POS0092 HERPES ZOSTER IN THE FILGOTINIB RHEUMATOID ARTHRITIS PROGRAM
Authors: K. Winthrop, M. H. Buch, J. Curtis, G. R. Burmester, D. Aletaha, K. Amano, A. Pechonkina, I. Tiamiyu, C. Leatherwood, L. Ye, Q. Gong, R. Besuyen, J. Galloway
Journal: Annals of the Rheumatic Diseases (2021)

Background: The once daily, oral Janus kinase (JAK)-1 preferential inhibitor filgotinib (FIL) improved signs and symptoms of rheumatoid arthritis (RA) in phase (P)3 trials. 1-3 Patients (pts) with RA have increased herpes zoster (HZ) reactivation risk vs the general population. JAK inhibition is associated with increased infection incidence, including HZ. 4 Objectives: To assess long-term safety of FIL across the global clinical program with respect to HZ. Methods: Pts meeting 2010 ACR/EULAR RA criteria in a pooled analysis of P2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (D3, F4) were included. Placebo (PBO)-controlled as-randomised analysis included pts receiving FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO up to week (W)12 (D1–2, F1–2); active-controlled as-randomised analysis included pts receiving FIL100, FIL200, adalimumab (ADA), or methotrexate (MTX) up to W52 (F1, F3). Long-term as-treated analysis included pts in all 7 studies receiving FIL100, FIL200, ADA, MTX, or PBO; data after re-randomisation were included and contributed to treatment received. Exposure-adjusted incidence rates (EAIR)/100 patient-years, calculated up to the last follow-up time or day, and differences with 95% confidence intervals (CIs) were calculated from the Poisson model. Logistic regression model was used for treatment-emergent (TE) HZ risk factor analysis and odds ratio (95% CI) and P value were provided. Results: Table 1 shows TE HZ EAIRs in a pooled analysis. Rates of HZ were lower for FIL200 vs PBO during the 12W PBO-controlled period. At 52W, HZ rates were higher for FIL200/100 vs active control. Long-term HZ rates increased for FIL200 vs FIL100. Table 1. EAIR of treatment-emergent herpes zoster N Patient-years exposure EAIR (95% CI ) EAIR diff (95% CI vs PBO/active control ) 12W PBO-controlled FIL200 777 179.8 0.6 (0.1, 3.9) −0.56 (−2.5, 1.3) FIL100 788 181.6 1.1 (0.3, 4.4) −0.02 (−2.2, 2.2) PBO 781 178.4 1.1 (0.3, 4.5) Active-controlled, as-randomised a FIL200 475 439.7 1.4 (0.6, 3.0) 0.69 (−0.7, 2.1) FIL100 480 443.4 0.9 (0.3, 2.4) 0.23 (−1.1, 1.5) ADA 325 297.6 0.7 (0.2, 2.7) Active-controlled, as-randomised a FIL200 626 578.0 1.7 (0.9, 3.2) 0.65 (−0.8, 2.2) FIL100 207 195.0 1.5 (0.5, 4.8) 0.46 (−1.6, 2.5) MTX 416 372.2 1.1 (0.4, 2.9) Long-term as-treated b FIL200 2267 4047.7 1.8 (1.4, 2.3) NC FIL100 1647 2032.9 1.1 (0.8, 1.7) NC a up to W52. b data cut for LTE FINCH 4, Sept 19, 2019; DARWIN 3, April 26 2019. ADA, adalimumab; CI, confidence interval; EAIR, exposure-adjusted incidence rate; FIL, filgotinib; MTX, methotrexate; NC, not calculated; PBO, placebo; W week. Figure 1 shows multivariate logistic regression model of TE risk factors. Of 104 pts with TE HZ in long-term as-treated analysis set, 5 receiving FIL200 had history of HZ; EAIR (95% CI) was 8.7 (3.6–21.0). Of 8 pts with multiple events, 3 had events of differing severity for the same HZ episode. EAIRs (95% CI) of TE HZ in Asia were: 3.7 (1.7–8.1) FIL200, n=197; 2.8 (1.3–6.3) FIL100, n=158; 0 ADA, n=40; 2.8 (0.4–19.6) MTX, n=43; and 3.4 (0.5–23.8) PBO, n=77 in long-term as-treated population. EAIRs (95% CI) in rest of the world were: 1.6 (1.2–2.1) FIL200, n=2070; 0.9 (0.6–1.5) FIL100, n=1489; 0.8 (0.2–3.1) ADA, n=285; 0.9 (0.3–2.9) MTX, n=373; and 0.7 (0.2–2.9) PBO, n=704 for all pts as-treated. Most TE HZ infections were mild to moderate and non-serious; 6 were serious; 2 were recurrences. No visceral TE HZ occurred across the FIL RA program; there was 1 case each of genital, disseminated, and ophthalmic HZ. The disseminated HZ occurred in a pt with prior HZ history. Lymphopenia was not associated with HZ during the PBO-controlled W12 period. Conclusion: HZ was more common in both FIL groups vs ADA or MTX up to 52 weeks but comparable vs PBO during the 12-week placebo-controlled period. In multivariate analyses, prior history of HZ, Asian region, and age ≥50 years were associated with increased HZ risk. References: [1]Genovese et al. JAMA. 2019;322:315–25. [2]Westhovens et al. Ann Rheum Dis . 2021; online first. [3]Combe et al. Ann Rheum Dis. 2021; online first. [4]Higarashi and Honda. Drugs . 2020;80:1183–201. Disclosure of Interests: Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Maya H Buch Speakers bureau: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Grant/research support from: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Jeffrey Curtis Grant/research support from: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Consultant of: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Daniel Aletaha Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Medac, Merck, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme, Grant/research support from: AbbVie, Merck Sharp &amp; Dohme, Novartis, and Roche, Koichi Amano Speakers bureau: AbbVie GK, Astellas, Chugai Pharmaceutical Co. Ltd., Eli Lilly, GlaxoSmithKline KK, Pfizer Japan, Mitsubishi-Tanabe Pharma, Grant/research support from: Asahi Kasei Pharma, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Cianna Leatherwood Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, BV, Employee of: Galapagos, BV, James Galloway Speakers bureau: Pfizer, Bristol-Myers Squibb, UCB and Celgene