A new SLE therapy: Yes, Virginia, it is possible to have a positive lupus trial

November 2010

Robert A. Eisenberg, MDI am pleased to be writing to you as the new Website Medical Editor. I will be working closely with the CIS Executive Committee on some new initiatives for 2010/2011, including updating the WEBbook of Biologic Therapies, a complete re-design of the website, linking to more patient registries, and increased promotion of CIS Educational Programs. I am also pleased to report that the virtual meetings from the 2010 PID National Conference and Annual Meeting have been posted on the CIS website for members and meeting attendees.

The following commentary is based in part on information presented at the 2010 Annual Meeting in Philadelphia. Going forward, I will post each month a new Medical Editor Opinions, by myself or by guest writers. These brief pieces will target a current topic in biologic immunotherapy in order to stimulate interest and discussion in the CIS community. I welcome any feedback about posted items, or suggestions for new topics or contributors. Please email me at webeditor@clinimmsoc.org.

Robert A. Eisenberg, MD, CIS Website Medical Editor


Belimumab (Benlysta®, HGS) may become the first new therapy approved for lupus in decades. It has received priority drug review status from the FDA, with a target date of December, 9 2010 (1). It is a fully human monoclonal antibody that neutralizes the soluble form of BLyS (a.k.a., BAFF, TALL-1, zTNF-4, THANK, and TNF13B,), an essential factor for B-cell survival and development (2). The available clinical trial results were summarized by Dr. William Freimuth at the 'Corporate Thursday' symposium of the first CIS Annual meeting, May 20-22, 2010, in Philadelphia (the slides are available to CIS members through the Website). In brief, two large (for lupus) phase III pivotal trials, BLISS-52 and BLISS-76, met their 52-week primary endpoints of a composite clinical response index (based on the SELENA SLEDAI, BILAG, and the Physicians Global Assessment). The following points are of particular interest in this development:

  1. The preclinical data in mice strongly suggested that BLyS would be a useful therapeutic target. Transgenic overexpressors developed lupus-like autoimmunity; knockouts were severely B-cell deficient; and spontaneous lupus mice overexpressed BLyS and could be treated effective by anti-BLyS therapy (3).
  2. Belimumab targets soluble BLyS, but not the cell bound form, which has unclear biological activity. It also does not block APRIL, a similar molecule that shares two of the three BLyS receptors and that may be particularly important for plasma cell survival and IgA expression.
  3. An earlier phase IIb trial failed to meet its primary endpoint, but a retrospective reanalysis of the data elucidated different entry and outcome criteria that would have produced a successful trial, had they been chosen prospectively (4). The phase III trials were predicated on the possible validity of this approach.
  4. The magnitudes of the responses in the BLISS-52 trials were not overwhelming: the response rate was 43.6%, 51.4% and 57.6% for placebo, low dose (1 mg/kg every mo) and high dose (10 mg/kg), respectively. But in other ways the data were reassuring. Most of the secondary outcomes were met, and in almost all cases, as with the primary outcome, the dose/response showed a logical trend favoring the higher dose. In addition, several biomarkers (autoantibodies, complement levels) responded to treatment, as did immunoglobulin levels. All B cell subsets, except memory cells, decreased in the peripheral blood.
  5. The primary outcome in the BLISS-76 trial, which was identical to that of the BLISS-52 trial, was met only in the high dose (10 mg/kg) group, and many of the secondary outcomes were not met. In addition, the dose/response trend was inconsistent. Furthermore, the same composite outcome was not met at 76 weeks.
  6. Preliminary reports from the long term follow up trial suggest increasing responses, decreasing flares, and further reductions in autoantibodies.
  7. No serious safety signals were seen so far in either trial or in the long term follow up, except for rare infusions reactions.

I would further emphasize the following conclusions and speculations:

  1. The apparently modest biological activity of belimumab in lupus may be in part due to the specific protocols of these randomized controlled trials. For example, the phase IIb trial subanalyses of flare prevention suggested that the agent might be particularly effective in preventing neurological and renal flares, which would be especially welcome. The suggestion of increasing efficacy over longer periods of treatment is also encouraging, although it needs rigorous demonstration (5).
  2. Other BLyS targeting agents are in development, including ones that target APRIL as well. A trial in lupus nephritis of one of the latter, atacicept (ZymoGenetics), was halted because of increased infections in patients concomitantly treated with mycophenolate, although a general lupus trial is continuing to recruit (6).
  3. The change in serological and cellular measures suggests that biomarkers such as B cell subsets may help to guide therapy either in selecting patients to treat or in predicting incipient clinical responses.
  4. The apparent safety of belimumab encourages the hope that its use may be extended to other autoimmune diseases (e.g., multiple sclerosis, vasculitis, Sjögren's syndrome) or transplantation. Perhaps it might eventually be used in combination regimens. In this regard, preclinical data indicate a synergistic effect with anti-CD20, although surprisingly, targeting the latter molecule has failed in recent lupus clinical trials (EXPLORER and LUNAR, Genentech) (7).
  5. The modest success of these belimumab trials should encourage the academic and pharmaceutical communities to continue to pursue novel targets in lupus and should provide some guidelines as to what are useful trial designs and outcome measures.

UPDATE: On December 3, HGS announced that the FDA had extended the target date for its priority review of belimumab from December 9, 2010, to March 10, 2011, for additional considerations. I do not think that this delay changes substantially the probability that the drug will be approved, which remains high, but far from certain. On March 9, 2011, the FDA approved belimumab for the treatment of lupus. The estimated cost will be about $35,000 per year.

Readers are invited to comment:

"If approved, how would you use belimumab in the immediate future? What will its role be ten years from now?"

References:

  1. Summarized on the HGS Website. http://www.hgsi.com/belimumab.html
  2. Cancro et al. J Clin Invest 119:1066, 2009
  3. Stohl et al. Arthritis Rheum 62:2432, 2010; Ramanujam et al. Arthritis Rheum 62:1457, 2010
  4. Wallace et al. Arthritis Rheum (Arthritis Care & Res) 61:1168 2009; Jacobi et al. Arthritis Rheum 62:201, 2010; Furie et al. Arthritis Rheum (Arthritis Care & Res) 61:1143, 2009
  5. Petri et al. Arthritis Rheum 60 (supplement):S774, 2009 (abstract)
  6. Zymogenetics news release on their Website at http://www.wikinvest.com/stock/ZymoGenetics_%28ZGEN%29/Filing/8-K/2008/Ex-99.1/D2066904
  7. Merrill et al. Arthritis Rheum 62: 222, 2010

*This is the first Medical Editor Opinions, a new feature on the CIS Website. The opinions are strictly those of the Medical Editor or Guest writer, and do not represent views or recommendations of the Society. Comments are welcome.