mg/day or no longer receiving corticosteroids increased (33.5 and 5.9 per cent at baseline and 45.5 and 12.5 per cent respectively, at week 116).
Secondary outcome measures in SL0008 also assessed the long-term effect of epratuzumab treatment on B-cells and other immunological parameters. Median absolute B-cell count decreased by 50 per cent at week 112, compared with EMBLEM baseline. CD22 expression on B-cells remained low relative to EMBLEM baseline throughout SL0008. No consistent trends were seen in median T-cell counts, which remained similar to EMBLEM baseline at week 112 and no consistent trends were observed for IgG or IgA, which remained within normal levels. IgM levels decreased slightly (-0.21g/L by week 112). At week 48, there was little correlation between BILAG improvement rate and B-cell levels. The moderate reduction in B-cell counts and the lack of correlation supports B-cell modulation rather than depletion as a mode of action for epratuzumab.
UCB stressed that these results from the long-term extension of EMBLEM should be viewed in the context of an open-label study without placebo control. Further studies are warranted to confirm these findings.
Iin 2006, UCB entered into a collaboration and licence agreement under which it was granted the exclusive worldwide rights to develop, market and sell epratuzumab, for all autoimmune disease indications. In 2011, the companies restructured the agreement, providing UCB with the flexibility to select a partner to sublicense its rights to for certain territories. UCB agreed to make a non-refundable cash payment totalling US$30 million upon execution of the amendment. In the event that UCB exercises its right to sublicense, Immunomedics will be entitled to receive an additional cash payment of US$30 million, and additional payments upon achievement of new regulatory and sales milestones pursuant to the amended agreement. In addition, Immunomedics will issue to UCB a five-year warrant to purchase 1 million shares of Immunomedics' common stock at an exercise price equal to US$8.00 per share. At the time of reporting the current data, Immunomedics' shares have increased in value by 47.3 per cent since the last day of trading in 2012, from US$2.92 at close on 31st December, to US$4.30 at close on 13th June.