CMSC & ACTRIMS 2014 Annual Meeting Dallas, Texas Disability progression after switching from natalizumab to fingolimod or injectable therapies: a NARCOMS analysis Stacey S Cofield, PhD May 30, 2014 Stacey S Cofield, 1 Robert J Fox, 2 Tuula Tyry, 3 Amber R Salter, 1 Denise Campagnolo, 4 Mary Jean Fanelli, 4 Terrie Livingston 4 1 University of Alabama at Birmingham, Birmingham, AL, USA; 2 Mellen Center for Multiple Sclerosis, Lerner College of Medicine, Cleveland, OH, USA; 3 St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA; 4 Biogen Idec, Cambridge, MA, USA Disclosures and acknowledgments Dr. Cofield received personal compensation from TEVA Pharmaceuticals, MedImmune, Orthotech Biotech, and the American Academy for Orthopedic Surgery for consulting services, research funds and/or DSMB service. Dr. Fox received consulting fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, Teva, Xenoport and grant support from Novartis. Dr. Tyry has nothing to disclose Ms. Salter has received consulting fees from GlaxoSmithKline Drs. Campagnolo, Fanelli, and Livingston are employees of Biogen Idec Inc. Funding: NARCOMS is supported in part by the CMSC and the Foundation of the CMSC. This study is supported in part by Biogen Idec. All data collection, management and analyses performed by NARCOMS. Acknowledgments: Editorial and writing support was provided by Nolan Campbell of Biogen Idec Inc. 2 1
Background Natalizumab is an effective treatment against disability progression in RRMS: - In AFFIRM, natalizumab decreased the risk of 6-month confirmed disability progression by 54% compared to placebo. 1 - In the 5-year interim analysis of TOP, 84% of natalizumab patients were free of 6-month confirmed disability progression. 2 After 2 years of natalizumab, the risk of PML increases in anti-JCV antibody positive patients, which may prompt evaluation of treatment options at that time. 3 Disability progression risks associated with transitioning treatment after 2 years of natalizumab have not been fully determined. RRMS=relapsing remitting multiple sclerosis; TOP=TYSABRI Observational Program; PML=progressive multifocal leukoencephalopathy; 1 Polman CH, et al. N Engl J Med 2006;354:899-910; 2 Butzkueven H, et al. JNNP 2014;doi: 10.1136/jnnp-2013-306936. 3 Bloomgren, et al. N 3 Engl J Med 2012;366:1870-80 Objective and study design Retrospectively compare disability progression, measured by increase in Patient Determined Disease Steps (PDDS) NARCOMS participants, after 2 years on natalizumab: - remained on natalizumab (NAT) or - transitioned to fingolimod (FIN) or - transitioned to injectable therapies (INJ: GA or IFN ) NAT, FIN, or INJ 2 continuous treatment reported Spring 2005 Spring 2013 years of NAT PDDS at PDDS ≥ 6 NAT start months after (baseline) 2 years 4 GA=glatiramer acetate; IFN =interferon-beta 2
PDDS The NARCOMS registry participants report disability in Patient-Determined Disease Steps (PDDS): - 0 = Normal - 1 = Mild disability (little to no effect on lifestyle) - 2 = Moderate disability (but no walking limitations) - 3 = Gait disability - 4 = Early cane (required for 3 blocks) - 5 = Late cane (required for 25 feet) - 6 = Bilateral support (required for 25 feet) - 7 = Wheelchair / scooter - 8 = Bedridden 5 Participant disposition Exclusions NAT for 2 years with ≥ 1 follow-up, N=604 No PDDS at baseline N=10 PDDS at start of NAT, N=594 No PDDS after 2 years of NAT N=57 PDDS ≥ 6 months after 2 years of NAT, N=537 DMTs other than NAT, FIN, INJ N=10 Only NAT treatment FIN treatment INJ (no other DMTs) N=50 N=71 N=406 Additional treatments Additional treatments 40 FIN only 64 INJ only 7 INJ + non-DMT 7 FIN + INJ 3 FIN + non-DMT 6 DMT=disease modifying therapy 3
Characteristics at start of natalizumab NAT FIN INJ N=406 N=50 N=71 p -value Age, years, mean (SD) 49.4 (9.3) 49.1 (8.4) 50.0 (8.8) 0.8858 Sex, % Female 79.5 70.0 81.7 0.2489 Race, % Caucasian 93.6 88.0 93.0 0.2992 Employment, % with 38.0 44.0 38.0 0.7104 Health insurance, % with 97.8 98.0 98.6 >0.9999 Age at diagnosis, years, 36.4 (9.4) 36.6 (9.0) 36.5 (9.0) 0.9614 mean (SD) Relapse in prior 6 months, 20.4 16.0 19.7 0.9570 % Yes PDDS, mean (SD) 3.4 (2.1) 3.6 (2.0) 3.9 (2.3) median (range) 3 (0-8) 4 (0-7) 4 (0-7) 0.1334 7 SD=standard deviation Total follow-up time NAT FIN INJ N=406 N=50 N=71 p -value Total follow-up, months, mean (SD) 45.6 (16.2) 52.9 (14.4) 57.7 (12.4) median (range) 48 (12-72) 54 (18-72) 60 (24-72) <0.0001 Follow-up after treatment transition, months, mean (SD) NA 13.8 (10.0) 20.4 (13.9) median (range) NA 12 (0-42) 18 (0-54) 0.0123 Those who transitioned to FIN or INJ had longer total follow-up time, including the initial 2 years on NAT. Those that transitioned to INJ had longer follow up time after DMT change compared to FIN. 8 NA=not applicable 4
Mean PDDS increase was lower in the NAT treatment group Mean PDDS increase from NAT start p = 0.0141 0.8 Mean PDDS increase 0.6 0.6 0.5 0.4 0.3 0.2 0.0 NAT FIN INJ (N=406) (N=50) (N=71) 9 Group differences in PDDS increase remained after covariate adjustment Covariate-adjusted mean PDDS increase from baseline p = 0.0036 0.8 0.7 Predictors of increased PDDS Mean PDDS increase worsening were: 0.6 0.6 • Older age ( p = 0.0014) • Male sex ( p = 0.0235) • Lower baseline PDDS ( p < 0.0001). 0.4 Follow-up time was not significantly 0.3 related to PDDS change ( p = 0.6930). 0.2 0.0 FIN NAT INJ (N=406) (N=50) (N=71) 10 5
PDDS increase occurred in a smaller proportion of participants in the NAT group Proportion of participants with ≥ 1 point PDDS increase p = 0.0296 50 46.0 42.3 % with PDDS increase 40 30.8 30 20 10 0 NAT FIN INJ (N=406) (N=50) (N=71) 11 SF-12 PCS worsened significantly in FIN and INJ Mean change in SF-12 PCS from NAT start p = 0.1279 0.0 Mean SF-12 PCS worsening -1.0 -1.3 -2.0 -3.0 -4.0 -4.2 -4.3 -5.0 NAT FIN INJ (N=406) (N=50) (N=71) 12 SF= short form; PCS= physical component score 6
Covariate adjusted group differences in mean SF-12 PCS change Covariate-adjusted mean SF-12 PCS worsening from baseline p = 0.0476 0.0 Predictors of SF-12 PCS Mean SF-12 PCS worsening worsening were: -1.0 • Older age ( p < 0.0001) • Higher baseline SF-12 PCS -1.4 -2.0 ( p < 0.0001). Follow-up time ( p = 0.53) and -3.0 -2.8 sex ( p = 0.44) were not significantly related to SF-12 -4.0 PCS change. -4.6 -5.0 NAT FIN INJ (N=406) (N=50) (N=71) 13 Propensity score paired analysis Propensity score pairing reduces potential bias in retrospective studies by selectively comparing participants with balanced baseline characteristics. - Propensity scores derived from age, sex, starting PDDS score, and prior relapse activity were used to pair participants. Characteristic NAT, N=50 FIN, N=50 NAT, N=45 INJ, N=45 PDDS, n (%): 0-2 15 (30) 15 (30) 11 (24) 11 (24) 3-5 24 (48) 24 (48) 21 (47) 21 (47) 6-7 9 (18) 9 (18) 12 (27) 12 (27) Relapse in prior 6 months, n (%): No 34 (68) 34 (68) 33 (73) 33 (73) Yes 8 (16) 8 (16) 7 (16) 8 (18) Sex, n (%): Female 33 (66) 33 (66) 37 (82) 39 (87) Age: mean (SD) 49.8 (6.9) 49.1 (8.4) 50.1 (7.9) 49.5 (8.1) 14 7
Observed lower mean PDDS increase in the NAT group Mean PDDS increase for paired Mean PDDS increase for paired NAT-FIN participants NAT-INJ participants p = 0.0584 p = 0.0216 0.8 0.8 0.7 Mean PDDS increase Mean PDDS increase 0.6 0.6 0.5 0.4 0.4 0.2 0.2 0.2 0.1 0.0 0.0 NAT NAT FIN INJ (N=50) (N=50) (N=45) (N=45) p -values are not significant after correcting for multiple comparisons 15 Observed fewer participants with PDDS increase in the NAT group Proportion of paired NAT-FIN Proportion of paired NAT-INJ participants with PDDS increase participants with PDDS increase p = 0.0211 p = 0.1967 50 50 46.7 46.0 % with PDDS increase % with PDDS increase 40 40 33.3 30 30 24.0 20 20 10 10 0 0 NAT NAT FIN INJ (N=45) (N=50) (N=50) (N=45) 16 8
Observed less mean SF-12 PCS worsening in the NAT group Mean change in SF-12 PCS for Mean change in SF-12 PCS for paired NAT-FIN participants paired NAT-INJ participants p = 0.4282 p = 0.6335 Mean SF-12 PCS worsening Mean SF-12 PCS worsening 0.0 0.0 -1.0 -2.0 -2.0 -2.1 -4.0 -3.0 -5.1 -6.0 -4.0 -6.6 -4.2 -5.0 -8.0 NAT NAT FIN INJ (N=50) (N=50) (N=45) (N=45) 17 Conclusions Transitioning off natalizumab after 2 years was associated with a significant increase in the likelihood of participant-reported disability progression and increased mean disability. Consistent with PDDS observations, transitioning off natalizumab was associated with patient reported SF-12 PCS worsening. Similar findings were observed using a propensity score paired analysis, but the differences were not statistically significant. 18 9
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