Ten Developments in the Use of Biologicals for Systemic Lupus Erythematosus
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- Wallace, D.J. Curr Rheumatol Rep (2013) 15: 337. doi:10.1007/s11926-013-0337-z
Belimumab has recently been approved, and several other types of biological therapy with different mechanisms of action are currently in phase II and III studies. This review puts these approaches in context, emphasizing mechanistic categories and clinical trial designs. Most of the promising approaches involve B cell depletion or modulation. Post-approval experience with belimumab is critically reviewed.
KeywordsBiologicalsTargeted therapySystemic lupus erythematosusSLEFDATreatmentCutaneous lupusBelimumabEpratuzumabT cell inhibition
Nearly one million people in the United States have either systemic lupus or lupus-related disorders or syndromes. The economic burden from direct and indirect costs is tens of billions of dollars a year . Up to half of women diagnosed during their reproductive years are divorced within five years. Thirty-to-forty percent of those diagnosed with SLE become disabled within ten years, 10,000 patients die from active lupus each year, and its affect on quality of life, medical and prescription bills, and hospitalizations is immeasurable . Despite advances in managing SLE and its co-morbidities, half of those with organ-threatening disease succumb within 20 years, a number that has not changed in 30 years . Biological agents and targeted therapy have substantially improved outcomes for a variety of rheumatic disorders, in particular rheumatoid arthritis, the spondyloarthropathies, and vasculitis. Although several of these agents are used “off label” for lupus, the first biological for this indication was not approved by the Food and Drug Administration (FDA) until 2011. This article will review the ten most important developments related to targeted therapy for SLE.
The 2010 FDA Guidance Document
FDA guidance document for industry for SLE: June, 2010. Lupus clinical trials should take the following into account in order for an agent to be considered for approval
Two adequate and well-controlled trials. Superiority trials with open-label extension opportunities are preferred.
Randomized controlled trials should be of one year duration and include patients who fulfill the American College of Rheumatology criteria for SLE
Patients should be stratified by severity
The BILAG-2004 is the preferred disease activity instrument. However, use of the SLEDAI, ECLAM, or SLAM alone or in combination with the BILAG-2004 is acceptable
Definitions for major responses, partial clinical responses, remission, reduction in flare, and increase in time to flare are provided
Corticosteroid use variability is best if it is minimized and steroid-sparing effects are defined
Patient-reported outcome measures should be evaluated
No currently available surrogate marker or biomarker is acceptable to fulfill Subparts H and E (e.g., the use of CD4 counts can fast-track an HIV drug), but if one is validated, the agency would consider use of the fast-track development mechanism
The Search for a Valid Responder Index for Biological Clinical Trials
Composite measures used in lupus trials
A. SLE responder index (SRI)—Successfully used for belimumab
1. At least a four point reduction in the SELENA version of the SLEDAI score
2. The failure to develop a new BILAG A or two BILAG B organ domain scores
3. No worsening (<10 %) in the physician global assessment
4. All the above must occur
B. BILAG-based combined lupus assessment (BICLA)—Successfully used for epratuzumab
1. BILAG improvement: A scores go to B/C/D; B scores go to C/D, no new BILAG A or two new BILAG B scores
2. No worsening in the SLEDAI score
3. No worsening (<10 %) in the physician global assessment
4. No treatment failure: steroids, antimalarials, or immune suppressives dosing not increased above baseline
Organ-Specific Measures: Developing Topical and Systemic Innovative Treatments for Cutaneous Lupus and Nephritis
The development of organ-specific improvement measures has been proposed for renal and dermatological manifestations of lupus; it is in progress for other manifestations. The risk of using these measurements as a primary outcome measure is that a positive result would lead to a narrow approval being granted (e.g., for cutaneous lesions only), when in reality the agent might be useful for many manifestations of the disease.
Topical or oral therapy in development for cutaneous lupus
Celgene CC-11050—PDE type 4 inhibitor
Celgene CC-11004—TNF alpha blockade
Celgene and Rigel 333—topical Syk kinase/Jak3 inhibitor
Novartis KP203 (KYORIN)—topical targets sphingosin-1-phosphate
Atitretinoin (Tocinto)—a retinoid
Astion (France) ASF 1096—topical salbutamol
percentage of patients starting a new immune suppressive;
urine/protein creatinine ratio;
urinalysis and urine sediment,vary widely from study to study [21••]. Additional problems include discerning nephritis from active lupus outside the kidney, the accuracy of functional renal imaging, and the importance of urinary biomarkers .
Approval of Belimumab for SLE
In March 2011, belimumab became the first drug approved for SLE for over 50 years. A human IgG1 agent which targets soluble B lymphocyte stimulation in maturing B cells, belimumab enables B cell apoptosis and prevents differentiation of IgG-producing plasma cells. Its effect occurs via prevention of B cell survival, depleting B cell numbers by approximately 70 % over six months. The pharmaceutical sponsors followed the recommendations of the FDA guidance document and avoided many common errors of previous study designs, as described below. Over 2000 patients were studied in the phase III clinical trials (BLISS-52 and BLISS-76) and the double-blind phase II trial. The study was adequately powered, did not mandate steroid use or tapering, included patients with moderate to severe activity, and enabled investigators to use community standard-of-care background therapy, with nonsteroidals, antimalarials, corticosteroids and immune-suppressive agents, in a manner which enabled realistic day-to-day flexibility. The use of a composite index was stringent enough to reveal differences between those who received the study drug and those given placebo. Long-term follow-up of this agent from the phase II trial revealed an excellent safety profile, steroid and immune-suppressive sparing properties, and improved quality of life [23, 24•, 25••].
Over 10,000 unique individuals have now received this agent. It seems to be most effective for patients who still have active disease despite treatment with the community standard-of-care background therapy listed above. In clinical trials response was approximately 50–60 %, but because of some confusion regarding who might most benefit from belimumab, fewer than 50 % of patients given the drug since its approval remain on it for more than six months.
Papers published since belimumab’s approval provide further insight into its systemic effects. Seven-year open-label follow-ups document its safety, steroid and immune-suppressive sparing properties, improvements to fatigue and quality of life, and suggestions that it is effective against nephritis, is associated with relatively low incidence of serious infection, reduces incidence of flares, and works especially well in combination with mycophenolate. It is safe and effective to give inactivated vaccines with the drug, and belimumab associated with sustained disease activity amelioration. Ongoing trials will address whether it can be used against Sjogren’s syndrome and vasculitis, and investigate whether it is effective for African Americans and children. Belimumab is also being developed as a subcutaneous preparation [26–30].
Non-Belimumab BlyS-Related Compounds
B cell intervention for SLE
1. Agents which kill B cells targeting CD20
(a) Rituximab—two failed double-blind trials, but some lupus phenotypes clearly respond and there is controlled evidence that it is effective in combination with cyclophosphamide
(b) Ocrelizumab—did not meet safety requirements and development has been halted
(c) Ofatumumab—fully human, approved for leukemia, had positive studies in RA, but lupus trial was halted for economic reasons
2. Agents which modulate B cells
(a) Epratuzumab—two positive phase II trials, two phase III trials in progress, has multiple actions on cell signaling and may work via trogocytosis
3. Agents which target BlyS/BAFF or APRIL in developing B cells
(a) Belimumab—on the market for two years. Reduces disease activity, is steroid and immune-suppressive-sparing and improves quality of life
(b) Atacicept—phase III trial fully enrolled. Cannot be used with mycophenolate.
(c) Blisbimod—phase II trial suggested that a high dose is effective for those with very active disease; phase III trial being initiated
(d) Tabalumab—not effective against RA, targets membrane and soluble BAFF as a subcutaneous preparation. Large phase III trials in progress
4. Agents which target plasma cells
(a) Borteozomib—on the market for multiple myeloma. Favorable case reports have appeared
(b) Carvezolib—clinical trials awaited
An Interesting B Cell Modulator: Epratuzumab
Epratuzumab is a humanized-IgG1 monoclonal antibody targeting CD22, acting as an agonist in it that promotes its expression. By engaging CD22, epratuzumab inhibits B cell receptor (BCR) activation and up-regulates adhesion molecules on both developing and mature B cells. Rapidly internalized, it has dose-related effects on cell signaling (which is why lower doses are more effective than higher doses in clinical trials), and is only modestly B cell depleting. It has no complement-mediated cytotoxicity . Epratuzumab mediates BCR-antigen trogocytosis, a process that involves the transfer of plasma membrane fragments from the presenting cell to the lymphocyte . This molecular reorganization at the interface between the lymphocyte and the antigen-presenting cell during conjugation is also known as the “immunological synapse” [37•]. A phase I trial demonstrated safety, and two randomized, double-blind, placebo-controlled multi-center studies were initiated in March 2005 and terminated in September 2006 because of interruption of drug supply. Ninety patients completed enough treatment to enable analysis. The 360 mg m−2 dose was found to be effective as measured by BILAG response, steroid-sparing properties, and improvement to quality of life . This was followed by the EMBLEM trial, which studied 227 patients. Patients who received the 600 mg weekly group had a statistically significant BICLA response and the drug had an excellent safety profile . Responses were substantially more likely among 74 patients treated with epratuzumab in the middle-range dose than among 38 patients given placebo (odds ratio 2.9). Patients receiving a higher dose did not respond. A large phase III trial (EMBODY) is currently in progress.
Rituximab is an anti-CD20 chimeric IgG1 agent that induces rapid and sustained reductions in B cell numbers, and leads to antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis of B cells. Approved for rheumatoid arthritis, many case series have found efficacy for patients with a wide variety of manifestations of SLE, particularly patients with arthritis, central nervous system and hematological involvement, and antiphospholipid syndrome [39, 40]. It is also effective in combination with cyclophosphamide. However, a placebo-controlled, randomized trial of 257 patients with active SLE, that excluded nephritis and central nervous system disease, and a similarly designed nephritis trial (EXPLORER and LUNAR), did not meet their primary outcome measure. This is probably because both groups were given highly effective concurrent therapy consisting of corticosteroids and immune suppressive agents [41, 42]. This writer believes that some lupus phenotypes do particularly well with rituximab, and that improved study designs will show this.
T Cell Inhibition
Abatacept is an IgG1 fusion protein that selectively inhibits co-stimulation of T cells by fusing with the extracellular domain of CTLA-4 Ig. Abatacept has been available for rheumatoid arthritis for nearly a decade, and there is much anecdotal evidence that lupus patients with synovitis or nephritis respond favorably to this agent. Two industry-sponsored trials of this agent for lupus patients with and without nephritis failed to reach their primary endpoint because of faulty study design [43, 44]. In these studies both groups were given high doses of steroids which were tapered after 2–3 months, and the primary outcome measure was the incidence of flares measured at 1 year. After 12 months patients receiving abatacept had less disease activity, and most flares occurred before month six, when the drug was not yet fully effective. Nevertheless, many secondary outcome measures improved. The NIH immune tolerance network study of over 150 nephritis patients given abatacept or placebo has completed enrollment. Definitions of renal response have been controversial and are discussed above. Additional studies with an improved design will begin in 2013.
Other agents inhibiting T cells have also been developed . Efalizumab was an LFA-1 inhibitor that was approved for psoriasis and was being studied in a cutaneous lupus trial that was halted when the agent was removed from the market because of reports of progressive multifocal leukoencephalopathy. Two companies are investigating agents that target the ICOS-B7 RPS pathway in patients with lupus in general, subacute cutaneous lupus, and lupus arthritis. Blocking the CD40L pathway is another promising approach. Studied since the 1990s, inhibition of this pathway was extremely effective in murine models of SLE and in some human studies. Unfortunately, these agents were responsible for thrombotic complications in lupus and renal transplant procedures that have since been discontinued. Two companies are evaluating different epitopes and conformations, which may have a better safety profile and may be in phase I settings in the next few months.
A Variety of Novel Approaches: Targeting the Innate Immune System, Cytokines, Toleragens, Cell Signaling Pathways, and Complement
Slow but steady advances have been made in developing targeted therapy involving the innate immune system, toleragens, cytokines, and complement. Most patients with active SLE have increased expression of type-1-interferon-induced genes and proteins in blood and involved tissues. Several monoclonal antibodies to interferon alpha and gamma have been studied in phase I and II clinical trials. Neither sifalumumab  nor rontalizumab  have borne out their original promise, and several other compounds are in development. Three companies are studying compounds that target toll-like receptors 7 and/or 9 in phase I initiatives .
Levels of IL-6 are increased in active lupus via increased B and T cell production. Blocking IL-6 reduces spontaneous immunoglobulin and anti-ds DNA production. Expression of IL-6 is increased in the kidneys, increasing mesangial cell proliferation. Urinary IL-6 levels are elevated with active lupus nephritis. A phase I trial of tocilizumab conducted at the National Institutes of Health found a prompt reduction in anti-ds DNA and acute-phase reactants, and improvement in disease activity and normalization of B cell subsets . Four companies are investigating the potential of anti-IL-6 strategies against SLE.
Other cytokine antagonists are being studied for SLE. There is evidence that inhibition of IL-18 may be effective in animal models, especially at the monocyte macrophage level . There has been much recent interest in IL-21, levels of which are markedly elevated in SLE patients and which promotes survival and expansion of CD8T + and NK cells, differentiation of Th 17 cells, and expansion of naïve and memory B cells into IgG-secreting plasma cells . A phase I trial of an IL-21 antagonist is in progress. Inhibition of IL-17 and promotion of T reg cells in animal models has generally been disappointing for lupus, but there remains much evidence that this is an important immunoregulatory pathway in SLE.
Edratide (a toleragen to the 16/6 anti-DNA idiotype) did not meet its primary endpoint; some clinical phenotypes did well, but I am not aware that this approach is being pursued . Lupuzor is a small P140 peptide toleragen to the splicosome that is immunomodulatory, but not immune suppressive, via a T cell approach. Two double-blind phase II trials have suggested some efficacy [47, 50]. Laquinimod shifts the immune axis toward Th2 and has had favorable results from a study of 3,000 patients with multiple sclerosis . Enrollment into lupus arthritis and nephritis trials is complete, and results should be reported in 2013.
Innovative approaches being investigated for SLE
1. T cell inhibition
(a) Abatacept—approved for RA for 10 years; two flawed industry-sponsored trials (non-nephritis and nephritis) did not meet primary endpoint, immune tolerance trial for nephritis fully enrolled, better designed industry trials in progress
(b) Blockade of the ICOS-B7 RPS pathway being studied by two companies for lupus, lupus arthritis, and subacute cutaneous disease
(c) Blockade of the CD40L pathway is being reconsidered. Original conformations and epitopes were thrombogenic or ineffective
2. Cytokine antagonists
(a) Tocilizumab had a favorable phase I trial conducted at the National Institutes of Health. Four other companies are studying anti IL-6 approaches
(b) IL-21 antagonist is in a phase I trial
(c) Agents that block IL-17 and IL-18 are promising in animal studies; human studies may be initiated soon
(a) Edratide is a toleragen to the 16/6 anti DNA idiotype. It did not meet its primary endpoint in a phase II study, but some subsets responded in this flawed trial design
(b) Lupuzor (small P140 peptide toleragen to the splicosome) has had two positive phase II trials; phase III trial being designed
(c) Laquinomod (shifts immune axis to Th2) has fully enrolled lupus arthritis and nephritis phase II trials
4. Innate immune system
(a) Sifalumumab (x) is an alpha interferon antagonist with modest effects
(b) Rontalizumab is an alpha interferon antagonist with modest effects
(c) At least four companies are targeting toll-like receptors 7 and/or 9 in phase I initiatives
(d) A gamma interferon antagonist is being studied for lupus nephritis
5. The human kinome
(a) Agents targeting the Jak/stat or tyrosine kinase pathway and cell surface receptors in general are being studied as topicals for cutaneous lupus. An oral agent (tofacitinib) has been approved for rheumatoid arthritis, and modest efficacy has been observed for Imatinib in scleroderma trials
6. Complement activation
(a) Eciluzumab is approved for paroxysmal nocturnal hemoglobinuria and had a successful phase I trial in SLE
Management of SLE with targeted therapy has greatly progressed. Until recently it would not have been possible to cover a few developments in biological therapy, let alone ten. Now that an FDA guide exists, in combination with improved metrics, several promising compounds, and commitment from industry and lupus advocacy groups, the procedure for managing lupus will be greatly altered over the next few years.
Conflict of interest
Dr Wallace consults for UCB, Pfizer, Amgen, and Lilly and consults and is on the speaker's bureau for Glaxo Smith Kline.