New guideline for the management of Systemic Lupus Erythematosus (SLE): Considerations for clinical development
This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.
Publication by the European Alliance of Associations for Rheumatology (EULAR) of its revised guideline for the treatment of patients with SLE presents a significant opportunity to improve the design of clinical trials of investigational drugs for this challenging condition, for which there is still an unmet medical need. Sponsors of investigational medicinal products can now better harmonize the background standard of care in clinical trials and make an appropriate choice of comparators depending on the intended population to be treated.
The EULAR Task Force agreed on five overarching principles and 13 recommendations for the use of authorized medicines for the treatment of SLE, which include Disease Modifying Anti Rheumatic Drugs (DMARDS), immunosuppressive drugs (ISDs), and biological therapies. This guideline includes recommendations on treatment strategy, assessment of response, use of combination and sequential therapies, and tapering of therapy:
- Hydroxychloroquine is recommended for all patients with Lupus at a target dose of 5 mg/kg real body weight/day, however individual’s risk for flares and retinal toxicity also needs to be taken into consideration.
- Glucocorticoids are recommended as ’bridging therapy’ during periods of disease activity; for maintenance treatment, they should be minimized to equal or less than 5mg/day (prednisone equivalent) and when possible withdrawn.
- Immunosuppressive medications such as methotrexate, azathioprine, mycophenolate, and/or biological agents such as anifrolumab or belimumab should be commenced promptly to control the disease and facilitate Glucocorticoid tapering/discontinuation. Cyclophosphamide and rituximab should be considered in organ-threatening and refractory disease, respectively.
- The updated guidance also provides recommendations for anchor drugs and add-on therapy for the treatment of active Lupus Nephritis.
Specific recommendations are also provided for cutaneous, neuropsychiatric, and hematological diseases, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, and cardiovascular disease. The guideline also highlights areas of unmet need, as there is a lack of targeted therapies in patients with severe disease including Lupus Nephritis and Neuropsychiatric Lupus.
Implications for clinical trial design
For most new medical products, the ideal clinical trial design to evaluate efficacy and safety is a randomized, controlled trial with a placebo or active comparator arm. In the case of SLE, because there are approved medicines, no patient enrolled in an SLE clinical trial should be treated with a placebo and should receive standard of care. Therefore, an important question becomes: What is the appropriate comparator to use or design for an SLE clinical trial?
The updated EULAR guideline provides a universal agreement on the current standard of care, which assists clinical trial sponsors in determining how to harmonize the background standard of care treatment and make an appropriate choice of comparators depending on the intended population to be treated.
When designing SLE clinical trials, the implications of the updated guideline include that all patients would be on some type of therapy following their SLE diagnosis. Hydroxychloroquine 5mgs daily is now recommended as standard of care. A maximum recommended maintenance dose of 5mg/day prednisone equivalent is also recommended which is stricter than the 7.5mg/day stated in the previous EULAR guideline. Additionally, to avoid long-term exposure to glucocorticoids, early use of immunosuppressive drugs is recommended in SLE. Patients are not required to have failed one or more conventional drugs before initiating a biological agent. Consequently, when determining patient eligibility criteria, a high level of disease activity should be considered as it can be more difficult to demonstrate a treatment effect if baseline disease activity is low and patients are already receiving active treatment, and if the new treatment is designed as an add-on therapy. Additionally, the planned clinical trial analysis methods should consider how the effects of the investigational SLE treatment should be contextualized, both in terms of how the results relate to current practice and where the new therapy would be placed in the current treatment paradigm.
Implications of prior clinical trial assessment by regulators
Anifrolumab was authorized by the FDA on 30 July 2021, as an add-on therapy for the treatment of adult patients with moderate to severe, active autoantibody-positive SLE, despite standard therapy. The pivotal trials enrolled patients with a SELENA SLEDAI score ≥6 but did not enroll patients with severe active Central Nervous System Lupus or severe active Lupus Nephritis. 99% of patients enrolled had a BILAG -2004 category C, D or E for both Renal and Neuropsychiatric categories. Additionally, while most patients enrolled were taking antimalarials alone or in combination with oral corticosteroids or other immunosuppressants 13% of patients were receiving oral corticosteroids alone at a mean dose of 10 mg/day and no patients were receiving a biological agent.
One of the pivotal studies failed on the primary endpoint of SLE responder index (SRI (4) response) and subsequently the sponsor changed the primary endpoint for the second pivotal study to British Isles Lupus Assessment group-based composite lupus assessment (BICLA), while that study was still blinded. A modest effect size was observed in the overall population. Subgroup analyses demonstrated some heterogeneity in treatment response as a larger treatment effect was observed in patients with high disease activity based on serological markers at baseline. Additional exploratory post hoc analyses were requested and an ad hoc expert group comprising methodological and clinical experts in SLE consulted during the EMA assessment before approval was granted.
Belimumab was the first biological product for the treatment of SLE and was authorized on 9 March 2011 by the FDA. The FDA initially granted an indication for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy. The pivotal trials enrolled patients with at least mild/moderate disease activity (eligible patients had a Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA SLEDAI) score ≥6). All eligible patients had to be stably treated on the standard of care therapies at that time (corticosteroids, antimalarials, NSAIDs, and /or immunosuppressives).
The FDA review found that the treatment response to belimumab was modest but was supported by prespecified and post hoc analyses which employed higher reductions in disease activity scores (≥5 through ≥10). Additionally, while a statistical improvement in primary efficacy renal response was seen overall, no statistical difference was demonstrated in estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 or no decrease in eGFR from pre-flare value of > 20 %. The initial FDA label also clearly stated that the efficacy of belimumab was not evaluated in patients with severe active Lupus Nephritis or in severe active Central Nervous System Lupus. On 16 December 2020, FDA approved an additional indication for the treatment of adult patients with active lupus nephritis who are receiving standard therapy.
While there are several considerations for trial designs following the approval of belimumab and anifolumab in the updated EULAR guidelines, consider these additional points too:
- SLE patients may be treated earlier with biological agents, it could therefore be more difficult to enroll biologically naïve patients. There may also be a need for an active comparator arm in the trial or to assess efficacy in more treatment-resistant patients depending on the intended indication.
- While the primary endpoints accepted to date (changes in BILAG and/or (SRI (4) response) are still relevant, clinical development in less treatment-experienced patients may present an opportunity to pursue an indication such as remission, as defined by the recent Definition of Remission In SLE (DORIS) criteria or a state of low disease activity, such as the Lupus Low Disease Activity state (LLDAS).
- While corticosteroids will be required as bridging strategies, there may be fewer patients on higher doses of maintenance steroids and therefore less opportunity to demonstrate a significant steroid-sparing effect.
- A larger effect and clinically relevant benefit may be demonstrated in patients with high disease activity at baseline. Therefore, enrolling a broader population with more severe disease should be considered as enrolling a milder population may necessitate additional post hoc analyses to demonstrate a positive benefit/risk. Subgroups of patients with more severe disease, such Lupus Nephritis and/or neuropsychiatric involvement could be considered, if feasible during the development. Subject to initial results, additional larger/confirmatory studies could then be planned for. Ultimately, enrolling more severe patients may also help address the current high unmet need for new therapies in SLE and the possibility of sponsors gaining broader indications when robust data has been demonstrated.
Would you like to understand more about the impact of the updated EULAR guidelines on your SLE trial design or selection of comparator? Our regulatory experts can help. Contact us to learn more.
References
https://ard.bmj.com/content/early/2023/10/11/ard-2023-224762
https://www.ema.europa.eu/en/medicines/human/EPAR/saphnelo#assessment-history-section
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761123Orig1s000TOC.cfm
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125370Orig1s000TOC.cfm