Four Basics About BAFF Inhibitors for SLE

January 4, 2014
William Stohl MD PhD

Last year's approval of belimumab (Benlysta) revolutionized lupus treatment. How safe and effective is it, actually? Do similar inhibitors of the B-cell activating factor BAFF, now in testing, appear even more promising? Here are the basics from an expert on the subject.

The world of systemic lupus erythematosus (SLE) turned topsy-turvy on March 9, 2011, when the Food and Drug Administration (FDA) approved the first new drug for the treatment of SLE in more than 50 years. The drug belimumab (Benlysta) is a monoclonal antibody that binds to and neutralizes BAFF (B cell activating factor; also known as BLyS for B lymphocyte stimulator), a key signaling factor in B-cell survival and maturation.1

Although limited “real-world” experience to date largely supports efficacy for belimumab,2-5 the bulk of the evidence comes largely from randomized, double-blind, placebo-controlled trials and their open-label extensions.

[1]   Overall, belimumab has a favorable safety profile.   

  • The incidence of adverse events, serious adverse events, and severe adverse events (including infections) for belimumab- and placebo-treated patients with SLE was essentially identical in phase-I (N = 70), phase-II (N = 449), and phase-III (N = 865 and N = 819) trials.6-10
  • After a year of treatment, serum levels of total IgG fell by only about 15%, and despite a decline in total B cells of approximately 55%, memory B cells were maintained, preserving protective antibody levels against pneumococcal, tetanus, and influenza antigens.11, 12
  • During 7 years of treatment with belimumab, rates of adverse events and infections among SLE patients (1746 patient-years) have either remained stable or have decreased.13
  • However, progressive multifocal leukoencephalopathy (PML) has now been reported in 2 SLE patients treated with belimumab. Chronic B-cell depletion may be associated with an increased risk for PML.14 It remains uncertain whether belimumab imparts an increased risk for developing this devastating and as yet non-treatable disorder.

[2]   Belimumab has statistically significant, albeit modest, efficacy in treating SLE.

  •  In the phase-II trial, using a novel evidence-based SLE responder index (SRI) to assess those patients who were “seropositive” (serum ANA titer 1:80 or positive serum anti-dsDNA antibody test, N = 321) at baseline, there was a 17% absolute difference in the proportion of clinical responders between patients treated with the FDA-approved 10 mg/kg dose of belimumab and those given placebo.15 This finding was confirmed prospectively in both phase-III trials (BLISS-52 and BLISS-76.).9 (See Figure, below.)

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In pooled analyses of the two phase-III trials, compared with subjects randomized to placebo the belimumab-treated patients showedsignificantly more frequent improvements in the mucocutaneous, immunological, musculoskeletal, vascular, and central nervous system domains, significantly fewer episodes of worsening in the immunological and hematological domains [16], and substantially smaller increases in average daily corticosteroid dose. 17

  • Belimumab had the greatest therapeutic benefit among SLE patients who at baseline had high disease activity, low serum complement levels, were anti-dsDNA-positive, or were taking corticosteroids.18
  • Among SLE patients with renal involvement who were taking Mycophenolate mofetil (MMF) at baseline, belimumab treatment significantly promoted renal improvement.19

[3]  Belimumab is very expensive. At the recommended dose of 10 mg/kg, assuming vial wastage, and not including physician/facility fees, the per-dose cost of the drug  for a patient weighing 65-76 kg is £769.50 or $1239 (based on an exchange rate of $1.61 for £1.00). At the recommended frequency (days 0, 14, and 28, and at 4-week intervals thereafter; a total of 15 infusions during the first year of treatment), the cost of drug for the first year would be $18,585.

[4]   At least three other BAFF antagonists are currently in clinical testing. Since none of these is yet approved for treatment of SLE, the only clinical experience to date is in the context of clinical trials.

Atacicept is a fusion protein between one of the BAFF receptors (TACI) and the Fc portion of IgG. In contrast to belimumab, atacicept not only binds and neutralizes BAFF but also binds and neutralizes APRIL (the acronym stands for “a proliferation-inducing ligand”), which is a potent survival factor for plasma cells that shares some receptors with BAFF.

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A priori, it is entirely logical to postulate that treatment with atacicept will have biological (and clinical) consequences meaningfully different from those of belimumab.

There are some safety concerns:

  • In the phase-I study of atacicept in SLE (N = 49), patients treated with drug experienced about a 30% reduction in serum IgG levels by as early as 4 weeks. Placebo subjects showed no change.20
  • A phase-II/III trial of atacicept in combination with MMF in SLE patients with nephritis was terminated prematurely when three of the four patients treated with atacicept rapidly developed hypogammaglobulinemia (serum IgG < 300 mg/dl). Two developed serious pneumonia.21

In another trial of atacicept tested at two doses, treatment with the higher dose (150 mg) was discontinued due to development of two fatal pulmonary infections (out of 145 patients given this dose).22

Atacicept’s  immunosuppressive potencymay lead to enhanced efficacy.

  • In the APRIL-SLE trial, atacicept-treated patients with the greatest decline in serum IgG levels experienced the fewest new flares.23
  • Judicious balancing of concurrent immunosuppressive medications (e.g., by limiting the dose of MMF or other potent immunomodulatory agents) may ameliorate the risk for serious infection while promoting clinical responses in a greater percentage of SLE patients than that seen with belimumab.

Blisibimod is a fusion protein between the Fc portion of IgG and a synthetic (non-self) peptide sequence selected for its ability to bind to BAFF with high affinity. As for belimumab (but unlike atacicept), blisibimod binds to BAFF but not to APRIL. Nevertheless, the biological (and therapeutic) activities of blisibimod and belimumab may not be identical:  Belimumab binds to BAFF only in its soluble form, whereas blisibimod binds to both soluble and membrane BAFF.

In a phase II trial of blisibimod among 547 patients with moderate to severe SLE:

  • The primary endpoint was not met, but post hoc analysis pointed to a benefit among patients with high disease activity at baseline.24
  • In the subgroup of patients with proteinuria (1 g/24 hr) at baseline, decreases were observed among those using blisibimod.25
  • Blisibimod has not caused increases in serious adverse events or infections compared to placebo.  This is also true for the open-label extension trial.26

Tabalumab is another anti-BAFF monoclonal antibody that, like blisibimod, binds to both soluble and membrane BAFF but not to APRIL. Tabalumab has undergone neither phase I nor phase II evaluation in SLE but has headed directly into two separate phase-III studies. No results are yet available. Although interim futility analyses of the two phase III trials prompted discontinuation of a tabalumab for rheumatoid arthritis (RA) due to lack of efficacy, RA and SLE are very different diseases. The phase III studies in SLE are continuing.

In summary, therapeutic BAFF antagonism with belimumab represents a step forward in our advance against SLE. But it is only a first step, and we are still a long way from complete success. Whether the other BAFF antagonists under development will improve on belimumab remains to be determined.

 

References:

1.  Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator.Arthritis Rheum (2003) 48:3253-3265.

2.   Ke X, Patel J, Kan H, et al. Characteristics and medication use patterns among belimumab users in a commercially insured population with systemic lupus erythematosus. Arthritis Rheum (2013) 65:S457.

3.   Askanase A, Reddy A, Buyon JP, et al.Favorable clinical response to belimumab to three months.Arthritis Rheum (2013) 65:S668.

4.   Yazdany J, Erkan D, Sanchez-Guerrero J, et al.Post-marketing experience with belimumab in U.S. lupus centers: data from the Lupus Clinical Trials Consortium, Inc. (LCTC) national patient registry. Arthritis Rheum (2013) 65:S681.

5.   Collins CE, Dall'Era M, Oglesby A, et al. 12-month outcomes associated with belimumab in patients with systemic lupus erythematosus in clinical practice settings: the Observe study. Arthritis Rheum (2013) 65:S738-739.

6.   Furie R, Stohl W, Ginzler EM, Becker M, et al.Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther (2008) 10:R109.

7.   Wallace DJ, Stohl W, Furie RA, et al.A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum (2009) 61:1168-1178.

8.   Navarra SV, Guzmán RM, Gallacher AE, et al.Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.Lancet (2011) 377:721-731.

9.   Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.Arthritis Rheum (2011) 63:3918-3930.

10.   Wallace DJ, Navarra S, Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus.Lupus (2013) 22:144-154.

11.  Stohl W, Hiepe F, Latinis KM, et al.Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.Arthritis Rheum (2012) 64:2328-2337.

12.  Chatham WW, Wallace DJ, Stohl W, et al. Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. J Rheumatol (2012) 39:1632-1640.

13.  Ginzler EM, Wallace DJ, Merrill JT, et al.Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol (2013) Epub ahead of print Nov 1 2013; doi:10.3899/jrheum.121368

14.  Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.Blood 2009;113:4834-4840.

15.  Furie RA, Petri MA, Wallace DJ, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum (2009) 61:1143-1151.

16.  Manzi S, Sánchez-Guerrero J, Merrill JT, et al.  Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials.Ann Rheum Dis (2012) 71:1833-1838.

17.  van Vollenhoven RF, Petri M, Wallace DJ, et al. Corticosteroid use across 52 weeks of belimumab therapy in patients with systemic lupus erythematosus: combined analyses from the BLISS trials. Arthritis Rheum (2013) 65:S672.

18.  van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis (2012) 71:1343-1349.

19.  Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus (2013) 22:63-72.

20.  Dall'Era M, Chakravarty E, Wallace D, et al.Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial.Arthritis Rheum (2007) 56:4142-4150.

21.  Ginzler EM, Wax S, Rajeswaran A, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther (2012) 14:R33.

22.  Wofsy D, Isenberg DA, Licu D, et al.Efficacy and safety of atacicept for prevention of flares in subjects with moderate to severe systemic lupus erythematosus (SLE). Arthritis Rheum (2013) 65:S675.

 23.  Isenberg DA, Wofsy D, Li Y, et al. Pharmacodynamics and predictive biomarkers in patients treated with atacicept: data from the APRIL-SLE trial. Arthritis Rheum (2013) 65:S1089.

 24.  Furie RA, Scheinberg MA, Leon G, et al. Blisibimod, an inhibitory of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus.Arthritis Rheum (2012) 64:4169.

 25.  Furie RA, Thomas M, Chu A, et al.Effects of chronic treatment with blisibimod, an inhibitor of B cell activating factor, on renal and inflammation biomarkers in patients with systemic lupus erythematosus: observations from the placebo-controlled Pearl-SC and open-label extension studies.Arthritis Rheum (2013) 65:S680-681.

 26.  Furie RA, Thomas M, Chu A, et al.  Effects of blisibimod, an inhibitor of B cell activating factor, on serum immunoglobulins and infection risk in patients with systemic lupus erythematosus: observations from the placebo-controlled Pearl-SC and open-label extension studies. Arthritis Rheum (2013) 65:S739-740.

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