LAUSR

Background: We conducted an integrated analysis of pooled safety data from all 17 atacicept clinical studies across multiple indications to date. Objectives: To characterize the overall safety profile of atacicept. Methods: Analyses were based on 3 pooled datasets: double-blind placebo (PBO)-controlled set (DBPC-S) (n=1568; key endpoint: treatment-emergent AEs [TEAEs]); systemic lupus erythematosus set (SLE-S; n=761; key endpoints: IgG change and serious infection rates, and mortality); and full analysis set (FA-S; n=1845; key endpoint: exposure-adjusted mortality). Results: Of 1568 patients (DBPC-S), 30.8% received PBO, and 8.2%, 24.5% and 36.5% received atacicept 25, 75 and 150 mg. Overall, baseline characteristics were balanced across treatment arms. Treatment exposure in patient-years (py) was similar with PBO and atacicept 75 and 150 mg but was lower with 25 mg (Table). Exposure-adjusted TEAE rates were generally higher with atacicept vs PBO; serious TEAE and infection rates were similar with atacicept and PBO (Table). TEAE-related discontinuation rates were higher with atacicept vs PBO (16.1 vs 10.9/100 py). In the SLE-S and DBPC-S, pharmacodynamic effects of atacicept (eg on IgG) were not associated with an increase in infection rates. Across all studies (FA-S), 11 patients died during treatment. Across all indications, exposure-adjusted mortality rates/100 py (95% CI) were 3.60 (0.90–14.38), 0.34 (0.05–2.43), 1.18 (0.49–2.82) for atacicept 25, 75 and 150 mg, and 0.44 (0.06–3.12) for PBO. In SLE patients, exposure-adjusted mortality rates/100 py were 1.45 (0.54–3.87) with atacicept 150 mg and 0.78 (0.29–2.07) across all atacicept-treated patients. The underlying disease and other causes were potential confounders in most cases. Conclusion: In this integrated safety analysis of atacicept, no consistent association was found between atacicept dose and specific TEAEs or mortality. These results support further development and evaluation of atacicept in patients in whom potential benefits may outweigh risks. Table.Exposure-adjusted TEAE rates by dose (DBPC-S) Placebo, n=483 Atacicept Total, n=1568 25 mg, n=129 75 mg, n=384 150 mg, n=572 All, n=1085 Total number of py 278.3 51.5 225.0 286.7 563.2 841.4 TEAE, n (rate per 100 py) Hypersensitivity 37 (13.9) 8 (15.7) 40 (19.1) 55 (20.4) 103 (19.4) 140 (17.6) Infections 211 (107.8) 43 (104.4) 180 (118.7) 281 (141.3) 504 (128.7) 715 (121.7) Serious infection 20 (7.3) 1 (1.9) 23 (10.5) 22 (7.7) 46 (8.3) 66 (7.9) Severe infection 9 (3.2) 0 11 (4.9) 16 (5.6) 27 (4.8) 36 (4.3) Herpes zoster 13 (4.7) 2 (3.9) 10 (4.5) 17 (6.1) 29 (5.2) 42 (5.1) Injection site reactions 54 (20.9) 27 (64.8) 109 (63.0) 156 (72.4) 292 (67.9) 346 (50.2) Severe hypogammaglobulinemia (IgG <3 g/L) 0 0 2 (0.9) 4 (1.4) 6 (1.1) 6 (0.7) Cardiac arrhythmias [all] 18 (6.6) 11 (22.4) 23 (10.6) 25 (8.9) 59 (10.8) 77 (9.4) Ventricular arrhythmias 5 (1.8) 0 4 (1.8) 6 (2.1) 10 (1.8) 15 (1.8) Ischemic heart disorders 11 (4.0) 3 (5.9) 13 (5.9) 11 (3.9) 27 (4.9) 38 (4.6) Embolic and thromboembolic events 11 (4.0) 1 (2.0) 6 (2.7) 9 (3.2) 16 (2.9) 27 (3.2) Vestibular disorders 19 (7.0) 5 (9.9) 18 (8.3) 26 (9.3) 49 (8.9) 68 (8.3) Demyelination 1 (0.4) 1 (1.9) 0 5 (1.7) 6 (1.1) 7 (0.8) Depression 14 (5.1) 3 (5.8) 8 (3.6) 11 (3.9) 22 (3.9) 36 (4.3) Malignant tumor 0 1 (1.9) 1 (0.4) 3 (1.1) 5 (0.9) 5 (0.6) Serious TEAE 51 (18.9) 15 (30.0) 51 (23.9) 61 (21.8) 127 (23.4) 178 (21.9) Severe TEAE 28 (10.2) 10 (19.6) 45 (20.9) 56 (20.0) 111 (20.3) 139 (17.0) Discontinuation of treatment due to TEAE 30 (10.9) 14 (27.6) 30 (13.4) 46 (16.1) 90 (16.1) 120 (14.3) Infection-related deaths, n (%) Deaths 0 0 0 2 (0.3)* 0 0 *Acute respiratory failure and probable leptospirosis (n=1); pneumonia and pulmonary alveolar hemorrhage (n=1) Disclosure of Interests: Caroline Gordon Grant/research support from: Sandwell and West Birmingham Hospitals NHS Trust have received funding from UCB to support research work done by my research group that was unrelated to any pharmaceutical product or clinical trial., Consultant for: I have provided consultancy advice and taken part in scientific advisory boards on the design and analysis of clinical trials and the management of lupus for GSK, EMD Serono and UCB. I have taken part in adjudication and safety monitoring committees for BMS., Speakers bureau: I have been paid by UCB for speaking at meetings., Roberto Bassi Employee of: Current employees of EMD Serono, Peter Chang Employee of: Current employees of EMD Serono, Amy Kao Employee of: Current employees of EMD Serono, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Victor Ona Employee of: Current employees of EMD Serono, Patricia Fleuranceau-Morel Employee of: Current employees of EMD Serono