UCSF UC San Francisco Previously Published Works Title Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double- blind, placebo-controlled trial. Permalink https://escholarship.org/uc/item/42p3g4xx Journal Annals of the rheumatic diseases, 77(6) ISSN 0003-4967 Authors Merrill, Joan T Shanahan, William R Scheinberg, Morton et al. Publication Date 2018-06-01 DOI 10.1136/annrheumdis-2018-213032 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Downloaded from http://ard.bmj.com/ on April 10, 2018 - Published by group.bmj.com ARD Online First, published on March 21, 2018 as 10.1136/annrheumdis-2018-213032 Clinical and epidemiological research EXTENDED REPORT Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial Joan T Merrill,1 William R Shanahan,2 Morton Scheinberg,3 Kenneth C Kalunian,4 David Wofsy,5 Renee S Martin2 Handling editor Josef S ABSTRacT that the greatest treatment effect is discernible using Smolen Background Targeted inhibitors of B-cell activating more stringent end points and focusing on patients factor (BAFF) have been evaluated in phase III trials in who enter with higher disease activity scores, ► Additional material is published online only. To view, over 4000 patients with systemic lupus erythematosus higher corticosteroid doses, demonstrable antidou- please visit the journal online (SLE). Post hoc analyses of these studies identify greater ble-stranded DNA (dsDNA) and low complement (http:// dx. doi. org/ 10. 1136/ treatment effect in patients entering with higher disease C3 or C4.5 6 annrheumdis- 2018- 213032). activity, greater corticosteroid doses, anti double- These observations provide important guidance 1Oklahoma Medical Research stranded DNA (dsDNA) and low complement C3 or C4. to clinical trial design, especially in light of the Foundation, Oklahoma City, Objectives To evaluate the efficacy and safety of too-common failures of large clinical trials in SLE. Oklahoma, USA blisibimod, a BAFF inhibitor, in a population of patients Moreover, the data provide important guidance to 2 Anthera Pharmaceuticals, Inc, with SLE enriched for high disease activity. treatment practice where use of high-dose cortico- Hayward, California, USA 3 steroids, immunosuppressive agents and cytotoxic Hospital Abreu Sodré (AACD), Methods 442 patients with SLE with antinuclear São Paulo, Brazil antibodies or anti-dsDNA and Safety of Estrogen in agents remain the standard-of-care for moderate 4University of California San Lupus Erythematosus National Assessment – Systemic and severe SLE despite their toxicities.7 8 Diego School of Medicine, La Lupus Erythematosus Disease Activity Index (SELENA- Blisibimod (A-623, AMG 623) is a potent and Jolla, California, USA SLEDAI) score ≥10 on standard-of-care medications selective BAFF inhibitor composed of a tetram- 5University of California, San Francisco, California, USA were randomised to receive weekly subcutaneous eric BAFF binding domain fused to a human IgG1 blisibimod (200 mg) or placebo. Corticosteroid taper was Fc region.9 Although the phase II Placebo-con- Correspondence to encouraged from week 8. The primary end point was the trolled Evaluation of A-623 Response in Lupus Dr Renee S Martin, Anthera week 52 SLE Responder Index-6 (SRI-6). (PEARL-SC) trial with blisibimod in SLE failed to Pharmaceuticals, Inc, Hayward, Results The SRI-6 primary end point was not met. meet the primary efficacy end point, SLE Responder California 94545, USA; There was a statistically significant steroid-sparing Index-5 (SRI-5), it corroborated the observations rmartin@ anthera. com effect, and significantly more blisibimod-treated subjects from larger Phase III trials in that better treat- Received 16 January 2018 achieved corticosteroid taper. Increased blisibimod ment effect was observed in subjects with higher Revised 1 March 2018 treatment effect on SRI-6 was observed in subjects disease activity, taking corticosteroids, who had Accepted 2 March 2018 who achieved a concomitant decrease in corticosteroid abnormalities in anti-dsDNA and/or complement.10 dose from baseline. In subjects with baseline urinary Furthermore, in keeping with the belimumab protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, observations,11 favourable effects on proteinuria significantly higher proportions of blisibimod subjects were observed.10 In addition, blisibimod treatment achieved >50% reduction in UPCR and/or UPCR was associated with significant decreases in anti- <56.5 mg/mmol. Reductions in SLE autoantibodies and dsDNA, immunoglobulins, total B-cell counts and B cells, and increases in complement C3 and C4 were fatigue12 and significant increases in complement observed with blisibimod. Blisibimod was well-tolerated. C3 and C4. Accordingly, the phase III Clinical and The most common adverse events were upper respiratory Health Assessments with BLISibimod SC, Study tract infection, urinary tract infection, injection site 1 (CHABLIS-SC1) trial prospectively evaluated a erythema/reaction and diarrhoea. population of subjects with SLE enriched for the Conclusions Although the SRI-6 end point was traits that, in earlier studies, were associated with not met, blisibimod was associated with successful greater treatment effect relative to background steroid reduction, decreased proteinuria and biomarker standard-of-care treatments. responses. Trial registration number NCT01395745. METHODS Patient population and trial design The CHABLIS-SC1 study (NCT01395745) was To cite: Merrill JT, INTRODUCTION conducted in Belarus, Brazil, Colombia, Georgia, Shanahan WR, Targeted, biologic inhibitors of B-cell activating Guatemala, Hong Kong, Korea, Singapore, Scheinberg M, et al. Ann Rheum Dis Epub ahead factor (BAFF), belimumab and tabalumab, have Malaysia, Mexico, Russia, Sri Lanka, Taiwan, of print: [please include Day been evaluated in four large phase III clinical trials Thailand and the Philippines. The study enrolled Month Year]. doi:10.1136/ in nearly 4000 patients with systemic lupus erythe- 442 adults aged ≥18 years who were seroposi- annrheumdis-2018-213032 matosus (SLE).1–4 Data from these studies indicate tive for anti-nuclear antibody (ANA) (≥1:80 in Merrill JT, et al. Ann Rheum Dis 2018;0:1–7. doi:10.1136/annrheumdis-2018-213032 1 Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& EULAR) under licence. Downloaded from http://ard.bmj.com/ on April 10, 2018 - Published by group.bmj.com Clinical and epidemiological research Table 1 Demographics and baseline disease characteristics Blisibimod Placebo Overall (n=245) (n=197) (n=442) Age, mean (SD) (years) 36.7 (10.98) 35.6 (10.78) 36.2 (10.89) Gender (female:male, %) 92.7:7.3 94.9:5.1 93.7:6.3 Race, n (%) Black or African-American 10 (4.1) 4 (2.0) 14 (3.2) White 167 (68.2) 132 (67.3) 299 (67.8) Asian 67 (27.3) 60 (30.6) 127 (28.8) Native Hawaiian or other Pacific 1 (0.4) 0 1 (0.2) Islander Figure 1 Disposition of subjects in the CHABLIS-SC1 trial, including Region, n (%) randomisation (5:4) into the treatment arms, numbers of subjects who Asia Pacific 67 (27.3) 60 (30.5) 127 (28.7) completed study and reasons for discontinuation (and numbers of Central and South America 89 (36.3) 58 (29.4) 147 (33.3) subjects). Europe 89 (36.3) 79 (40.1) 168 (38.0) Weight, mean (SD) (kg) 65.1 (15.46) 64.8 (15.31) 65.0 (15.38) BMI, mean (SD) (kg/m2) 25.1 (5.33) 25.0 (4.96) 25.0 (5.17) immunofluorescence assay) or anti-dsDNA (≥30 IU/mL), met SELENA-SLEDAI mean score (SD) 13.4 (4.31) 13.5 (4.01) 13.5 (4.18) at least four of the SLE Classification Criteria defined by the SELENA-SLEDAI activity, n (%) American College of Rheumatology (ACR),13 and had a base- Total score ≤12 133 (54.3) 107 (54.3) 240 (54.3) line disease activity score of ≥10 on the SELENA-SLEDAI scale Total score >12 112 (45.7) 89 (45.2) 201 (45.5) despite concomitant and stable use of systemic corticosteroids at Dermal 234 (95.5) 188 (95.9) 422 (95.7) the lesser of 0.5 mg/kg or 40 mg/day of prednisone or equivalent. Immunologic 222 (90.6) 178 (90.8) 400 (90.7) Other standard-of-care medications in stable doses were allowed Musculoskeletal 193 (78.8) 159 (81.1) 352 (79.8) (antimalarials, methotrexate, mycophenalate, azathioprine, Renal 78 (31.8) 54 (27.6) 132 (29.9) leflunomide, non-steroidal anti-inflammatory drugs). Subjects BILAG A, B or C domain score, n (%) were excluded from study if they had active vasculitis, central Mucocutaneous 236 (96.3) 190 (96.9) 426 (96.6) nervous system lupus or severe active lupus nephritis, protein- Musculoskeletal 209 (85.3) 169 (86.2) 378 (85.7) uria >6 g/24 hours (or equivalent) or a history of malignancy Haematological 121 (49.4) 101 (51.5) 222 (50.3) in the last 5 years, HIV infection, hepatitis B or C infection or Renal 96 (39.2) 64 (32.7) 160 (36.3) tuberculosis or recent use of a B-cell targeted drug, investiga- Constitutional 35 (14.3) 28 (14.3) 63 (14.3) tional agents, cyclophosphamide or other alkylators, transfusion, intravenous immunoglobulin, plasmapheresis, plasma exchange, PGA score, mean (SD) 1.59 (0.475) 1.64 (0.475) 1.61 (0.475) high-dose corticosteroid, antitumour necrosis factor-α or other PGA score (range) 0.1–2.7 0.4–2.8 0.1–2.8 biologics, ciclosporin or live vaccines. Corticosteroid dose (prednisone 15.6 (8.58) 15.6 (9.75) 15.6 (9.11) dose equivalent, mg (SD)) Eligible subjects were randomly assigned using an interac- tive web-based randomisation system in a 5:4 ratio to receive <Median prednisone dose, n (%) 108 (44.1) 103 (52.3) 211 (47.7) subcutaneous blisibimod 200 mg once weekly or corresponding ≥Median prednisone dose, n (%) 137 (55.9) 94 (47.7) 231 (52.3) volume and frequency-matched placebo using a double-blind Systemic SLE medications, n (%) interactive web response system.