Disclosures Funding source: This study is supported by Novartis - - PDF document

disclosures
SMART_READER_LITE
LIVE PREVIEW

Disclosures Funding source: This study is supported by Novartis - - PDF document

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


slide-1
SLIDE 1

Changes in the immune cell profile, clinical and safety outcomes in fingolimod-treated patients with relapsing multiple sclerosis: interim results of the FLUENT study

1Autoimmunity Center of Excellence, Multiple Sclerosis Center, University of Michigan, Ann Arbor, MI, USA; 2Mellen Center, Cleveland Clinic, Cleveland, OH, USA; 3Center for Neuroinflammation and Experimental Therapeutics,

and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;

4UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA; 5Stanford University, Stanford, CA, USA; 6Missouri Baptist Medical Center, St Louis, MO, USA; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Platform Presentation DXM03 May 31, 2019 Yang Mao-Draayer1, Jeffrey Cohen2, Amit Bar-Or3, Bruce A.C. Cree4, May H. Han5, Barry Singer6, Scott Kolodny7, Xiangyi Meng7, Lesley Schofield7, Marina Ziehn7, on behalf of the FLUENT study investigators

2

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.

slide-2
SLIDE 2

3

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 subsets1

  • Rare occurrences of opportunistic infections, including cases of PML, have been reported with fingolimod in the

post-marketing setting1,2

  • 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.

4

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

FLUENT study endpoints

*Baseline defined as the start of the 12-month treatment window in FLUENT. JCV, John Cunningham virus; NK, natural killer.

slide-3
SLIDE 3

5

Patients:

  • Aged ≥18 years
  • Diagnosed with RMS as defined by 2010 revised McDonald criteria1
  • Fingolimod-naïve or receiving continuous fingolimod 0.5 mg/day for ≥2 years

Study design and patients

12-month, prospective, multicenter, 2-cohort, nonrandomized,

  • pen-label, Phase 4 study

RMS, relapsing forms of multiple sclerosis.

  • 1. Polman CH, et al. Ann Neurol 2011;69:292-302.

Baseline 3 months 6 months 12 months

Screening Period (Up to 4 weeks) Open-label Treatment Phase 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

6

Baseline characteristics

*Cohort 1, n=164; Cohort 2, n=215. MS, multiple sclerosis.

Cohort 1 Fingolimod-naïve (N=166) Cohort 2 Continuous fingolimod (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, median (range) 3.36 (0.0, 33.5) 11.66 (2.3, 40.6) 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

slide-4
SLIDE 4

7

Cohort 1 Fingolimod-naïve

  • 1200 -1000 -800
  • 600
  • 400
  • 200

100

Mean change from Baseline to Month 6 LSM (95% Cl)*

Cohort 2 Continuous fingolimod

Mean change from Baseline to Month 6 LSM (95% Cl)*

  • 1200 -1000 -800
  • 600
  • 400
  • 200

100

Change from Baseline to Month 6 in innate and adaptive immune cell subsets

*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. 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+)

Cells/μL

8

Change from Baseline to Month 6 in absolute and differential CD4+, CD8+, and CD19+ cell counts

*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.

an=158; bn=154; cn=212; dn=116; en=184; fn=180; gn=110; hn=107; in=181; jn=178; kn=159; ln=155; mn=185; nn=111; on=108; pn=182; qn=179.

ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean; SD, standard deviation.

Cohort 1: Fingolimod-naïve Cohort 2: Continuous fingolimod

CD4+ CD8+ CD19+ CD4+ CD8+ CD19+ Absolute Cell Counts

Baseline Mean (SD) cells/μL 932.35 (451.07)a 416.97 (258.48)a 257.88 (167.78)b 64.59 (122.82)c 124.99 (213.84)c 21.34 (45.29)c Month 6 Mean (SD) cells/μL 53.09 (111.68)d 119.76 (145.24)d 19.86 (16.51)d 71.52 (111.99)e 117.38 (100.76)e 21.53 (34.63)f Mean change from Baseline to Month 6 LSM (95% CI)* −883.84 (−909.53, −858.15)g −247.21 (−276.50, −217.93)g −232.58 (−236.07, −229.08)h −3.55 (−18.00, 10.89)i −9.61 (−24.98, 5.75)i −0.60 (−5.47, 4.28)j

Differential Cell Counts

% at Baseline Mean (SD) 49.20 (10.62)k 21.77 (7.85)k 13.87 (7.21)l 11.97 (12.66)c 25.31 (14.41)c 4.80 (5.30)c % at Month 6 Mean (SD) 11.31 (9.89)d 25.48 (14.79)d 5.40 (4.28)d 12.88 (13.66)m 25.09 (13.75)m 4.77 (5.21)i Mean change from Baseline to Month 6 LSM (95% CI)* −38.97 (−41.06, −36.88)n 5.66 (3.24, 8.08)n −8.40 (−9.27, −7.53)o 0.11 (−0.90, 1.13)p 0.07 (−0.65, 0.80)p 0.29 (−0.21, 0.79)q

slide-5
SLIDE 5

9

Change from Baseline to Month 6 in biomarker levels and Baseline JCV Status

*At baseline, patients in Cohort 2 had been continuously treated with fingolimod for ≥2 years.

†Adjusted change from Baseline to Month 6 (pg/mL). ANCOVA model with gender as a factor and duration of disease and corresponding Baseline as covariates. an=157; bn=214; cn=99; dn=185, en=162; fn=116; gn=194.

ANCOVA, analysis of covariance; CI, confidence interval; JCV, John Cunningham virus; LSM, least square mean; SD, standard deviation.

Cohort 1 Fingolimod-naïve Cohort 2 Continuous fingolimod*

Baseline, mean (SD), pg/mL 12.26 (10.99)a 9.58 (7.57)b Month 6, mean (SD), pg/mL 9.32 (6.03)c 9.90 (9.99)d Mean change from Baseline to Month 6 LSM (95% CI)† −2.09 (−3.95, −0.23) −0.73 (−2.08, 0.62) Baseline index, mean (SD) 1.28 (1.29)e 1.39 (1.26)b Change from Baseline to Month 6, mean (SD) 0.04 (0.29)f 0.04 (0.47)g

Serum neurofilament light chain Anti-JCV antibody index Combined Cohort 1 & 2 JCV serology at Baseline (Day 1), n (%)

Indeterminate Negative Positive

49 (13.0) 96 (25.5) 232 (61.5)

10

Summary of adverse events

AE, adverse event.

Event, n (%) Cohort 1 Fingolimod-naïve (N=166) Cohort 2 Continuous fingolimod (N=216)

AE 87 (52.4) 87 (40.3) Treatment-emergent AE 86 (51.8) 86 (39.8) Serious AE 7 ( 4.2) 11 ( 5.1) AE leading to treatment discontinuation 17 (10.2) 12 ( 5.6)

slide-6
SLIDE 6

11

Adverse events occurring in ≥3% of patients in Cohort 1 or 2

Treatment-emergent adverse events by Preferred Term. URTI, upper respiratory tract infection

Event, n (%) Cohort 1 Fingolimod-naïve (N=166) Cohort 2 Continuous fingolimod (N=216)

Headache 12 (7.2) 4 (1.9) Fall 5 (3.0) 10 (4.6) URTI 7 (4.2) 4 (1.9) Pain in extremity 7 (4.2) 3 (1.4) Anxiety 6 (3.6) 3 (1.4) Fatigue 6 (3.6) 3 (1.4) Lymphopenia 8 (4.8) 1 (0.5) Nausea 5 (3.0) 2 (0.9) Dizziness 5 (3.0) 1 (0.5) Hypoesthesia 5 (3.0) 1 (0.5) Tremor 5 (3.0)

12

Conclusions

  • Fingolimod-naïve patients (Cohort 1) showed reductions in immune cell subset counts following 6 months
  • f fingolimod treatment

Greater reductions of naïve and central memory T cells than effector memory T cells and regulatory B cells

  • Shifts in cell subsets were less pronounced in Cohort 2 than Cohort 1, likely due to Cohort 2 receiving

continuous fingolimod for ≥2 years prior to entering observation period

  • Changes in immune cell subsets of Cohort 1 patients were expected and are characteristic of people

initiating fingolimod

  • Lack of long-term change in patients treated with fingolimod for ≥2 years suggests that immune cell subsets

are not significantly modified with longer-term treatment

  • In our findings, we observed:

Small reductions in serum neurofilament levels (sNfL) in both Cohorts

  • Change in sNfL from Baseline to Month 6 w as larger in Cohort 1 vs Cohort 2

No demonstrable change from baseline in anti-JCV antibody index in either Cohort

JCV, John Cunningham virus.

slide-7
SLIDE 7

Thank you

14

View an augmented reality (AR) presentation of:

  • Neuroaxonal damage in MS
  • Fingolimod mechanism of action
  • FLUENT Study content

FLUENT Study AR Experience

Get started Scan the QR code using your smart device’s camera or enter the URL FLUENTstudyAR.com on your camera-enabled mobile device

 FLUENT Study AR marker

The AR presentation requires a mobile device using either iOS 11.2.1, or Android 6,

  • r later. An alternative 3D model view may

be available for older devices.

slide-8
SLIDE 8

Back-up slides

16

Change from Baseline to Month 6 in adaptive immune cell subsets

*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. an=149; bn=108; cn=97; dn=187; en=173; fn=155; gn=150; hn=113; in=104; jn=210; kn=183; ln=179; mn=211; nn=180.

ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean; SD, standard deviation.

Cohort 1: Fingolimod-naïve Cohort 2: Continuous fingolimod

Baseline Mean (SD) cells/μL Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* Baseline Mean (SD) cells/μL† Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* CD4+ naïve T cells

405.70 (280.37)a 7.01 (36.07)b −410.63 (−419.82, −401.43)c 3.45 (20.74)d 4.48 (22.38)e −0.20 (−4.03, 3.62)f

CD4+ central memory T cells

369.77 (217.87)a 18.65 (55.76)b −366.86 (−380.71, −353.00)c 16.40 (45.22)d 17.95 (41.18)e −0.14 (−7.22, 6.94)f

CD4+ effector memory T cells

73.68 (43.65)a 18.24 (22.48)b −51.79 (−56.84, −46.73)c 22.88 (41.31)d 20.81 (32.13)e −3.13 (−7.67, 1.40)f

CD4+ Th1 cells

53.22 (38.53)g 7.81 (14.90)h −43.43 (−46.68, −40.17)i 11.18 (31.97)j 11.80 (33.18)k −0.68 (−3.03, 1.67)l

CD4+ Th2 cells

35.30 (30.11)g 1.62 (4.02)h −36.15 (−37.10, −35.21)i 1.12 (4.02)m 1.67 (5.54)k 0.40 (−0.44, 1.24)n

CD4+ Th17 cells

54.81 (36.80)g 3.04 (8.06)h −52.93 (−54.82, −51.05)i 2.36 (5.98)m 2.86 (6.98)k 0.36 (−0.66, 1.39)n

slide-9
SLIDE 9

17

Change from Baseline to Month 6 in adaptive immune cell subsets

*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. an=149; bn=108; cn=97; dn=187; en=173; fn=155; gn=211; hn=147; in=114; jn=102; kn=177; ln=175.

ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean; SD, standard deviation.

Cohort 1: Fingolimod-naïve Cohort 2: Continuous fingolimod

Baseline Mean (SD) cells/μL Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* Baseline Mean (SD) cells/μL† Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* CD8+ naïve T cells

149.26 (116.87)a 3.84 (20.86)b −138.98 (−144.27, −133.68)c 1.76 (8.89)d 3.02 (15.07)e 0.70 (−1.89, 3.30)f

CD8+ central memory T cells

92.26 (75.34)a 5.78 (15.65)b −84.76 (−88.53, −81.00)c 5.63 (14.89)d 5.87 (12.44)e −0.19 (−2.31, 1.93)f

CD8+ effector memory cells

108.27 (93.37)a 56.11 (99.79)b −27.89 (−50.62, −5.15)c 63.94 (115.56)d 50.71 (39.94)e −9.39 (−16.32, −2.45)f

CD19+ naïve B cells

199.45 (133.80)h 15.96 (13.55)I −182.60 (−184.88, −180.33)j 18.10 (33.86)g 17.54 (19.86)k −1.07 (−4.36, 2.22)l

CD19+ memory B cells

61.44 (73.89)h 3.65 (5.94)I −55.24 (−56.53, −53.95)j 3.33 (22.64)g 3.99 (21.13)k 0.27 (−0.56, 1.10)l

CD19+ regulatory B cells

12.19 (12.79)h 5.18 (5.13)i −7.24 (−8.09, −6.39)j 5.23 (7.67)g 5.96 (5.06)k 1.00 (0.17, 1.83)l

18

Change from Baseline to Month 6 in innate immune cell subsets

*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. an=152; bn=114; cn=105; dn=196; en=181; fn=165; gn=151.

ANCOVA, analysis of covariance; CI, confidence interval; LSM, least square mean; SD, standard deviation.

Cohort 1: Fingolimod-naïve Cohort 2: Continuous fingolimod

Baseline Mean (SD) cells/μL Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* Baseline Mean (SD) cells/μL† Month 6 Mean (SD) cells/μL Mean change from Baseline to Month 6 LSM (95% CI)* Monocytes (CD14+)

333.27 (170.13)a 389.44 (154.19)b 63.77 (36.57, 90.97)c 249.17 (113.29)d 386.84 (136.05)e 121.04 (101.23, 140.85)f

Neutrophils (CD16+)

4058.48 (1592.26)g 3475.09 (1487.56)b −849.39 (−1122.85, −575.93)c 3698.56 (1532.91)d 3336.13 (1281.79)e −439.53 (−620.05, −259.01)f

Natural killer cells (CD56+)

167.07 (98.23)g 134.25 (86.66)b −31.31 (−46.08, −16.55)c 180.81 (114.21)d 152.82 (87.12)e −26.69 (−37.67, −15.71)f