PERSPECTIVES TIMELINE
The evolution of drug discovery in systemic lupus erythematosus Daniel J. Wallace Abstract | Drug discovery in systemic lupus erythematosus (SLE) has lagged behind other rheumatic diseases, in large part because of difficulty in measuring change or improvement in a disorder that involves multiple organ systems to varying degrees at different times. The metrics currently used as primary endpoints are composite indices that rely mainly on disease assessment measures derived before the era of clinical trials of targeted therapies. Only one agent has been approved for the treatment of SLE since 1957. This monograph reviews the evolution of drug development for SLE, problems and pitfalls that have been encountered, and outlines the domains used to evaluate SLE in the clinic. Finally, several initiatives underway to improve clinical trial design are outlined. Wallace, D. J. Nat. Rev. Rheumatol. advance online publication 30 June 2015; doi:10.1038/nrrheum.2015.86
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of the immune system. The disease affects somewhere between 200,000 and 500,000 individuals in the USA, predominantly young women in their reproductive years. 1 Mild disease is currently managed with NSAIDs, antimalarial drugs and low-dose corticosteroids, whereas moderate to severe SLE warrants the use of higher doses of corticosteroids and immunosuppressive agents. Over the past decade, targeted therapies have been studied for the management of refractory disease. However, the development of new agents to manage SLE has lagged behind that of other auto immune rheumatic disorders. This lack of advancement is in large part because SLE is a heterogeneous disorder with effects on nine principal domains (organ systems) that are difficult to measure and quantify, and that can be at variance with each other. The past 30 years has witnessed the introduction of guidelines, disease definitions, candidate surrogate markers or biomarkers, metrics and composite indices to guide the Competing interests The author has acted as a consultant for GSK, Merck Serono and UCB.
treatment of SLE (Figure 1). Despite these developments, many study drugs have not met their primary or secondary endpoints— a situation that has led to a re-examination of SLE trial design. Since 1959, only one agent (belimumab) has been approved by the FDA for use in SLE; other available agents such as rituximab, tacrolimus, azathioprine, methotrexate, cyclophosphamide and mycophenolate mofetil are widely used off-label, but insurance coverage for such treatments is often limited for hundreds of thousands of US patients with SLE or lupus-related disorders. This manuscript reviews the evolution of drug discovery for SLE with the goal of outlining approaches to develop improved methodologies so that further advances can be made in this field.
Lessons from early trials
Based on clinical experience and eminence- based intuition, aspirin, corticosteroids and hydroxychloroquine were approved for use in SLE in the 1950s by the FDA. Additionally, chloroquine and quinacrine (in combination with hydroxychloro quine) were approved for cutaneous lupus in 1959 as Triquin, but the sponsor (Winthrop) withdrew this agent from the market in 1972 when the FDA placed ne w r e quirements on combinat ion drug regimens.2
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As summarized elsewhere,3 reports evaluating the efficacy of azathioprine, methotrexate, nitrogen mustard, chlorambucil, cyclophosphamide, ciclosporin, apheresis and pulse corticosteroids between 1950 and 1996 were usually from small, single-centre and often retrospective studies. Clinical trials not involving patients with lupus nephritis evaluated disease flare rates by use of a variety of clinical measures, subjective measures of improvement and the ability to taper corticosteroids. Only a handful of studies prospectively examined renal disease, by evaluating steroid dose, renal function and survival, proteinuria, levels of anti- double-stranded DNA (dsDNA) antibodies, C3 complement, serum albumin and urine sediment, mortality and c omplications (for example, infections). Between 1971 and 1996, a landmark initi ative at the NIH compared interventions for lupus nephritis including prednisone, oral or intravenous cyclophosphamide and azathioprine.4,5 These studies found that intravenous cyclophosphamide with oral corticosteroids was superior to other combinations of therapies. This effort represented a huge advance in SLE trial methodology, even though use of statistics was minimal and outcomes for membranous and proliferative nephritis were not evaluated separately.6 The suggestion of the superiority of intravenous cyclophosphamide was evident only after 5–7 years. This lag time had the unintended consequence of discouraging pharmaceutical companies from developing targeted therapies for SLE, and shifted research and development efforts towards rheumatoid arthritis. Another large multicentre NIH-funded trial of apheresis taught investigators that when two effective, aggressive therapies are compared (high-dose corticosteroids plus cyclophosphamide, with or without plasma exchange), it is hard to discern a difference in clinical outcome.7 Most of the above studies were trials carried out to learn more about the management of SLE. Many of the advances in clinical trials over the past 60 years are products of the initiative of practitioners independent of pharmaceutical companies and not involving biologic agents, such as the NIH initiatives mentioned above and ADVANCE ONLINE PUBLICATION | 1
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PERSPECTIVES Hydroxychloroquine, chloroquine and quinacrine combined as Triquin for SLE First use of LE cell preparation First use of nitrogen mustard for SLE 1948
1957
First multicentre controlled SLE trial (apheresis)
First industry-sponsored trial (DHEA) and phase I trials of targeted therapies SF-36 instrument developed
NIH lupus nephritis studies Methotrexate and chlorambucil studied in SLE 1959
Hydroxychloroquine approved for SLE, joining steroids and aspirin Availability of ANA testing
1965
1970s
1984
1992
First efforts to measure SLE disease activity (e.g. SLEDAI)
Azathioprine and cyclophosphamide studied in SLE
Revised FDA guidance document issued
First organ-specific measures validated (CLASI) Draft FDA guidance document released
1993
1994
1996
SRI-4 published and endorsed by the FDA
Anti-CD40L preparations studied 1997
1998
2005
2009
Development of flare instruments
Belimumab approved
2010
2011
First SLE-specific validated patient response measures published 2012
2014
Damage index published
BILAG index published
OMERACT presents list of domains to measure SLE disease activity over time
More than 20 failed SLE trials published from the USA and Western Europe
Figure 1 | A timeline summarizing drug development for SLE. Studies with immunosuppressive drugs and other disease-modifying agents evolved Nature | Rheumatology between 1948 and the 1990s. Clinical trial methodology in rheumatology in general was further addressed by OMERACT in Reviews the 1990s and in SLE specifically by the FDA guidance documents and more recently by the development of composite response indices. Targeted therapies were first studied in the 1990s, leading to the approval of belimumab in 2011. Abbreviations: ANA, anti-nuclear antibody; BILAG, British Isles Lupus Assessment Group; CD40L, CD40 ligand; CLASI, clinical lupus assessment for skin involvement; DHEA, dehydroepiandrosterone; LE, lupus erythematosus; OMERACT, Outcome Measures in Rheumatology; SF-36, short-form 36; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index.
Box 1 | FDA guidance* for SLE drug development20 ■■ Two adequate and well-controlled clinical trials must be conducted, preferably superiority trials with long-term open-label extension ■■ Randomized controlled trials should be ≥1 year in duration ■■ Patients enrolled in trials should fulfill the ACR criteria for SLE ■■ Patients should be stratified at study entry on the basis of disease severity ■■ BILAG‑2004 is the preferred disease activity index; SLEDAI, ECLAM and SLAM are acceptable ■■ Use standard definitions (provided in the guidance document) for major and partial clinical responses, remission, flare reduction, increase in time to flare and steroid-sparing effects ■■ Variability in steroid use should be minimized ■■ Patient-reported outcome measures should be evaluated ■■ Subpart H and E relating to the use of biomarkers are potentially applicable to SLE if such a biomarker or surrogate marker is validated‡ *Summary of the main points from the FDA guidance for industry on the development of medicinal products for the treatment of SLE.20 ‡The FDA can fast-track approval for an indication if validated candidate biomarkers or surrogate markers are met as primary endpoints. Abbreviations: BILAG, British Isles Lupus Assessment Group; ECLAM, European consensus lupus activity measure; SLAM, systemic lupus activity measure; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index.
subsequent studies of hydroxychloroquine, methotrexate, leflunomide, mycophenolate, tacrolimus and cyclophosphamide.8–13 The first registrational clinical trial (carried out to have an agent approved by regulatory authorities for sale and marketing) in SLE involved dehydroepiandrosterone (DHEA, also known as prasterone). This steroid precursor of androgens and, to a lesser extent, oestrogens is still used in the USA as a treatment for SLE in overthe-counter or compounded formulations. For a 10-year period beginning in 1994, DHEA was studied in controlled settings and found to be steroid-sparing, promote type 2 T helper (TH2) cell activity, improve bone density and decrease fatigue. 14,15 Although eminence-based consensus was that this drug was mildly effective for the treatment of SLE, an FDA advisory board
recommended, by a narrow margin, against approval on the basis of post hoc analyses that demonstrated failure of the agent to improve levels of anti-dsDNA antibodies, SLE disease activity index (SLEDAI) scores or erythrocyte sedimentation rates. 14,15 Despite sincere efforts by industry and regulatory authorities to gain approval for the use of DHEA in SLE, a major unmet need became apparent in the lack of a clear and consistent strategy for getting a drug to market. The advent of biologic therapies ultimately fast-tracked the development of this process (Figure 1).
Setting a new course
SLE therapy advanced into the modern era with a small number of phase I trials, conducted between 1991 and 1996, of targeted therapies including mAb3E10
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(a mouse monoclonal antibody targeting dsDNA), anti-CD5 IgG–ricin immunotoxin, anti-CD4 antibody (MAX.16H5) and recombinant human DNase.3 Although no improvements and rapid tachyphylaxis were noted with these largely murine preparations, the feasibility of the technology led to two innovative phase II trials. These trials, undertaken between 1997 and 2004, tested two different preparations of monoclonal antibodies targeting CD40 ligand (BG9588 and IDEC‑131). However, the studies were hampered by poor design (the BG9588 trial took 2 years to enroll the first patient) or adverse reactions (once begun, the BG9588 trial was cancelled owing to high rates of myocardial infarctions and thrombo embolic events; IDEC‑131 simply did not have any effects).16,17 Clearly, direction was needed regarding the conduct of and choice of metrics used for trials of candidate drugs for SLE. To this end, in 2004 the FDA held hearings and received input from several hundred stakeholders in industry, academic and community rheumatologists, other practitioners who treat patients with SLE, advocacy organizations and patients, which culminated in the release of a draft guidance document on the development of drugs for SLE.18 Guidelines for lupus nephritis were issued in 2010 but were subsequently withdrawn.19 The major points of the 2005 document were that, for registrational trials, a candidate drug for SLE must be safe, should improve quality of life, should ideally demonstrate change via a clinical response index, should demonstrate change via a disease www.nature.com/nrrheum
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PERSPECTIVES Table 1 | Measures for evaluating SLE activity subject to change with interventions23–25
Box 2 | Biologics studied since 2005
Domain/outcome
Measure(s)
Notes
Disease activity
SLEDAI and in versions and modifications (SLEDAI, SLEDAI-2K, Mex-SLEDAI, SELENA-SLEDAI)
First developed in 1985 and widely used
Drugs no longer in development for SLE ■■ Abetimus, ocrelizumab, rontiluzumab, tabalumab, sirukumab26–30
SRI‑50
In use since 2010 to assess 50% improvement
BILAG index
Widely used since 1993 in different versions (for example, BILAG‑2004)
SLAM and its versions (SLAM, SLAM‑R, SLAQ)
Widely used since 1989 but now rarely used
Flare indices: SELENA-SLEDAI Flare Index, BILAG (development of new A or B scores)
In use since 2010
Others: ECLAM, LAI, SIS, RIFLE
Rarely used
SLICC–ACR damage index
In use since 1996 Physician-completed
LDIQ
Patient-completed
Renal biopsy, end stage renal disease
Measures of renal damage
SF‑36
Generic questionnaire (not SLE-specific) In use since 1994
LupusQoL, SLE Symptom Checklist, SLEQoL, L‑QoL
SLE-specific questionnaire
Patient-reported outcomes: Lupus Impact Tracker, Lupus Foundation of America Patient-Reported Outcome (in development)
SLE-specific
Organ damage
n/a
Hospitalization
n/a
Death
n/a
Economic costs and effects
Direct and indirect costs
n/a
Health utilities, pharmacoeconomics
n/a
Composite response indices
SRI
SLEDAI-based
BICLA
BILAG-based
Organ-specific
CLASI
For cutaneous lupus
Nephritis
Definitions provided for partial and complete response
Ability to taper corticosteroids; autoantibodies; complement and complement-split products; cell subsets (for example, B cells); cytokines; markers of innate immunity (for example, interferon signature)
No biomarkers or surrogate markers have been qualified or accepted to date; candidate categories are listed
Damage
Health-related quality of life
Adverse events
Biomarkers, surrogate markers
Abbreviations: BICLA, BILAG-based combined lupus assessment; BILAG, British Isles Lupus Assessment Group; CLASI, clinical lupus assessment for skin involvement; ECLAM, European consensus lupus activity measure; LAI, lupus activity index; LDIQ, lupus organ damage instrument; L‑QoL, SLE quality of life questionnaire; Mex-SLEDAI, Mexican SLEDAI; n/a, not applicable; RIFLE, response index for lupus erythematosus; SELENA, Safety of Estrogen in Lupus National Assessment; SF‑36, short-form 36; SIS, NIH systemic lupus index score; SLAM, systemic lupus activity measure; SLAM‑R, systemic lupus activity measure (revised); SLAQ, systemic lupus activity questionnaire; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SLEQoL, SLE-specific quality of life questionnaire; SLICC, Systemic Lupus International Collaborative Clinics; SRI, SLE response index.
activity index, and should slow the progression of damage. No specific clinical response index was endorsed, but the damage index specifically mentioned was the ACR–SLICC (American College of Rheumatology– Systemic Lupus International Collaborative Clinics) damage index. The BILAG (British Isles Lupus Assessment Group) index, SLEDAI, SLAM (systemic lupus activity
measure) and ECLAM (European consensus lupus activity measure), were also mentioned, as well as the use of validated and acceptable metrics. This guidance shifted focus to the treatment of generalized SLE but encouraged the development of organ-specific meas ures (for example, kidney or skin) and the use of biomarkers or surrogate markers
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Drugs currently under study from a registrational standpoint ■■ Atacicept, epratuzumab, lupuzor, sifilumumab, edratide, abatacept, blisbimod, several iterations of anti-IL‑6 agents31–38 Drugs currently under study from a nonregistrational standpoint ■■ Etanercept, infliximab, rituximab39–41
that could shorten trial duration. The 2005 FDA document was partly responsible for the development of SLE-specific quality of life measures (such as LupusPRO, a patientreported outcome tool), clinical response indices (for example, the systemic lupus response index [SRI] and the BILAG-based composite lupus assessment [BICLA]), and organ-specific measures such as the CLASI (clinical lupus assessment for skin involvement) for cutaneous lupus. Within a year of publication of the draft guidance, numerous lupus trials were initiated or planned. Incorporating constructive input from stakeholders, the guidance document was revised and finalized in 2010.20 More detailed and specific than the 2005 draft guidance document, the major points of the 2010 version are summarized in Box 1. Belimumab was approved in March 2011 as a result of successfully following the pathway for drug development suggested by these documents and most ongoing clinical trials also follow this guidance. Interestingly, the primary endpoint used in the belimumab studies (the SRI) was not mentioned in either version of the guidance document, but was a product of collaboration between the FDA and industry as trials of this drug progressed.21
Evaluating SLE activity
The past 30 years has seen increased accuracy and precision in defining what constitutes improvement in SLE. The measures in current use are summarized in Table 1. The Lupus Activity Criteria Count (1984) was the first effort to put together a group of symptoms, signs and laboratory findings as a metric to follow the course of the disease over time.22 Numerous indices have since been developed, some of which are more widely used than others. In 1998, the Outcome Measures in Rheumatology (OMERACT) initiative published a list of domains that could assess changes in the ADVANCE ONLINE PUBLICATION | 3
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PERSPECTIVES Drug mechanism of action applicable to SLE
Drug not available Drug already available Assessing repurposing effects
Assessing new agent effects
Specific organ domain management
Prevent disease development in those at risk
Prevent disease flares
Induction therapy for early active disease
Maintenance of improvement
Devising outcome measures
Clinical response measures (e.g. SLEDAI)
Composite measures (e.g. SRI)
Damage indices
Flare indices
SLE-specific PROs
Biomarkers or surrogate markers
Pharmacoeconomic considerations
Figure 2 | New approaches to be considered for drug development in SLE. The design of clinical Nature Reviews | Rheumatology trials for putative agents in SLE vary according to whether or not the drug is already available (and subject to repurposing), and whether it targets a specific aspect of SLE or SLE as a multiple-organ-system disease. Is the new agent intended to be used for induction, maintenance, flare prevention or disease prevention? SLE outcome measures are undergoing a transformation to improve their accuracy and relevancy. Abbreviations: PRO, patient-reported outcome; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index. Box 3 | SLE drug development—key messages ■■ In the past 60 years, only one new agent (belimumab) has been approved by the FDA in the USA for the treatment of systemic lupus erythematous (SLE) ■■ SLE is a very difficult disease to study in clinical trials, given the involvement of multiple organ systems to varying degrees at different times, as well as the difficulty in measuring inflammation. Since the metrics currently used to assess improvement in studies were introduced in the 1980s and 1990s, before clinical trials were performed, efforts to improve upon these metrics are in progress ■■ SLE is best evaluated using a composite response measure and other instruments that take into account disease activity, organ damage, health-related quality of life and patient-reported outcomes, as well as adverse events, pharmacoeconomics, organ-specific measures, and biomarkers/surrogate markers of activity ■■ Clinical trials underway include registrational studies, repurposing studies, and studies investigating existing agents for specific aspects of SLE ■■ Initiatives to rethink SLE clinical trials are focused on moving beyond the 2010 FDA guidelines. These initiatives include improved trial designs and recruitment strategies, new composite measures based on data from completed trials, and enrichment protocols that enable enrollment of fewer patients and shorter study duration ■■ Clinical trials undertaken in the next few years will, for the first time, address disease prevention, flare mitigation, interventions in early disease to induce remission and limit subsequent flares, and evaluation of organ-specific disease as well as outcome measures
manifestations of SLE over time.23 None of the metrics published before 2000 were intended specifically for use in clinical trials, and thus have inherent weaknesses when employed for that intent (Table 1).24,25
Current status and future outlook
Tremendous strides have been made, in the development of new therapies for SLE in general and in clinical trials specifically, since the first trials of biologic agents more than 20 years ago. Unfortunately, only one targeted agent has been approved and no
agents are being considered for approval at this time. Box 2 summarizes the current status of trials. Phase II and III clinical trials underway include registrational studies (for new agents, typically with pharmaceutical company sponsorship), initiatives of advocacy organizations (such as repurposing studies, in which agents approved for use in other diseases are assessed for use in SLE), or individual or group efforts—usually not part of an organized industry effort—to examine existing agents for specific aspects of SLE (for example, organ-specific approaches for
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nephritis). The past 20 years has witnessed the failure of many promising agents to meet their primary endpoints. This disappointment has led to reconsideration of how SLE clinical trials should be approached. Several innovative ideas and measures to improve clinical trials are under consideration by pharmaceutical companies, biotechnology start-ups and SLE organizations that underwrite and otherwise support drug development (Figure 2). One suggestion is to create a new paradigm for the design of clinical trials. Examples include designing superiority rather than equivalence trials, being sensitive to international clinical standa rds of practice, making clinical research organizations more user-friendly for academic trial sites, improving the quality of reference lab oratories, and revising the requirement for anti-nuclear antibody positivity in relation to patient participation. Another proposal is to improve the clinical trial ‘landscape’ by undertaking studies with more efficient and mission-relevant approaches. These approaches include prevention of disease development among those at risk, induction trials limited to patients with early and/ or active disease, initiatives to maintain improvement and prevent flares, and focusing on organ-specific studies. The possibility of performing smart, cost-effective, smallscale trials is also being evaluated, along with repurposing agents already on the market (the safety of which is already documented) and withdrawing effective drugs to assess their efficacy as short-term, highly focused interventions. Additional improvements to SLE clinical trials could include the use of improved composite disease activity measures, data-mining of completed studies, evaluating candidate surrogate markers or biomarkers, optimizing trial sites and patient recruitment strategies, and educating patients and investigators about the benefits of participation. Although survival and quality of life for patients with SLE has improved over the past 60 years due to advances in medical care (for example, dialysis) and the introduction of new medications, including novel anti biotics, hypertensive drugs, renal replacement therapy, immunosuppressive agents and biologic drugs, these patients still have a decreased life expectancy and quality of life. The development of new therapeutic interventions, combinations of interventions and improved trial design represents a promising approach to fulfilling this huge unmet need in the management of SLE (Box 3). www.nature.com/nrrheum
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PERSPECTIVES Conclusions
For patients with SLE, rates of morbidity and mortality remain unacceptably high despite the introduction of novel antibiotics, hypertensive drugs, renal replacement therapy, immunosuppressive agents and biologic drugs over the past 60 years. The lupus community is working together to create new methodologies for use in the design of clinical trials with more-efficient and missionrelevant approaches compared with past and current trials. If these efforts are successful, the next decade could witness the approval of a new group of targeted therapies for SLE that will hopefully not only decrease inflammation and prevent damage, but also improve outcomes and quality of life.
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Division of Rheumatology, Cedars–Sinai Medical Center, 8737 Beverly Boulevard, Suite 302, West Hollywood, CA 90048, USA. [email protected]
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41.
double-blind, phase III study. Arthritis Rheum.65, 2368–2379 (2013). Aranow, C. et al. A phase 2 multicenter randomized double-blind, placebo-controlled, proof‑of‑concept study to evaluate the efficacy and safety of sirukumab in patients with active lupus nephritis [abstract 2835]. Arthritis Rheum. 66 (Suppl.), S1239 (2014). Kalunian, K. C. et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis2014-206090. Isenberg, D. et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate‑to‑severe systemic lupus erythematosus (SLE): 52 week data (APRIL-SLE randomized trial. Ann. Rheum. Dis. http:// dx.doi.org/10.1136/annrheumdis‑2013‑ 205067. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non‑life‑threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 3077–3087 (2010). Urowitz, M., Isenberg, D. & Wallace, D. J. Prelude—Edratide phase-II study outcome— from predefined analyses to more recent assessment approaches. Ann. Rheum. Dis. 70 (Suppl. 3), 315 (2011). Zimmer, R., Scherbarth, H. R., Rillo, O. L., Gomez-Reino, J. J. & Muller, S. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann. Rheum. Dis. 72, 1830–1835 (2013). Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010). Furie, R. A. et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate‑to‑severe systemic lupus erythematosus, the PEARL‑SC study. Ann Rheum Dis. http://dx.doi.org/10.1136/ annrheumdis‑2013‑205144. Khamastha, M. et al. Safety and efficacy of sifalimumab, an anti interferon-α monoclonal antibody in a phase 2b study of moderate to severe SLE [abstract L4]. Arthritis Rheum. 66 (Suppl. 1), S312 (2014). Wallace, D. J. et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomized, double-blind, placebo-controlled, multicenter study. Ann. Rheum. Dis. 73, 183–190 (2014). Aringer, M. et al. Adverse events and efficacy of TNF-α blockade with infliximab in patients with systemic lupus erythematosus: long-term follow-up of 13 patients. Rheumatology (Oxford) 48, 1451–1454 (2009). Merrill, J. T. et al. Efficacy and safety of rituximab in moderately‑to‑severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 1215–1227 (2010). Cortés-Hernández, J., Egri, N., VilardellTarrés, M. & Ordi-Ros, J. Etanercept in refractory lupus arthritis: an observational study. Semin. Arthritis Rheum. http://dx.doi.org/10.1016/ j.semarthrit.2015.01.006.
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The evolution of drug discovery in systemic lupus erythematosus Daniel J. Wallace Abstract | Drug discovery in systemic lupus erythematosus (SLE) has lagged behind other rheumatic diseases, in large part because of difficulty in measuring change or improvement in a disorder that involves multiple organ systems to varying degrees at different times. The metrics currently used as primary endpoints are composite indices that rely mainly on disease assessment measures derived before the era of clinical trials of targeted therapies. Only one agent has been approved for the treatment of SLE since 1957. This monograph reviews the evolution of drug development for SLE, problems and pitfalls that have been encountered, and outlines the domains used to evaluate SLE in the clinic. Finally, several initiatives underway to improve clinical trial design are outlined. Wallace, D. J. Nat. Rev. Rheumatol. advance online publication 30 June 2015; doi:10.1038/nrrheum.2015.86
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of the immune system. The disease affects somewhere between 200,000 and 500,000 individuals in the USA, predominantly young women in their reproductive years. 1 Mild disease is currently managed with NSAIDs, antimalarial drugs and low-dose corticosteroids, whereas moderate to severe SLE warrants the use of higher doses of corticosteroids and immunosuppressive agents. Over the past decade, targeted therapies have been studied for the management of refractory disease. However, the development of new agents to manage SLE has lagged behind that of other auto immune rheumatic disorders. This lack of advancement is in large part because SLE is a heterogeneous disorder with effects on nine principal domains (organ systems) that are difficult to measure and quantify, and that can be at variance with each other. The past 30 years has witnessed the introduction of guidelines, disease definitions, candidate surrogate markers or biomarkers, metrics and composite indices to guide the Competing interests The author has acted as a consultant for GSK, Merck Serono and UCB.
treatment of SLE (Figure 1). Despite these developments, many study drugs have not met their primary or secondary endpoints— a situation that has led to a re-examination of SLE trial design. Since 1959, only one agent (belimumab) has been approved by the FDA for use in SLE; other available agents such as rituximab, tacrolimus, azathioprine, methotrexate, cyclophosphamide and mycophenolate mofetil are widely used off-label, but insurance coverage for such treatments is often limited for hundreds of thousands of US patients with SLE or lupus-related disorders. This manuscript reviews the evolution of drug discovery for SLE with the goal of outlining approaches to develop improved methodologies so that further advances can be made in this field.
Lessons from early trials
Based on clinical experience and eminence- based intuition, aspirin, corticosteroids and hydroxychloroquine were approved for use in SLE in the 1950s by the FDA. Additionally, chloroquine and quinacrine (in combination with hydroxychloro quine) were approved for cutaneous lupus in 1959 as Triquin, but the sponsor (Winthrop) withdrew this agent from the market in 1972 when the FDA placed ne w r e quirements on combinat ion drug regimens.2
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As summarized elsewhere,3 reports evaluating the efficacy of azathioprine, methotrexate, nitrogen mustard, chlorambucil, cyclophosphamide, ciclosporin, apheresis and pulse corticosteroids between 1950 and 1996 were usually from small, single-centre and often retrospective studies. Clinical trials not involving patients with lupus nephritis evaluated disease flare rates by use of a variety of clinical measures, subjective measures of improvement and the ability to taper corticosteroids. Only a handful of studies prospectively examined renal disease, by evaluating steroid dose, renal function and survival, proteinuria, levels of anti- double-stranded DNA (dsDNA) antibodies, C3 complement, serum albumin and urine sediment, mortality and c omplications (for example, infections). Between 1971 and 1996, a landmark initi ative at the NIH compared interventions for lupus nephritis including prednisone, oral or intravenous cyclophosphamide and azathioprine.4,5 These studies found that intravenous cyclophosphamide with oral corticosteroids was superior to other combinations of therapies. This effort represented a huge advance in SLE trial methodology, even though use of statistics was minimal and outcomes for membranous and proliferative nephritis were not evaluated separately.6 The suggestion of the superiority of intravenous cyclophosphamide was evident only after 5–7 years. This lag time had the unintended consequence of discouraging pharmaceutical companies from developing targeted therapies for SLE, and shifted research and development efforts towards rheumatoid arthritis. Another large multicentre NIH-funded trial of apheresis taught investigators that when two effective, aggressive therapies are compared (high-dose corticosteroids plus cyclophosphamide, with or without plasma exchange), it is hard to discern a difference in clinical outcome.7 Most of the above studies were trials carried out to learn more about the management of SLE. Many of the advances in clinical trials over the past 60 years are products of the initiative of practitioners independent of pharmaceutical companies and not involving biologic agents, such as the NIH initiatives mentioned above and ADVANCE ONLINE PUBLICATION | 1
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PERSPECTIVES Hydroxychloroquine, chloroquine and quinacrine combined as Triquin for SLE First use of LE cell preparation First use of nitrogen mustard for SLE 1948
1957
First multicentre controlled SLE trial (apheresis)
First industry-sponsored trial (DHEA) and phase I trials of targeted therapies SF-36 instrument developed
NIH lupus nephritis studies Methotrexate and chlorambucil studied in SLE 1959
Hydroxychloroquine approved for SLE, joining steroids and aspirin Availability of ANA testing
1965
1970s
1984
1992
First efforts to measure SLE disease activity (e.g. SLEDAI)
Azathioprine and cyclophosphamide studied in SLE
Revised FDA guidance document issued
First organ-specific measures validated (CLASI) Draft FDA guidance document released
1993
1994
1996
SRI-4 published and endorsed by the FDA
Anti-CD40L preparations studied 1997
1998
2005
2009
Development of flare instruments
Belimumab approved
2010
2011
First SLE-specific validated patient response measures published 2012
2014
Damage index published
BILAG index published
OMERACT presents list of domains to measure SLE disease activity over time
More than 20 failed SLE trials published from the USA and Western Europe
Figure 1 | A timeline summarizing drug development for SLE. Studies with immunosuppressive drugs and other disease-modifying agents evolved Nature | Rheumatology between 1948 and the 1990s. Clinical trial methodology in rheumatology in general was further addressed by OMERACT in Reviews the 1990s and in SLE specifically by the FDA guidance documents and more recently by the development of composite response indices. Targeted therapies were first studied in the 1990s, leading to the approval of belimumab in 2011. Abbreviations: ANA, anti-nuclear antibody; BILAG, British Isles Lupus Assessment Group; CD40L, CD40 ligand; CLASI, clinical lupus assessment for skin involvement; DHEA, dehydroepiandrosterone; LE, lupus erythematosus; OMERACT, Outcome Measures in Rheumatology; SF-36, short-form 36; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index.
Box 1 | FDA guidance* for SLE drug development20 ■■ Two adequate and well-controlled clinical trials must be conducted, preferably superiority trials with long-term open-label extension ■■ Randomized controlled trials should be ≥1 year in duration ■■ Patients enrolled in trials should fulfill the ACR criteria for SLE ■■ Patients should be stratified at study entry on the basis of disease severity ■■ BILAG‑2004 is the preferred disease activity index; SLEDAI, ECLAM and SLAM are acceptable ■■ Use standard definitions (provided in the guidance document) for major and partial clinical responses, remission, flare reduction, increase in time to flare and steroid-sparing effects ■■ Variability in steroid use should be minimized ■■ Patient-reported outcome measures should be evaluated ■■ Subpart H and E relating to the use of biomarkers are potentially applicable to SLE if such a biomarker or surrogate marker is validated‡ *Summary of the main points from the FDA guidance for industry on the development of medicinal products for the treatment of SLE.20 ‡The FDA can fast-track approval for an indication if validated candidate biomarkers or surrogate markers are met as primary endpoints. Abbreviations: BILAG, British Isles Lupus Assessment Group; ECLAM, European consensus lupus activity measure; SLAM, systemic lupus activity measure; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index.
subsequent studies of hydroxychloroquine, methotrexate, leflunomide, mycophenolate, tacrolimus and cyclophosphamide.8–13 The first registrational clinical trial (carried out to have an agent approved by regulatory authorities for sale and marketing) in SLE involved dehydroepiandrosterone (DHEA, also known as prasterone). This steroid precursor of androgens and, to a lesser extent, oestrogens is still used in the USA as a treatment for SLE in overthe-counter or compounded formulations. For a 10-year period beginning in 1994, DHEA was studied in controlled settings and found to be steroid-sparing, promote type 2 T helper (TH2) cell activity, improve bone density and decrease fatigue. 14,15 Although eminence-based consensus was that this drug was mildly effective for the treatment of SLE, an FDA advisory board
recommended, by a narrow margin, against approval on the basis of post hoc analyses that demonstrated failure of the agent to improve levels of anti-dsDNA antibodies, SLE disease activity index (SLEDAI) scores or erythrocyte sedimentation rates. 14,15 Despite sincere efforts by industry and regulatory authorities to gain approval for the use of DHEA in SLE, a major unmet need became apparent in the lack of a clear and consistent strategy for getting a drug to market. The advent of biologic therapies ultimately fast-tracked the development of this process (Figure 1).
Setting a new course
SLE therapy advanced into the modern era with a small number of phase I trials, conducted between 1991 and 1996, of targeted therapies including mAb3E10
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(a mouse monoclonal antibody targeting dsDNA), anti-CD5 IgG–ricin immunotoxin, anti-CD4 antibody (MAX.16H5) and recombinant human DNase.3 Although no improvements and rapid tachyphylaxis were noted with these largely murine preparations, the feasibility of the technology led to two innovative phase II trials. These trials, undertaken between 1997 and 2004, tested two different preparations of monoclonal antibodies targeting CD40 ligand (BG9588 and IDEC‑131). However, the studies were hampered by poor design (the BG9588 trial took 2 years to enroll the first patient) or adverse reactions (once begun, the BG9588 trial was cancelled owing to high rates of myocardial infarctions and thrombo embolic events; IDEC‑131 simply did not have any effects).16,17 Clearly, direction was needed regarding the conduct of and choice of metrics used for trials of candidate drugs for SLE. To this end, in 2004 the FDA held hearings and received input from several hundred stakeholders in industry, academic and community rheumatologists, other practitioners who treat patients with SLE, advocacy organizations and patients, which culminated in the release of a draft guidance document on the development of drugs for SLE.18 Guidelines for lupus nephritis were issued in 2010 but were subsequently withdrawn.19 The major points of the 2005 document were that, for registrational trials, a candidate drug for SLE must be safe, should improve quality of life, should ideally demonstrate change via a clinical response index, should demonstrate change via a disease www.nature.com/nrrheum
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PERSPECTIVES Table 1 | Measures for evaluating SLE activity subject to change with interventions23–25
Box 2 | Biologics studied since 2005
Domain/outcome
Measure(s)
Notes
Disease activity
SLEDAI and in versions and modifications (SLEDAI, SLEDAI-2K, Mex-SLEDAI, SELENA-SLEDAI)
First developed in 1985 and widely used
Drugs no longer in development for SLE ■■ Abetimus, ocrelizumab, rontiluzumab, tabalumab, sirukumab26–30
SRI‑50
In use since 2010 to assess 50% improvement
BILAG index
Widely used since 1993 in different versions (for example, BILAG‑2004)
SLAM and its versions (SLAM, SLAM‑R, SLAQ)
Widely used since 1989 but now rarely used
Flare indices: SELENA-SLEDAI Flare Index, BILAG (development of new A or B scores)
In use since 2010
Others: ECLAM, LAI, SIS, RIFLE
Rarely used
SLICC–ACR damage index
In use since 1996 Physician-completed
LDIQ
Patient-completed
Renal biopsy, end stage renal disease
Measures of renal damage
SF‑36
Generic questionnaire (not SLE-specific) In use since 1994
LupusQoL, SLE Symptom Checklist, SLEQoL, L‑QoL
SLE-specific questionnaire
Patient-reported outcomes: Lupus Impact Tracker, Lupus Foundation of America Patient-Reported Outcome (in development)
SLE-specific
Organ damage
n/a
Hospitalization
n/a
Death
n/a
Economic costs and effects
Direct and indirect costs
n/a
Health utilities, pharmacoeconomics
n/a
Composite response indices
SRI
SLEDAI-based
BICLA
BILAG-based
Organ-specific
CLASI
For cutaneous lupus
Nephritis
Definitions provided for partial and complete response
Ability to taper corticosteroids; autoantibodies; complement and complement-split products; cell subsets (for example, B cells); cytokines; markers of innate immunity (for example, interferon signature)
No biomarkers or surrogate markers have been qualified or accepted to date; candidate categories are listed
Damage
Health-related quality of life
Adverse events
Biomarkers, surrogate markers
Abbreviations: BICLA, BILAG-based combined lupus assessment; BILAG, British Isles Lupus Assessment Group; CLASI, clinical lupus assessment for skin involvement; ECLAM, European consensus lupus activity measure; LAI, lupus activity index; LDIQ, lupus organ damage instrument; L‑QoL, SLE quality of life questionnaire; Mex-SLEDAI, Mexican SLEDAI; n/a, not applicable; RIFLE, response index for lupus erythematosus; SELENA, Safety of Estrogen in Lupus National Assessment; SF‑36, short-form 36; SIS, NIH systemic lupus index score; SLAM, systemic lupus activity measure; SLAM‑R, systemic lupus activity measure (revised); SLAQ, systemic lupus activity questionnaire; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SLEQoL, SLE-specific quality of life questionnaire; SLICC, Systemic Lupus International Collaborative Clinics; SRI, SLE response index.
activity index, and should slow the progression of damage. No specific clinical response index was endorsed, but the damage index specifically mentioned was the ACR–SLICC (American College of Rheumatology– Systemic Lupus International Collaborative Clinics) damage index. The BILAG (British Isles Lupus Assessment Group) index, SLEDAI, SLAM (systemic lupus activity
measure) and ECLAM (European consensus lupus activity measure), were also mentioned, as well as the use of validated and acceptable metrics. This guidance shifted focus to the treatment of generalized SLE but encouraged the development of organ-specific meas ures (for example, kidney or skin) and the use of biomarkers or surrogate markers
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Drugs currently under study from a registrational standpoint ■■ Atacicept, epratuzumab, lupuzor, sifilumumab, edratide, abatacept, blisbimod, several iterations of anti-IL‑6 agents31–38 Drugs currently under study from a nonregistrational standpoint ■■ Etanercept, infliximab, rituximab39–41
that could shorten trial duration. The 2005 FDA document was partly responsible for the development of SLE-specific quality of life measures (such as LupusPRO, a patientreported outcome tool), clinical response indices (for example, the systemic lupus response index [SRI] and the BILAG-based composite lupus assessment [BICLA]), and organ-specific measures such as the CLASI (clinical lupus assessment for skin involvement) for cutaneous lupus. Within a year of publication of the draft guidance, numerous lupus trials were initiated or planned. Incorporating constructive input from stakeholders, the guidance document was revised and finalized in 2010.20 More detailed and specific than the 2005 draft guidance document, the major points of the 2010 version are summarized in Box 1. Belimumab was approved in March 2011 as a result of successfully following the pathway for drug development suggested by these documents and most ongoing clinical trials also follow this guidance. Interestingly, the primary endpoint used in the belimumab studies (the SRI) was not mentioned in either version of the guidance document, but was a product of collaboration between the FDA and industry as trials of this drug progressed.21
Evaluating SLE activity
The past 30 years has seen increased accuracy and precision in defining what constitutes improvement in SLE. The measures in current use are summarized in Table 1. The Lupus Activity Criteria Count (1984) was the first effort to put together a group of symptoms, signs and laboratory findings as a metric to follow the course of the disease over time.22 Numerous indices have since been developed, some of which are more widely used than others. In 1998, the Outcome Measures in Rheumatology (OMERACT) initiative published a list of domains that could assess changes in the ADVANCE ONLINE PUBLICATION | 3
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PERSPECTIVES Drug mechanism of action applicable to SLE
Drug not available Drug already available Assessing repurposing effects
Assessing new agent effects
Specific organ domain management
Prevent disease development in those at risk
Prevent disease flares
Induction therapy for early active disease
Maintenance of improvement
Devising outcome measures
Clinical response measures (e.g. SLEDAI)
Composite measures (e.g. SRI)
Damage indices
Flare indices
SLE-specific PROs
Biomarkers or surrogate markers
Pharmacoeconomic considerations
Figure 2 | New approaches to be considered for drug development in SLE. The design of clinical Nature Reviews | Rheumatology trials for putative agents in SLE vary according to whether or not the drug is already available (and subject to repurposing), and whether it targets a specific aspect of SLE or SLE as a multiple-organ-system disease. Is the new agent intended to be used for induction, maintenance, flare prevention or disease prevention? SLE outcome measures are undergoing a transformation to improve their accuracy and relevancy. Abbreviations: PRO, patient-reported outcome; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index. Box 3 | SLE drug development—key messages ■■ In the past 60 years, only one new agent (belimumab) has been approved by the FDA in the USA for the treatment of systemic lupus erythematous (SLE) ■■ SLE is a very difficult disease to study in clinical trials, given the involvement of multiple organ systems to varying degrees at different times, as well as the difficulty in measuring inflammation. Since the metrics currently used to assess improvement in studies were introduced in the 1980s and 1990s, before clinical trials were performed, efforts to improve upon these metrics are in progress ■■ SLE is best evaluated using a composite response measure and other instruments that take into account disease activity, organ damage, health-related quality of life and patient-reported outcomes, as well as adverse events, pharmacoeconomics, organ-specific measures, and biomarkers/surrogate markers of activity ■■ Clinical trials underway include registrational studies, repurposing studies, and studies investigating existing agents for specific aspects of SLE ■■ Initiatives to rethink SLE clinical trials are focused on moving beyond the 2010 FDA guidelines. These initiatives include improved trial designs and recruitment strategies, new composite measures based on data from completed trials, and enrichment protocols that enable enrollment of fewer patients and shorter study duration ■■ Clinical trials undertaken in the next few years will, for the first time, address disease prevention, flare mitigation, interventions in early disease to induce remission and limit subsequent flares, and evaluation of organ-specific disease as well as outcome measures
manifestations of SLE over time.23 None of the metrics published before 2000 were intended specifically for use in clinical trials, and thus have inherent weaknesses when employed for that intent (Table 1).24,25
Current status and future outlook
Tremendous strides have been made, in the development of new therapies for SLE in general and in clinical trials specifically, since the first trials of biologic agents more than 20 years ago. Unfortunately, only one targeted agent has been approved and no
agents are being considered for approval at this time. Box 2 summarizes the current status of trials. Phase II and III clinical trials underway include registrational studies (for new agents, typically with pharmaceutical company sponsorship), initiatives of advocacy organizations (such as repurposing studies, in which agents approved for use in other diseases are assessed for use in SLE), or individual or group efforts—usually not part of an organized industry effort—to examine existing agents for specific aspects of SLE (for example, organ-specific approaches for
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nephritis). The past 20 years has witnessed the failure of many promising agents to meet their primary endpoints. This disappointment has led to reconsideration of how SLE clinical trials should be approached. Several innovative ideas and measures to improve clinical trials are under consideration by pharmaceutical companies, biotechnology start-ups and SLE organizations that underwrite and otherwise support drug development (Figure 2). One suggestion is to create a new paradigm for the design of clinical trials. Examples include designing superiority rather than equivalence trials, being sensitive to international clinical standa rds of practice, making clinical research organizations more user-friendly for academic trial sites, improving the quality of reference lab oratories, and revising the requirement for anti-nuclear antibody positivity in relation to patient participation. Another proposal is to improve the clinical trial ‘landscape’ by undertaking studies with more efficient and mission-relevant approaches. These approaches include prevention of disease development among those at risk, induction trials limited to patients with early and/ or active disease, initiatives to maintain improvement and prevent flares, and focusing on organ-specific studies. The possibility of performing smart, cost-effective, smallscale trials is also being evaluated, along with repurposing agents already on the market (the safety of which is already documented) and withdrawing effective drugs to assess their efficacy as short-term, highly focused interventions. Additional improvements to SLE clinical trials could include the use of improved composite disease activity measures, data-mining of completed studies, evaluating candidate surrogate markers or biomarkers, optimizing trial sites and patient recruitment strategies, and educating patients and investigators about the benefits of participation. Although survival and quality of life for patients with SLE has improved over the past 60 years due to advances in medical care (for example, dialysis) and the introduction of new medications, including novel anti biotics, hypertensive drugs, renal replacement therapy, immunosuppressive agents and biologic drugs, these patients still have a decreased life expectancy and quality of life. The development of new therapeutic interventions, combinations of interventions and improved trial design represents a promising approach to fulfilling this huge unmet need in the management of SLE (Box 3). www.nature.com/nrrheum
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PERSPECTIVES Conclusions
For patients with SLE, rates of morbidity and mortality remain unacceptably high despite the introduction of novel antibiotics, hypertensive drugs, renal replacement therapy, immunosuppressive agents and biologic drugs over the past 60 years. The lupus community is working together to create new methodologies for use in the design of clinical trials with more-efficient and missionrelevant approaches compared with past and current trials. If these efforts are successful, the next decade could witness the approval of a new group of targeted therapies for SLE that will hopefully not only decrease inflammation and prevent damage, but also improve outcomes and quality of life.
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Division of Rheumatology, Cedars–Sinai Medical Center, 8737 Beverly Boulevard, Suite 302, West Hollywood, CA 90048, USA. [email protected]
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