OP0281 PHARMACODYNAMIC EFFECT OF SEQUENTIAL BELIMUMAB (BEL) AND RITUXIMAB (RTX) THERAPY IN PATIENTS (PTS) WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE): THE PHASE 3, RANDOMISED, PLACEBO-CONTROLLED BLISS-BELIEVE STUDY

Abstract

BackgroundBEL is approved for active SLE and lupus nephritis (adults only). Despite failed trials,1 RTX remains in the SLE treatment armamentarium. Sequential BEL and RTX therapy offers a promising strategy to target B cells by distinct but complementary mechanisms.ObjectivesTo assess the pharmacodynamic effects of BEL and a single RTX cycle on immunologic biomarkers in adults with SLE.MethodsIn this 104-week (wk) study (NCT03312907), all pts with active SLE received subcutaneous BEL 200 mg/wk for 52 wks. Pts were randomised to receive intravenous (IV) RTX 1000 mg at Wks 4 + 6 (BEL/RTX), IV PBO at Wks 4 + 6 (BEL/PBO), or continued treatment with standard therapy (BEL/ST). For BEL/RTX and BEL/PBO pts, a 52-wk treatment-free observational phase followed the 52-wk treatment phase; BEL/ST pts continued to receive BEL for 104 wks. Changes from baseline (BL) in anti-dsDNA and C3/C4 levels, and counts of total B cells (CD19+) and B-cell subsets (CD20+; naïve; memory; activated B-cells), were analysed.Results292 pts received ≥1 study treatment dose (BEL/PBO n=72; BEL/RTX n=144; BEL/ST n=76). For pts assessed at Wk 52, reductions from BL in anti-dsDNA levels were seen in all 3 groups with a significant difference between BEL/RTX and BEL/PBO (p=0.0495). C3/C4 levels increased from BL to Wks 52 and 104 in all groups, with trends for greater increases with BEL/RTX versus BEL/PBO (Table 1). At Wk 52, total B cells and most B-cell subsets decreased in all 3 groups (Table 1), with significant differences between BEL/RTX and BEL/PBO (p<0.0001 for all). During the observation period, repopulation of total CD19+ B cells (comprising mostly of naïve CD20+CD27-) towards BL levels by Wk 104 was most evident with BEL/RTX, while low circulating CD20+CD27+ memory B cell levels remained relatively unchanged (Table 1).Table 1.Absolute changes in biomarkers for treatment phase completers*Median (25th, 75thpercentile)Change from BLAt Wk 52At Wk 104BEL/PBOBEL/RTXBEL/STBEL/PBOBEL/RTXBEL/STn=54n=102n=58n=24n=44n=50Anti-dsDNA (IU/ml)-9 (-83, 1)-51 (-155, -3)-5 (-61, 0)-9.5 (-197, 2)-55 (-329, -2)-6.5 (-57, -1)C3 (md/dl)8.5 (-8, 21)15† (0, 30)1‡ (-6, 11)6 (-5.5, 19.5)11 (-7, 27)7.5 (-5, 23)C4 (md/dl)2 (0, 5)4† (2, 9)2‡ (-1, 4)1.5 (-1.5, 4.5)3 (0, 8)3 (1, 5)B cells and B-cell subsets (cells/ml)n=48n=93n=55n=20n=40n=47CD19+-57,570 (-120,810, -5861)-95,313 (-193,946, -44,240)-57,399 (-152,403, -12,562)-41,343 (-105,789, 23,819)-11,932 (-77,822, 45,773)-48,783 (-151,528, -15,603)CD20+-58,112 (-110,681, -3126)-93,482 (-189,567, -42,636)-57,428 (-147,094, -3590)-40,773 (-95,658, 25,547)-3986 (-75,942, 49,021)-45,110 (-143,321, -15,063)Naïve CD20+CD27--60,929 (-112,623, -15,316)-61,405 (-152,261, -28,496)-62,477 (-142,009, -16,191)-22,210 (-72,131, 28,335)6941 (-62,669, 67,355)-51,254 (-142,712, -14,736)Activated CD95+-5012 (-12,701, 278)-9991 (-17,900, -5560)-3895 (-10,068, -1347)-3834 (-13,274, 1490)-5821 (-11,216, -233)-5641 (-14,810, -3341)Memory CD20+CD27+9,586 (1500, 30,983)-15,076 (-42,880, -6376)5532 (-146, 14,393)-13,927 (-24,816, -3064)-11,534 (-25,646, -2958)-1229 (-8466, 7300)*Excluded from analysis: all pts who discontinued the investigational product before Wk 52 and BEL/ST pts if discontinued before Wk 104, and BEL/PBO and BEL/RTX pts who re-started BEL after Wk 53; †n=101; ‡n=57.ConclusionAn improvement in anti-dsDNA and C3/C4 levels was generally observed across all 3 treatment groups with greater reductions in anti-dsDNA antibodies following BEL/RTX versus BEL/PBO and BEL/ST. We believe that BEL induced a pharmacodynamic window for subsequent RTX treatment for a marked reduction in circulating memory B cells and other B-cell subsets. Our findings underscore the need for better understanding of the bridge from pharmacodynamic to clinical outcomes, given that BEL/RTX did not show an improvement in disease control over BEL/PBO.1References[1]Aranow C, et al. Arthritis Rheumatol 2021;73 (suppl 10).AcknowledgementsThis analysis of the GSK Study 205646 was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Nicholas Thomas, PhD, Fishawack Indicia Ltd. UK, part of Fishawack Health, and was funded by GSK.Disclosure of InterestsY.K. Onno Teng Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, KezarBio, Otsuka, Vifor Pharma, Grant/research support from: GSK, Vifor Pharma, Aurinia Pharmaceuticals, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Kenneth L Clark Shareholder of: GSK, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, Yun Irene Gregan Shareholder of: GSK, Employee of: GSK, James Groark Shareholder of: GSK, Employee of: GSK, Robert Henderson Shareholder of: GSK, Employee of: GSK, Josephine Ocran-Appiah Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK, Don Shanahan Shareholder of: GSK, Employee of: GSK, Paul-Peter Tak Shareholder of: GSK, Employee of: GSK, Cynthia Aranow Consultant of: BMS, Kezar, GSK, Grant/research support from: GSK