Changes in the immune cell profile, clinical and safety outcomes in fingolimod-treated patients with relapsing multiple sclerosis: interim results of the FLUENT study Yang Mao-Draayer 1 , Jeffrey Cohen 2 , Amit Bar-Or 3 , Bruce A.C. Cree 4 , May H. Han 5 , Barry Singer 6 , Scott Kolodny 7 , Xiangyi Meng 7 , Lesley Schofield 7 , Marina Ziehn 7 , on behalf of the FLUENT study investigators Platform Presentation DXM03 May 31, 2019 1 Autoimmunity Center of Excellence, Multiple Sclerosis Center, University of Michigan, Ann Arbor, MI, USA; 2 Mellen Center, Cleveland Clinic, Cleveland, OH, USA; 3 Center for Neuroinflammation and Experimental Therapeutics, and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 4 UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA; 5 Stanford University, Stanford, CA, USA; 6 Missouri Baptist Medical Center, St Louis, MO, USA; 7 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Disclosures Funding source: This study is supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Yang Mao-Draayer has received consulting and/or speaker fees from Biogen, Bayer Pharmaceuticals, Celgene, EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme, and Teva, and research support from Genzyme, NIH NIAID Autoimmune Center of Excellence, Novartis, and Chugai. Jeffrey Cohen has received consulting fees from Adamas and Celgene and research support from Biogen Idec, Roche/Genentech, GSK, Merck/EMD Serono, Medimmune, Novartis, Celgene/Receptos, and Sanofi-Genzyme. Amit Bar-Or has received consulting and/or speaker fees and research support from Biogen Idec, Roche/Genentech, GSK, Merck/EMD Serono, Medimmune, Novartis, Celgene/Receptos, and Sanofi-Genzyme. Bruce A.C. Cree has received consulting fees from AbbVie, Akili, Alexion, Biogen, EMD Serono, GeNeuro, Novartis, Sanofi- Genzyme, and TG Therapeutics. May H. Han has served on advisory boards for Novartis and has received speaker fees from Sanofi-Genzyme, and research support from Accorda, Hoffman La Roche, MedImmune, Novartis, Receptos, and Teva. Barry Singer has received consulting and/or speaker fees from Acorda, Bayer, Biogen, Celgene, EMD Serono, Genentech, Novartis, Sanofi-Genzyme, Teva, and TG Therapeutics, and research support from AbbVie, Acorda, Alkermes, Biogen, MedImmune, Novartis, Roche, and Sanofi-Genzyme. Scott Kolodny , Xiangyi Meng , Lesley Schofield , and Marina Ziehn are employees of Novartis Pharmaceuticals Corporation. Acknowledgments: Medical w riting and editorial support in the development of this poster w ere provided by Catherine Simonson of Indicia Medical, part of the Fishaw ack Group of Companies, Oxford, UK and funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Ryan Winger of Novartis Pharmaceuticals Corporation contributed to the concept and design of the FLUENT study. Chelsea Elam of Novartis Pharmaceuticals Corporation provided data for, and review ed, this presentation. 2
Introduction • Fingolimod – once-daily oral sphingosine 1-phosphate receptor modulator indicated for RMS – prevents egress of lymphocytes from lymph nodes, and differentially affects immune cell subsets 1 • Rare occurrences of opportunistic infections, including cases of PML, have been reported with fingolimod in the post-marketing setting 1,2 • Changes in innate and adaptive components of immune system were not investigated in pivotal clinical trials � Relationship between anti-JCV antibody and immune cell subsets during fingolimod treatment has not been explored • FLUENT study: investigated temporal effects of fingolimod on immune cell subtypes and biomarkers in: 3 � Fingolimod-naïve patients with RMS � Patients w ith RMS receiving continuous fingolimod therapy for ≥2 years • FLUENT may provide insights into the utility of immunologic profiling to evaluate patients’ response to therapy as well as potential risks of infection , including PML NCT03257358. JCV, John Cunningham virus; PML, progressive multifocal leukoencephalopathy; RMS, relapsing forms of multiple sclerosis. 1. Gilenya Prescribing Information. Novartis Pharmaceuticals Corporation, 2018; 2. Druart C, et al. Patient Relat Outcome Meas. 2018;9:1-10; 3. Cohen J, et al. Mult Scler J Exp Transl Clin. 2019;5(1):2055217318819245. doi: 10.1177/2055217318819245. eCollection 2019 Jan–Mar. 3 FLUENT study endpoints Primary endpoint • Changes from Baseline* to Month 6 in peripheral blood cellular components of innate (monocytes, neutrophils, NK cells) and adaptive (T cells, B cells) immune system, including their subsets Secondary endpoints • Change from Baseline* to Months 3 and 12 in immune cell subtype profile • Anti-JCV antibody status at Months 3, 6, and 12 • Change from Baseline* in anti-JCV antibody index at Months 3, 6, and 12 • Clinical variables (T1/2 lesions; patient-determined disease steps) Exploratory endpoint • Change from Baseline* in serum neurofilament light chain levels at Months 3, 6, and 12 *Baseline defined as the start of the 12-month treatment window in FLUENT. JCV, John Cunningham virus; NK, natural killer. 4
Study design and patients 12-month, prospective, multicenter, 2-cohort, nonrandomized, open-label, Phase 4 study Screening Period Open-label Treatment Phase (Up to 4 weeks) Cohort 1 (N=200) Patients w ith RMS beginning treatment of prescribed, commercially available fingolimod 0.5 mg/day for up to 12 months Cohort 2 (N=200) Patients w ith RMS w ho have been receiving continuous, commercially available fingolimod 0.5 mg/day for ≥2 years w ill continue treatment for the next 12 months Baseline 3 months 6 months 12 months Patients: • Aged ≥18 years • Diagnosed with RMS as defined by 2010 revised McDonald criteria 1 • Fingolimod-naïve or receiving continuous fingolimod 0.5 mg/day for ≥2 years RMS, relapsing forms of multiple sclerosis. 5 1. Polman CH, et al. Ann Neurol 2011;69:292-302. Baseline characteristics Cohort 1 Cohort 2 Fingolimod-naïve Continuous fingolimod (N=166) (N=216) Age, years, median (range) 41.0 (18, 68) 50.0 (24, 71) Female, n (%) 129 (77.7) 158 (73.1) Time from MS diagnosis to treatment, years, 3.36 (0.0, 33.5) 11.66 (2.3, 40.6) median (range) Patients with ≥1 relapse in past year, n (%)* 102 (61.4) 32 (14.8) Patients with ≥1 relapse in past 2 years, n (%)* 117 (70.5) 47 (21.8) 1st patient enrolled 9/19/17; last patient last visit estimated 7/30/19 *Cohort 1, n=164; Cohort 2, n=215. MS, multiple sclerosis. 6
Change from Baseline to Month 6 in innate and adaptive immune cell subsets Cohort 1 Cohort 2 Cells/μL Fingolimod-naïve Continuous fingolimod Absolute CD4+ CD4+ naïve T CD4+ central memory T CD4+ effector memory T CD4+ Th1 CD4+ Th2 CD4+ Th17 Absolute CD8+ CD8+ naïve CD8+ central memory CD8+ effector memory Absolute CD19+ CD19+ naïve B CD19+ memory B CD19+ regulatory B Monocytes (CD14+) Neutrophils (CD16+) Natural killer cells (CD56+) - 1200 -1000 -800 -600 -400 -200 0 100 - 1200 -1000 -800 -600 -400 -200 0 100 Mean change from Baseline to Month 6 LSM (95% Cl)* Mean change from Baseline to Month 6 LSM (95% Cl)* *Adjusted change from Baseline to Month 6 (cells/μL). ANCOVA model with gender as a factor and duration of disease and corresponding Baseline as covariates. At baseline, patients in Cohort 2 had been continuously treated with fingolimod for ≥2 years. ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean. 7 Change from Baseline to Month 6 in absolute and differential CD4+, CD8+, and CD19+ cell counts Cohort 1: Fingolimod-naïve Cohort 2: Continuous fingolimod CD4+ CD8+ CD19+ CD4+ CD8+ CD19+ Absolute Cell Counts Baseline 932.35 416.97 257.88 64.59 124.99 21.34 Mean (SD) cells/μL (451.07) a (258.48) a (167.78) b (122.82) c (213.84) c (45.29) c Month 6 53.09 119.76 19.86 71.52 117.38 21.53 Mean (SD) cells/μL (111.68) d (145.24) d (16.51) d (111.99) e (100.76) e (34.63) f Mean change from −883.84 −247.21 −232.58 −3.55 −9.61 −0.60 Baseline to Month 6 (−909.53, −858.15) g (−276.50, −217.93) g (−236.07, −229.08) h (−18.00, 10.89) i (−24.98, 5.75) i (−5.47, 4.28) j LSM (95% CI)* Differential Cell Counts % at Baseline 49.20 21.77 13.87 11.97 25.31 4.80 Mean (SD) (10.62) k (7.85) k (7.21) l (12.66) c (14.41) c (5.30) c % at Month 6 11.31 25.48 5.40 12.88 25.09 4.77 Mean (SD) (9.89) d (14.79) d (4.28) d (13.66) m (13.75) m (5.21) i Mean change from −38.97 5.66 −8.40 0.11 0.07 0.29 Baseline to Month 6 (−41.06, −36.88) n (3.24, 8.08) n (−9.27, −7.53) o (−0.90, 1.13) p (−0.65, 0.80) p (−0.21, 0.79) q LSM (95% CI)* *Adjusted change from Baseline to Month 6 (cells/μL). ANCOVA model with gender as a factor and duration of disease and corresponding Baseline as covariates. At baseline, patients in Cohort 2 had been continuously treated with fingolimod for ≥2 years. a n=158; b n=154; c n=212; d n=116; e n=184; f n=180; g n=110; h n=107; i n=181; j n=178; k n=159; l n=155; m n=185; n n=111; o n=108; p n=182; q n=179. ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean; SD, standard deviation. 8
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