17 May SLE: BAFF Antagonist For Treatment of Severely Active Disease
MedicalResearch.com Interview with:
Dr Renee Martin
Anthera Pharmaceuticals, Inc.
25801 Industrial Blvd, Suite B.,
Hayward, CA 94545,
MedicalResearch: What are the main findings of the study?
Dr. Martin: The PEARL-SC study identified many key elements that inform the further development of blisibimod for treatment of SLE:
i. That patients with severely active disease responded well to blisibimod,
ii. That a dose of 200mg blisibimod administered subcutaneously once per week improved measures of SLE disease activity,
iii. That greater treatment effect was observed when the SRI-7 and SRI-8 endpoints were evaluated, presumably because the criteria for these endpoints (including 7- or 8- point improvements in SELENA-SLEDAI score, respectively, along with no new BILAG A or 2B scores, and no worsening of physician’s global assessment score) demand substantial improvement in disease activity compared with baseline, and are unlikely to be met by chance (e.g. in the placebo group), and
iv. That blisibimod was safe and well-tolerated over 24-52 weeks of continuous therapy.
MedicalResearch: How does blisibimod compare to BAFF-targeting monoclonal antibodies in development for SLE?
Dr. Martin: Blisibimod is a ‘peptibody’ consisting of four BAFF-binding domains fused to the Fc domain of human IgG1, and is structurally distinct from the anti-BAFF monoclonal antibodies such as belimumab and tabalumab. Compared with tabalumab and belimumab, blisibimod’s binding affinity for BAFF (1 pM) is 126–250-fold higher, while its serum half-life (8–10 days) is approximately half as long.
MedicalResearch: Were any of the findings unexpected?
Dr. Martin: The observations that blisibimod, an inhibitor of B-cell activating factor (BAFF), was well-tolerated and improves SLE disease activity in patients with SLE is not unexpected. We were pleased to see that the SRI-7 and SRI-8 responder rates were so high in patients treated with 200mg blisibimod compared with placebo, and also that the effects of blisibimod to significantly decrease proteinuria were so rapid in onset.
Furthermore, in a subgroup (n = 278) of ‘severe’ SLE subjects defined by baseline SELENA-SLEDAI ≥10 and receiving corticosteroids at any dose, the SRI responder rates in the 200 mg QW blisibimod group were significantly higher compared with regimen-match placebo when evaluated using the SRI-8 end point.
In totality, this data has guided the Phase 3 development program for blisibimod in SLE, focused on severe SLE patients with and without renal involvement, an unmet medical need.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Martin: The completed clinical trial with blisibimod provides the first evidence that subcutaneous administration of a biologic therapeutic may lead to improvements in SLE disease activity, as well as disease-associated pharmacodynamic markers, including peripheral B cells, autoantibodies and decreased complement consumption. Furthermore, the effect to significantly decrease the urinary protein:creatinine ratio suggests that blisibimod may have therapeutic potential beyond SLE in patients with mechanistically analogous autoimmune renal damage, such as lupus nephritis and IgA nephropathy.
These are the first data to demonstrate that a subcutaneously-administered biologic therapeutic agent can improve disease activity in patients with SLE. Development of new treatment options for SLE is critical for patients and physicians alike as only one new therapeutic agent has been approved in the last 50 years.
Furthermore, the development of a subcutaneous treatment option is important for patients and their families as it has the potential to provide meaningful clinical benefit without the inconvenience of frequent and lengthy dosing visits to the clinic for patients who are typically women in the prime of their career.
MedicalResearch: What recommendations do you have for future research as a result of this study?
The findings of this study support research with blisibimod in SLE. In particular, they optimize critical design elements for Phase 3 research in SLE: the responsive population, the drug dose and the endpoint. These elements are reflected in the Phase 3 CHABLIS-SC1 trial which aims to evaluate the effects of 200 mg blisibimod administered subcutaneously once per week in patients who continue to have severely-active (SELENA-SLEDAI≥10), seropositive SLE despite ongoing treatment with corticosteroid and other standard-of-care SLE medication. The CHABLIS-SC study has been initiated and is currently enrolling.
In addition, the potential effects seen in patients with higher levels of renal involvement, as measured by the rapid and significant improvements in proteinuria, inspires further research on the benefits of BAFF inhibition in patients suffering from kidney disease. Blisibimod is currently being evaluated in patients with IgA nephropathy, a disease characterized by a progression to End-Stage Renal Disease caused by kidney damage arising from glomerular deposition of immune complexes, in a Phase 2/3 clinical trial called BRIGHT-SC.
The improvements in proteinuria also suggest that blisibimod may be beneficial to patients lupus nephritis for whom the disease prognosis remains grim.