Objective. High mobility group box chromosomal protein 1 (HMGB-1) is a ubiquitous chromatin component expressed in nucleated mammalian cells. It has recently and unexpectedly been demonstrated that stimulated live mononuclear phagocytes secrete HMGB-1, which then acts as a potent factor that causes inflammation and protease activation. Macrophages play pivotal roles in the pathogenesis of arthritis. The aim of this study was to determine whether synovial macrophage expression of HMGB-1 is altered in human and experimental synovitis.Methods. Intraarticular tissue specimens were obtained from healthy Lewis rats, Lewis rats with Mycobacterium tuberculosis-induced adjuvant arthritis, and from patients with rheumatoid arthritis (RA). Specimens were immunohistochemically stained for cellular HMGB-1. Extracellular HMGB-1 levels were assessed in synovial fluid samples from RA patients by Western blotting.Results. Immunostaining of specimens from normal rats showed that HMGB-1 was primarily confined to the nucleus of synoviocytes and chondrocytes, with occasional cytoplasmic staining and no extracellular matrix deposition. In contrast, inflammatory synovial tissue from rats with experimental arthritis as well as from humans with RA showed a distinctly different HMGB-1 staining pattern. Nuclear HMGB-1 expression was accompanied by a cytoplasmic staining in many mononuclear cells, with a macrophage-like appearance and an extracellular matrix deposition. Analysis of synovial fluid samples from RA patients further confirmed the extracellular presence of HMGB-1; 14 of 15 samples had HMGB-1 concentrations of 1.8-10.4 g/ml.Conclusion. The proinflammatory mediator HMGB-1 was abundantly expressed as a nuclear, cytoplasmic, and extracellular component in synovial tissues from RA patients and from rats with experimental arthritis. These findings suggest a pathogenetic role for HMGB-1 in synovitis and indicate a new potential therapeutic target molecule.High mobility group box chromosomal protein 1 (HMGB-1; previously called high mobility group 1 [HMG-1] or amphoterin) is an intranuclear factor that facilitates protein interactions with chromatin (1). Hmgb1 knockout mice die shortly after birth because of hypoglycemia secondary to insufficient glucocorticoid receptor expression, which is under HMGB-1-mediated transcriptional control (2). HMGB-1 is ubiquitously present in the nucleus of almost all mammalian cells and is highly conserved between species (3). Beyond this intranuclear role, it has recently been discovered that HMGB-1 is secreted by certain cells, including activated monocytes and macrophages, and plays important roles in inflammation and tumor metastasis (4,5). The molecule is a late mediator of endotoxin lethality in mice and

Objective. To assess the effects of treatment with rituximab plus methotrexate on patient-reported outcomes in patients with active rheumatoid arthritis (RA) who experienced inadequate response to anti-tumor necrosis factor therapy. Conclusion. Rituximab produced rapid, clinically meaningful, and statistically significant improvements in patientreported pain, fatigue, functional disability, health-related quality of life, and disease activity. These effects were sustained throughout the study.

The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio ¼ 0.61; p ¼ 0.052) and lowered mean AE SD annualized A flare rates (0.86 AE 1.47 vs. 1.41 AE 2.14; p ¼ 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p ¼ 0.027). Prednisone rescue for A flares was similar in rituximab-(24%) and placebo-treated (14%) patients (p ¼ 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares. Lupus (2011) 20, 709-716.

BackgroundIn a 24-week, phase 2 clinical study (NCT02708095) in patients with systemic lupus erythematosus (SLE), baricitinib (BARI), an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis and atopic dermatitis, inhibited the type l interferon gene signature, multiple other cytokine pathways, and improved disease activity (1) (2).ObjectivesTo further evaluate the efficacy and safety of BARI in patients with SLE.MethodsPatients with active SLE receiving stable background therapy were randomised 1:1:1 to BARI 2-mg, 4-mg, or placebo (PBO) once daily in two identically designed, 52-week, phase 3 randomised, PBO-controlled studies. In SLE-BRAVE-I (NCT03616912) and -II (NCT03616964), 760 and 775 patients, respectively were enrolled in a balanced manner across regions, although different countries per region participated in each study. The primary endpoint for both studies was the proportion of patients achieving an SLE Responder Index-4 (SRI-4) response at week 52. Glucocorticoid tapering was encouraged but not required per protocol.ResultsThe mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) at baseline was 10.1 for both SLE-BRAVE-I and -II participants; musculoskeletal and mucocutaneous domains were the most common domains involved at baseline. In SLE-BRAVE-I, the proportion of SRI-4 responders at week 52 among patients treated with BARI 4-mg (56.7%), but not BARI 2-mg (49.8%), was significantly greater than in patients treated with PBO (45.9%, p = 0.016) (Table 1). No difference was seen in SLE-BRAVE-II (47.1%, 46.3%, and 45.6%, BARI 4-mg, 2-mg, and PBO, respectively). None of the key secondary endpoints, including glucocorticoid tapering or time to first severe flare (SFI), were met in either study. The proportions of patients with serious adverse events (SAEs) were 7.1% and 8.6% for PBO, 9.4% and 13.4% for BARI 2-mg and 10.3% and 11.2% for BARI 4-mg in SLE-BRAVE-I and II, respectively.Table 1.Efficacy and safety of baricitinib in patients with SLE-BRAVE-I and -IISLE-BRAVE-ISLE-BRAVE-IIEfficacy measurePBO (N=253)BARI 2-mg (N=255)BARI 4-mg (N=252)PBO (N=256)BARI 2-mg (N=261)BARI 4-mg (N=258)SRI-4 (W52)116 (45.9)126 (49.8)142 (56.7)*116 (45.6)120 (46.3)121 (47.1)SRI-4 (W24)99 (39.1)114 (44.8)117 (46.5)98 (38.6)104 (40.0)108 (42.1)Severe Flares (n, events)38 (15.0)34 (13.3)26 (10.3)26 (10.2)29 (11.1)29 (11.2)HR for time to first severe flare (SFI) HR [CI]NA0.8 [0.52, 1.32]0.65 [0.40, 1.08]NA1.1 [0.65, 1.89]1.1 [0.67, 1.94]Glucocorticoid sparing36 (30.8)31 (29.2)36 (34.0)33 (31.7)34 (29.8)36 (34.3)LLDAS (W52)66 (26.2)65 (25.7)74 (29.7)59 (23.2)62 (24.0)65 (25.4)Safety measureTEAE210 (83.0)210 (82.4)208 (82.5)198 (77.3)199 (76.2)200 (77.5)SAE18 (7.1)24 (9.4)26 (10.3)22 (8.6)35 (13.4)29 (11.2)Data are n (%) patients, unless otherwise indicated. BARI=baricitinib; CI=confidence interval; HR=hazard ratio compared with PBO; LLDAS=lupus low disease activity state; N=number of patients in the analysis population; n=number of patients in the specified category; PBO=placebo; TEAE=treatment-emergent adverse event; SAE=serious adverse event; W=week. *p≤0.05 vs PBO.ConclusionAlthough phase 2 data suggested BARI as a potential treatment for patients with SLE (2), the SLE-BRAVE-I and -II phase 3 study results were discordant for the primary outcome measure, with only SLE-BRAVE-I positive, making it difficult to elucidate benefit. Additional analyses are being performed to understand this discordance. No new safety signals were observed.References[1]Dörner T, Tanaka Y, et al. Lupus Sci Med. 2020;7(1).[2]Wallace DJ, Furie RA, et al. Lancet. 2018;392(10143):222-31.Disclosure of InterestsEric F. Morand Speakers bureau: Astra Zeneca, Eli Lilly, Novartis, Sanofi, Consultant of: Amgen, AstraZeneca, Asahi Kasei, Biogen, BristolMyersSquibb, Capella, Eli Lilly, EMD Serono, Genentech, Glaxosmithkline, Janssen, Neovacs, Sanofi, Servier, UCB, Wolf, Grant/research support from: Janssen, AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, GlaxoSmithKline, Yoshiya Tanaka Speakers bureau: Gilead, Abbvie, Behringer-Ingelheim, Eli Lilly, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers, Astra-Zeneca, Consultant of: Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, Abbvie, Grant/research support from: Asahi-Kasei, Abbvie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa, Behringer-Ingelheim, Richard Furie Consultant of: Eli Lilly, Edward Vital Consultant of: Eli Lilly (consultant and honoraria), Ronald van Vollenhoven Consultant of: Abbvie, Biotest, BMS, Celgene, Crescendo, Eli Lilly and Company, GSK, Janssen, Merck, Novartis, Pfizer, Roche, UCB, Vertex, Grant/research support from: Abbvie, Amgen, BMS, GSK, Pfizer, Roche, UCB, Kenneth Kalunian Consultant of: Eli Lilly, Marta Mosca Consultant of: Eli Lilly, GSK, Astra Zeneca, Thomas Dörner Speakers bureau: AbbVie, Eli Lilly, BMS, Novartis, BMS/Celgene, Janssen, Consultant of: AbbVie, Eli Lilly, BMS, Novartis, BMS/Celgene, Janssen, Daniel J. Wallace Consultant of: Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer, Maria Silk Shareholder of: Eli Lilly, Employee of: Eli Lilly, christina dickson Shareholder of: Eli Lilly, Employee of: Eli Lilly, Inmaculada De La Torre Shareholder of: Eli Lilly, Employee of: Eli Lilly, Gabriella Meszaros Shareholder of: Eli Lilly, Employee of: Eli Lilly, Bochao Jia Shareholder of: Eli Lilly, Employee of: Eli Lilly, Brenda Crowe Shareholder of: Eli Lilly, Employee of: Eli Lilly, Michelle A Petri Consultant of: Eli Lilly

Background:Obinutuzumab, a type II anti-CD20 mAb, resulted in rapid and complete B-cell depletion and improved renal responses in proliferative lupus nephritis (LN) in the Phase 2 NOBILITY trial and will be further evaluated in the Phase 3 REGENCY trial. Recent analyses suggest alternative urinary sediment, serum creatinine (SCr), and urine protein/creatinine ratio (UPCR) requirements may be better measures of response in LN than those used in NOBILITY [1,2].Objectives:To evaluate the NOBILITY response definitions and to report the results of NOBILITY using alternative definitions of renal response.Methods:126 patients with active Class III/IV LN were randomized to obinutuzumab or placebo in combination with mycophenolate and glucocorticoids. NOBILITY complete renal response (CRR) required UPCR < 0.5, SCr ≤ the upper limit of normal (ULN) of the reference laboratory and not increased > 15% from baseline SCr, and inactive urinary sediment. Exploratory analyses were conducted, and alternative response definitions were evaluated post hoc.Results:NOBILITY CRR was increased with obinutuzumab over placebo at Week 52 (35% vs. 23%, P = 0.11) and Week 76 (40% vs. 18%, P = 0.007). Response rates were low among patients with baseline SCr < 0.65 mg/dL (n = 45) due to the requirement that SCr not increase > 15% from baseline; increasing this threshold to 25% increased the response rate to a level similar to other groups (Figure). Alternative response definitions demonstrated increased rates of response in both treatment groups and similar benefits of obinutuzumab over placebo at Weeks 52 and 76 (Table).Conclusion:Obinutuzumab resulted in consistent treatment benefits across a range of renal response definitions in NOBILITY and will be further evaluated in REGENCY. A requirement that SCr not increase > 15% from baseline may be overly restrictive in patients with low baseline SCr (< 0.65 mg/dL), where a change of 15% represents < 0.1 mg/dL and is of questionable clinical relevance. These findings may inform LN clinical trial design and more accurately reflect clinical practice.References:[1]Dall’era M et al.Arthritis Rheumatol. 2015;67:1305-13.[2]Almaani S et al.J Am Soc Nephrol. 2019;30:669 [abstract].Table.Data from NOBILITY at weeks 52 and 76 using several response definitionsDefinition of responseWeek 52Week 76OBI (n = 63)PBO (n = 62)Diff.OBI (n = 63)PBO (n = 62)Diff.NOBILITY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 15% from baseline SCr, and < 10 RBC/hpf without casts35%23%12%*40%18%22%**REGENCY complete responseUPCR < 0.5, SCr ≤ ULN and not increased > 25% from baseline SCr43%29%14%*54%31%23%**UPCR < 0.8 only64%48%15%*64%47%17%*UPCR < 0.8 with SCr requirementUPCR < 0.8 and SCr ≤ ULNornot increased > 15% from baseline SCr60%48%12%*64%45%18%**NOBILITY overall responseCRR or ≥ 50% reduction in UPCRawith SCr not increased > 15% from baseline and urinary RBCs not increased > 50% from baseline56%36%20%**51%29%22%**REGENCY overall responseCRR or ≥ 50% reduction in UPCRawith SCr not increased > 25% from baseline68%45%23%**67%50%17%**OBI, obinutuzumab; PBO, placebo.* P < 0.2 vs. placebo group. ** P < 0.05 vs. placebo group.a≥ 50% reduction in UPCR to a value < 1 (< 3 if the baseline UPCR was ≥ 3). All response definitions required no use of rescue medications or early withdrawal.Acknowledgments:This study was funded by F. Hoffmann-La Roche.Disclosure of Interests:Zahir Amoura Grant/research support from: GSK, Roche, Consultant of: GSK, Astra Zeneca, Amgen, Philippe Rémy: None declared, Luis Fernando Quintana Porras: None declared, Laurent Chiche: None declared, Dominique Chauveau: None declared, Dario Roccatello: None declared, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Thomas Schindler Employee of: F. Hoffmann-La Roche, Jay Garg Employee of: Genentech, Matthew D. Cascino Employee of: Genentech, Brad H Rovin Grant/research support from: GSK, Consultant of: GSK, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS

Background:BLISS-LN (GSK Study BEL114054; NCT01639339), the largest lupus nephritis (LN) study to date, showed that intravenous (IV) belimumab (BEL) + standard therapy (ST) improved outcomes compared with ST alone in patients (pts) with active LN.1Objectives:To assess additional safety and efficacy data of BEL + ST in pts with LN in a 6-month open-label (OL) phase beyond 2 years of double-blind (DB) treatment in BLISS-LN.Methods:In this OL phase, eligible completers of the DB phase received monthly BEL 10 mg/kg IV + ST for 6 months. Endpoints: safety; Primary Efficacy Renal Response (PERR; uPCR ≤0.7; eGFR no worse than 20% below OL baseline eGFR or ≥60 ml/min/1.73 m2; no prohibited medications) and Complete Renal Response (CRR; uPCR <0.5; eGFR no worse than 10% below OL baseline eGFR or ≥90 ml/min/1.73 m2; no prohibited medications) at OL Week 28; proportion of pts with SLEDAI score <4; corticosteroid use; biomarkers. Analyses were based on observed data and summarised relative to the OL baseline (last value measured prior to the first dose of OL treatment).Results:We enrolled 257 pts (57.4% of pts in BEL114054) and treated 255 pts. All treated pts were included in the safety population (123 pts switched from placebo [PBO] to BEL; 132 pts remained on BEL). Efficacy was assessed in the safety population, excluding 1 pt due to non-compliance (mITT population; PBO to BEL: 122 pts; BEL to BEL: 132 pts). 96.5% of pts completed the OL phase; 3.5% withdrew, mainly due to adverse events (AE; 2.0%).Overall, 168/255 (65.9%) pts had ≥1 AE (76/123 [61.8%] PBO to BEL pts; 92/132 [69.7%] BEL to BEL pts); 15/255 (5.9%) pts had ≥1 serious AE (5/123 [4.1%] PBO to BEL pts; 10/132 [7.6%] BEL to BEL pts); 1 (0.8%) pt died in the PBO to BEL group.Proportions of PERR and CRR responders increased from OL baseline to OL Week 28 (Table 1. below)Proportions of pts who attained SLEDAI scores <4 increased from OL baseline to OL Week 28 in the BEL to BEL group and decreased in the PBO to BEL group. Among pts receiving average daily prednisone-equivalent doses of ≤5 mg or ≤7.5 mg dose was maintained from OL baseline to OL Week 28 (Table 1. below)In pts with autoantibodies at OL baseline, anti-dsDNA and anti-C1q levels decreased from OL baseline to OL Week 28 in both groups. Among pts with low C3/C4 levels at OL baseline, C3/C4 levels increased from OL baseline to OL Week 28 in both groups (Table 1. below)Conclusion:In this OL phase of BLISS-LN, proportions of PERR and CRR responders increased in both the BEL-naïve and BEL-experienced groups; and no new safety signals were observed. Improvements in biomarker levels were observed, especially in pts who switched from PBO to BEL.Funding:GSK.References:[1]Furie R, et al. N Engl J Med. 2020;383(12):1117-28.Table 1.Responses at OL baseline and OL Week 28 (mITT population, N=254)OL baseline*OL Week 28PBO to BEL(n=122)BEL to BEL(n=132)PBO to BEL(n=122)BEL to BEL(n=132)n122132118122PERR, n (%)73 (59.8)†93 (70.5)†79 (66.9)91 (74.6)CRR, n (%)44 (36.1)†63 (47.7)†57 (48.3)76 (62.3)SLEDAI score <4n122132120122Responders, n (%)44 (36.1)†64 (48.5)†40 (33.3)64 (52.5)Prednisone-equivalent dosen122132121128≤5 mg, n (%)59 (48.4)78 (59.1)60 (49.6)75 (58.6)≤7.5 mg, n (%)62 (50.8)85 (64.4)66 (54.5)83 (64.8)Anti-dsDNA (IU/ml)‡n85648161Median (IQR) levels107.0 (49.0, 212.0)65.5 (42.5, 126.5)--Median (IQR) % change from baseline---30.2 (-46.3, -6.8)-10.7 (-27.2, 9.1)Anti-C1q (U/ml)§n64605854Median (IQR) levels71.7 (36.6, 167.5)47.1 (33.0, 75.7)--Median (IQR) % change from baseline---23.0 (-41.5, 0.5)-16.5 (-33.0, 6.1)C3 (mg/dl)‖n45374435Median (IQR) levels78.0 (72.0, 83.0)80.0 (71.0, 84.0)--Median (IQR) % change from baseline--6.2 (-4.2, 14.6)4.7 (-4.8, 16.9)C4 (mg/dl)‖n18121811Median (IQR) levels7.5 (6.0, 8.0)7.0 (7.0, 8.5)--Median (IQR) % change from baseline--23.6 (11.1, 37.5)11.1 (0.0, 57.1)*DB Week 104 visit and the OL baseline visit were the same visit; †Post hoc analyses; ‡Among anti-dsDNA positive pts at OL baseline (≥30 IU/ml); §Among anti-C1q positive pts at OL baseline (≥22.2 U/ml); ‖Among pts with low C3 (<90 mg/dl)/C4 (<10 mg/dl) levels at OL baseline.Acknowledgements:Medical writing assistance was provided by Olga Conn, PhD, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Richard Furie Consultant of: GSK, Grant/research support from: GSK, Brad H Rovin Consultant of: GSK, Frederic Houssiau Consultant of: GSK, Grant/research support from: UCB, Gabriel Contreras Consultant of: Genentech, Merck, Grant/research support from: Genentech, Merck, Paula Curtis Shareholder of: GSK, Employee of: GSK, Anuradha Madan Shareholder of: GSK, Employee of: GSK, Angela Jones-Leone Shareholder of: GSK, Employee of: GSK, Mohamed Okily Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

Background:KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which is active in >15 autoimmune disease models, including murine models of systemic lupus erythematosus (SLE)/lupus nephritis (LN).1,2,3 Selective inhibition of the immunoproteasome modulates both innate and adaptive immune effector cells, resulting in reduced inflammatory T helper cell subsets (Th1 and Th17), increased regulatory T cells, and decreased plasma cells and autoantibodies. KZR-616 was well tolerated in two healthy volunteer studies of 100 subjects receiving up to 75 mg subcutaneously (SC). Target levels of immunoproteasome inhibition were observed at doses ≥30 mg.3,4 KZR-616 is currently in Phase 2 studies for several autoimmune indications, including the ongoing Phase 2 portion of the MISSION Study (KZR-616-002; NCT0339013) in patients with LN.Objectives:Results of the completed MISSION Phase 1b dose escalation portion of the study are reported.Methods:In the open-label, multicenter, dose escalation Phase 1b portion, SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid therapy were administered weekly KZR-616 subcutaneously at doses of 45 mg (cohort 1), 60 mg (cohort 2), 60 mg following step-up doses of 30 mg and 45 mg (cohort 2a), 60 mg following a step-up dose of 30 mg (cohorts 2b, 2c) or 75 mg following a step-up dose of 30 mg (cohort 3) for 13 weeks with follow-up through Week 25 (W25); a lyophilized formulation was used for cohorts 2b, 2c and 3. The disease activity measures assessed were: SLEDAI-2K, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender and swollen joint counts, Physician and Patient Global Assessments, and Patient Assessment of Pain. Safety and tolerability were assessed in the safety population (patients receiving at least one dose of KZR-616).Results:The Phase 1b portion of MISSION enrolled 47 SLE patients, including 2 patients with active proliferative LN. The most common treatment-emergent adverse events (TEAE) were injection site reactions, which were mostly mild. Infections occurred at a low rate, and there were no reports of peripheral neuropathy, prolonged hematologic AEs, or clinically significant laboratory abnormalities. No discontinuations were observed in cohorts 2b and 2c; no serious AEs were reported in cohort 3 and TEAEs were consistent with those reported in earlier cohorts. Mean values of all measures of disease activity improved in evaluable patients who completed the 13-week treatment period, and improvements were generally maintained at W25. All patients with elevated anti-double-stranded DNA antibody (anti-dsDNA) levels at baseline (n=7) had a reduction in levels with 3 of 7 experiencing a >50% reduction in their levels. Two of two patients with active proliferative LN had a >50% reduction in UPCR and experienced reductions in SLEDAI-2K scores as well as anti-dsDNA levels. Exposure to KZR-616, similar to that reported in healthy volunteers, was dose-proportional across doses, and no accumulation was observed.Conclusion:KZR-616 SC, once weekly for 13 weeks up to 75 mg, appears to be safe and well-tolerated in patients with active SLE on stable background therapy in the MISSION Phase 1b. At doses ≥45mg, efficacy was noted, including improvements in proteinuria in two of two patients with LN and serologic improvement in all 7 patients with quantifiable levels of anti-dsDNA antibodies at baseline. KZR-616 60 mg SC weekly for 24 weeks is currently being evaluated in the MISSION Phase 2 in patients with LN. Based on the results of MISSION, inhibition of the immunoproteasome with KZR-616 represents a novel strategy to treat autoimmune diseases.References:[1]Basler M et al. Clin Exp Rheumatol 2015 (suppl 92);S74.[2]Muchamuel T et al. Ann Rheumatol Dis 2018;77(suppl 2);685.[3]Muchamuel T et al. ASN 2020 Virtual Conference.[4]Snyder B et al. ACR/ARP 2019 Annual Meeting.[5]Fan RA et al. ACR/ARP 2019 Annual Meeting.Acknowledgements:Kezar Life Sciences acknowledges the support of site investigators and patient participants in the MISSION studyDisclosure of Interests:Richard Furie Consultant of: Genentech;Kezar Life Sciences, Grant/research support from: Kezar Life Sciences, SV Parikh Consultant of: Aurinia Pharmaceuticals, BMS, GlaxoSmithKline, and Kezar Life Sciences, Grant/research support from: Aurinia Pharmaceuticals;EMD-Serono, Jinhai Wang Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Darrin Bomba Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences, Richard Leff Employee of: Kezar Life Sciences [part-time], Christopher Kirk Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences -- full-time employee, Noreen Henig Shareholder of: Kezar Life Sciences, Employee of: Kezar Life Sciences

Background Blisibimod, a potent inhibitor of B cell activating factor (BAFF), was evaluated in a Phase 2b clinical trial in patients with SLE. Objectives To determine the effect of subcutaneous blisibimod on SLE disease activity, including rate of response to the SLE responder index (SRI). Methods 547 serologically-active SLE patients with baseline SELENA-SLEDAI ≥6 were randomized to receive blisibimod (100mg weekly (QW), 200mg QW, or 200mg Q4W) or placebo in matchin dosing regimens. The primary endpoint was a comparison at Week 24 of the percentage of subjects in the pooled blisibimod and placebo groups who achieved an SRI-5 response (SRI with ≥5 point improvement in SELENA–SLEDAI). Results The primary endpoint was not met due to the lack of efficacy in the two lower doses. However, SRI-5 response was higher in subjects receiving blisibimod 200mg QW compared with placebo (p=0.02 at Week 20). SRI improvements compared with placebo were higher still in subjects who attained SELENA–SLEDAI improvements of ≥8, and in patients with severe disease (SELENA–SLEDAI≥10 and receiving corticosteroids, n=278, figure 1 ). Despite declining patient numbers, response to blisibimod remained higher than placebo beyond Week 24 while N>30 subjects per cohort. Numerically higher response was also observed with blisibimod in all components of the SRI. Blisibimod was safe and well-tolerated at all dose levels with no meaningful imbalances in serious adverse events or infections compared with placebo. Image/graph Conclusions These are the first evidence that SLE disease activity may be improved with subcutaneous injections of a novel biologic therapy. Disclosure of Interest R. Furie Consultant for: Anthera Pharmaceuticals, M. Scheinberg: None Declared, G. Leon: None Declared, E. Ramiterre: None Declared, M. Thomas: None Declared, A. Chu: None Declared, C. Hislop Employee of: Anthera Pharmaceuticals, R. Martin: None Declared, M. Petri Employee of: Anthera Pharmaceuticals