OP0233 EFFICACY, SAFETY, AND PHARMACODYNAMIC EFFECTS OF THE BRUTON’S TYROSINE KINASE INHIBITOR, FENEBRUTINIB (GDC-0853), IN MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS IN A PHASE 2 CONTROLLED STUDY
Authors: D. Isenberg, R. Furie, N. S. Jones, P. Guibord, J. Galanter, C. Lee, A. Mcgregor, B. Toth, J. Rae, O. Hwang, A. Lokku, P. Miranda, V. De Souza, J. Jaller-Raad, A. Maura Fernandes, R. Garcia Salinas, L. Chinn, M. J. Townsend, A. Morimoto, K. Tuckwell
Journal: Annals of the Rheumatic Diseases (2020)

Background: Fenebrutinib (GDC-0853, FEN) is an oral, non-covalent, and selective inhibitor of Bruton’s tyrosine kinase (BTK) in clinical development for autoimmune diseases. Objectives: This was a randomized, placebo-controlled, multi-center study to evaluate the efficacy, safety, and pharmacodynamic effects of FEN in patients with moderate-to-severe systemic lupus erythematosus (SLE) activity. Methods: Patients who met SLICC or revised ACR SLE criteria, had ≥1 serologic marker of SLE, SLEDAI ≥8, and were on ≥1 standard of care (SOC) therapy were included; patients with renal or CNS involvement, or exposure to B cell depleting or calcineurin inhibitor therapy were excluded. Patients were randomized to placebo (PBO), FEN 150 mg QD, or FEN 200 mg BID, for 48 weeks. A corticosteroid taper was recommended, with burst and taper permitted from Week 0 (W0) to W12 and W24 to W36. The primary endpoint was SRI-4 at W48. Post hoc subgroup analyses were conducted based on patient baseline disease characteristics. Results: This study enrolled 260 patients, with the majority recruited in Latin America, USA, and Western Europe. At W48, the SRI-4 response rates for FEN 150 mg QD and FEN 200 mg BID were 51% (95% CI: -8.5, 21.2; p value 0.37) and 52% (95% CI: -7.3, 22.4; p value 0.34), respectively, compared to 44% for PBO (Table 1). Post-hoc analysis showed larger responses in subgroups of patients with higher baseline disease activity (Table 1). Safety results were similar between FEN and PBO arms, although more serious adverse events were observed in the FEN 200 mg BID arm. Study discontinuations were balanced across the 3 arms (24-26%). FEN treatment significantly reduced levels of CD19+ B cells, anti-dsDNA autoantibodies, IgG, and a BTK-dependent RNA signature highly expressed in plasmablasts by W48 compared to PBO; C4 levels modestly improved with FEN vs. PBO (Table 2). Table 1. SRI-4 Response (%) at W48 in Primary Analysis and in Post-hoc Patient Subgroups PBO FEN 150 mg QD FEN 200 mg BID SRI-4 Response (%) at W48 44 n =84 51 n =87 52 n =88 SRI-4 Response (%) in Baseline Subgroups At least 1 BILAG A 48 n =42 54 n =39 59 n =46 At least 1 BILAG A and SLEDAI increased DNA binding 37 n =19 53 n =17 65 n =26 SLEDAI arthritis with at least 4 swollen joints 39 n =57 50 n =54 57 n =54 SLEDAI arthritis with at least 4 tender joints 39 n =71 53 n =70 59 n =69 CLASI &gt;=10 21 n =14 36 n =11 31 n =16 Table 2. Key Biomarker Results PBO FEN 150 mg QD FEN 200 mg BID Median (%) Change from Baseline at W48 Plasmablast signature -19.7% n =52 -54.3% * n =53 -51.7% * n =57 CD19 + B cells (cells/µl) -0.50 n =38 -57.0 * n =49 -57.5 * n =48 Anti-dsDNA # (IU/ml) +6.9 n =31 -38.3 * n =36 -75.7 * n =33 Total IgG (g/L) -0.20 n =65 -1.25 * n =64 -1.56 * n =64 C3 (g/L) -0.02 n =65 +0.01 n =67 -0.01 n =66 C4 (g/L) 0.00 n =65 +0.02 * n =67 +0.01 * n =66 #Patients who were positive at baseline (&gt;30 IU/mL) *Denotes significant vs. PBO; Kruskal-Wallis false-discovery rate controlled two sided ( p -value ≤0.05) Conclusion: The primary endpoint of SRI-4 for FEN was not met despite evidence of strong BTK target and pathway inhibition. FEN had an acceptable safety profile. Several disease activity subgroups were suggestive of a greater treatment effect on SRI-4 compared to PBO Disclosure of Interests: David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Nicholas S. Jones Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Pascal Guibord Shareholder of: Roche, Employee of: Roche, Joshua Galanter Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Chin Lee Shareholder of: Genentech/Roche and Eli Lilly, Employee of: Genentech/Roche, Anna McGregor Employee of: Genentech/Roche, Balazs Toth Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Julie Rae Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Olivia Hwang Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Armend Lokku Shareholder of: Roche, Employee of: Roche, Pedro Miranda Consultant of: Study Investigator for Genentech, Viviane de Souza Consultant of: Study investigator for Genentech, Juan Jaller-Raad Consultant of: Study investigator for Genentech, Anna Maura Fernandes Consultant of: Study investigator for Genentech, Rodrigo Garcia Salinas Consultant of: Study investigator for Genentech, Leslie Chinn Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Alyssa Morimoto Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche