Background The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial. Methods This double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial enrolled adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia. Participants were eligible for the study if they had no unstable or severe underlying medical or psychiatric conditions; had no history of a laboratory-confirmed SARS-CoV-2 infection; were not pregnant or breastfeeding; and had no previous receipt of an adenovirus-vectored, coronavirus, or SARS-CoV-2 vaccine. After informed consent was obtained, 25 mL of whole blood was withdrawn from all eligible participants who were randomised in a 1:1 ratio to receive a single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 10 10 viral particle (vp)/mL Ad5-nCoV vaccine; study staff and participants were blinded to treatment allocation. All participants were contacted weekly by email, telephone, or text message to self-report any symptoms of COVID-19 illness, and laboratory testing for SARS-CoV-2 was done for all participants with any symptoms. The primary efficacy objective evaluated Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination on Jan 15, 2021. The primary safety objective evaluated the incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection. This trial is closed for enrolment and is registered with ClinicalTrials.gov ( NCT04526990 ). Findings Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis. One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7–70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36–58]). In the primary safety analysis undertaken at the time of the efficacy analysis (36 717 participants), there was no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in bo...

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Background and Aims B cells are central to the pathogenesis of systemic lupus erythematosus and lupus nephritis (LN). Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, induces more potent B-cell depletion than rituximab. Patients with LN who received obinutuzumab with standard-of-care (mycophenolate mofetil [MMF]) immunosuppression (Phase II NOBILITY study; NCT02550652) showed improved clinical responses through Week 104 compared with those who received MMF alone. Further, sustained as opposed to unsustained B-cell depletion up to Week 52 in those who received obinutuzumab was associated with a higher incidence of complete renal response (CRR) at Week 76.1,2 This analysis aims to characterize the kinetics of B-cell recovery after the last dose of obinutuzumab in NOBILITY and the impact of these kinetics on response and safety. Method A total of 125 patients with active Class III/IV LN receiving MMF and corticosteroids were randomized and received either obinutuzumab 1000 mg (n = 63) or placebo (n = 62) on Day 1 and Weeks 2, 24 and 26, and followed through Week 104 or to B-cell recovery, whichever was longer.1 B cells were measured using both a T and B natural killer cell (TBNK) assay with a lower limit of quantification (LLoQ) of 10 CD19+ cells/µL and a high-sensitivity minimal residual B-cell 1.1 (MRB1.1) assay with an LLoQ of 0.4 cells/µL. Peripheral B-cell depletion was defined as ≤0.4 cells/µL. Peripheral B-cell recovery was defined as ≥20 cells/µL or the patient's predose baseline, whichever was lower. Time to peripheral B-cell recovery after the last dose of obinutuzumab (Week 26 in 57 of 63 patients), the relationship of time to recovery to efficacy at Week 104 and safety throughout the main study and follow-up period were evaluated (severe adverse event [SAE] and infectious SAE rates, adjusted for patient-years [PY] at risk). Results Of 63 patients who received obinutuzumab, 4 did not achieve full B-cell depletion during the study. By Week 24, 59 patients (93.7%) achieved B-cell depletion (before obinutuzumab redosing); of those, 4 discontinued prior to B-cell recovery, and 4 completed the study at or after Week 104 but before achieving B-cell recovery. The remaining 51 patients constitute the population for this analysis. Based on the distribution of time to B-cell recovery, 93 weeks after the last obinutuzumab infusion was used to group patients (Figure 1). Of the 51 patients, 3 (5.9%) recovered B cells before redosing at Week 26; 1 of the 3 achieved CRR at Week 104. A total of 37 patients (72.5%) attained B-cell recovery within 93 weeks of their last dose of obinutuzumab (median time to B-cell recovery, 78.1 weeks), 18 of 37 (48.6%) and 23 of 37 (62.2%) achieved CRR and overall renal response (ORR) at Week 104, respectively. In these 37 patients, SAE and infectious SAE rates per 100 PY were 13 and 8, respectively. In 11 patients (21.6%), >93 weeks passed after their last dose to achieve B-cell recovery. Nine of 11 patients achieved B-cell recovery with a median time of 102 weeks, and 2 of 11 had not yet achieved B-cell recovery at the time of writing. Five of 11 patients (45.5%) achieved CRR, and 8/11 (72.7%) achieved ORR at Week 104. In these 11 patients, SAE and infectious SAE rates per 100 PY were 10 and 0, respectively. Conclusion Most patients in NOBILITY recovered peripheral B cells within 80 weeks after the last obinutuzumab dose. In 5.9% of patients, recovery occurred very rapidly, even before redosing at 26 weeks, whereas in ≈20%, recovery took >2 years (Figure 2). Renal response rates at Week 104 were similar among patients who recovered B cells within 2 years of their final obinutuzumab infusion, those who recovered later and those who are still depleted, suggesting a greater mechanistic effect of early sustained depletion vs duration of depletion. Within the limitation of small sample size, the SAE and infectious SAE rates appear to be similar regardless of duration of B-cell depletion.

Background:Systemic lupus erythematosus (SLE) is a chronic disease characterized by periodic flares associated with poor outcomes and subsequent organ damage (1-2). Flare prevention is important for optimal patient management and development of effective therapies.Objectives:To identify patient-level factors associated with flares among patients with moderate/severe SLE.Methods:We conducted a post-hoc analysis of 260 patients with active, autoantibody+ SLE enrolled in a phase II randomized clinical trial (Fenebrutinib) (3). The relationship between baseline demographic (age, gender, ethnicity, BMI), region (US/EU, outside US/EU), disease severity (PGA, SLEDAI-2K, BILAG domain involvement), disease duration, serologic markers (C3, C4, ANA, anti-dsDNA Ab, anti-Smith Ab), treatment arm, standard of care (SOC) and flares (BILAG and SFI) over 48 wks was assessed by survival analysis and multiple Cox Proportional Hazard models. We examined concordance between BILAG and SFI flares using Cohen’s Kappa Index.Results:The overall rate of flare was low (n=37 SFI flare, n=25 BILAG flare). Median time to first flare was 8 wks for SFI flares compared to 12 wks for BILAG flares. There was no difference in flare rate by treatment arm. Cumulative flare hazard increased over time. Concordance between SFI and BILAG flares was 0.14. Multivariable analyses identified a higher flare rate for both SFI and BILAG-defined flares in patients with severe disease at baseline (PGA >1.7, SLEDAI-2K ≥10) and <7 y disease duration.Flares were more common in patients ANA, anti-dsDNA and anti-Smith+ at baseline compared to patients with <3 + markers (p<.001). Furthermore, anti-dsDNA (p = .03) and/or anti-Smith (p = .001) positivity at baseline were better indicators of higher flare rate compared to ANA (p = 0.5). Low baseline complement level (C3 and C4) was associated with a higher flare rate (p = .03 and p = .03 respectively).Patients from non-US/EU regions had a higher flare rate compared to patients from the US/EU, despite receiving more frequent SOC therapy and higher baseline corticosteroid doses (≥10 mg/d). Overall, flare-free probability was comparable at 48 wks regardless of baseline corticosteroid dose but patients receiving <10 mg/d had a median time to flare of 4 vs 24 wks for those receiving ≥10 mg/d (p = .004).Conclusion:In this study, flares were more common among patients with more severe disease, shorter disease duration, multiple serologic markers, were from outside the US/EU, and received lower steroid doses at baseline.References:[1]Fernandez D and Kirou KA. Curr Rheumatol Rep 2016 18:14.[2]Stoll T, et al. Rheum (Oxford) 2004 43(8):1039–44.[3]Isenberg D, et al. Arth Rheum 2019 71 suppl 10.Baseline Factors (%)No Flare n=206FlareBILAG n=25SFI n=37BILAG and SFI n=8Age (mean (SD))41.8 (12)35.2 (9)40.4 (10)34.9 (8)Female199 (97)24 (96)35 (95)7 (88)PGA (mean (SD))1.7 (0.5)1.7 (0.4)1.9 (0.5)1.7 (0.6)BILAG A/B any domain197 (96)23 (92)35 (95)7 (88)SLEDAI 2K >=1087 (42)18 (72)17 (46)4 (50)Disease duration (y) (mean (SD))9.4 (7)5.3 (4)6.6 (6)2.9 (3)ANA +203 (99)24 (96)35 (95)8 (100)anti-dsDNA +102 (50)18 (72)21 (57)5 (63)anti-Smith +45 (22)13 (52)12 (32)4 (50)Low C357 (28)12 (48)13 (35)3 (38)Low C426 (13)7 (28)4 (11)1 (13)Non US/EU157 (76)21 (84)32 (87)8 (100)Corticosteroid130 (63)14 (56)21 (57)5 (63) ≥10 mg/d80 (39)9 (36)14 (38)4 (50)Immunosuppressant74 (36)12 (48)15 (41)3 (38)Antimalarial135 (66)14 (56)21 (57)5 (63)Notes: included patients 18-75 y; 1+ serologic marker of SLE; SLEDAI-2K >=8, PGA>=1; 1+ oral SOC treatmentSFI = SELENA- SLEDAI Flare IndexDisclosure of Interests:Lisa Lindsay Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Huiyan (Ashley) Mao Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ji (Emmy) Cheng Shareholder of: Employee of Hoffmann-La Roche Limited, Employee of: Employee of Hoffmann-La Roche Limited, Ching-Yi Chuo Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Nicholas Jones Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Matthew D. Cascino Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc., Katie Tuckwell Shareholder of: Employee of Genentech, Inc., Employee of: Employee of Genentech, Inc.