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Disclosures and acknowledgments Dr. Cofield received personal - - PDF document

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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

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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 Livingston4

1University of Alabama at Birmingham, Birmingham, AL, USA; 2Mellen Center for

Multiple Sclerosis, Lerner College of Medicine, Cleveland, OH, USA; 3St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA; 4Biogen Idec, Cambridge, MA, USA

CMSC & ACTRIMS 2014 Annual Meeting Dallas, Texas

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

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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

  • ptions at that time.3
  • Disability progression risks associated with transitioning treatment

after 2 years of natalizumab have not been fully determined.

3

RRMS=relapsing remitting multiple sclerosis; TOP=TYSABRI Observational Program; PML=progressive multifocal leukoencephalopathy;

1Polman CH, et al. N Engl J Med 2006;354:899-910; 2Butzkueven H, et al. JNNP 2014;doi: 10.1136/jnnp-2013-306936.3Bloomgren, et al. N

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)

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Spring 2005 Spring 2013

2 continuous years of NAT PDDS at NAT start (baseline) PDDS ≥ 6 months after 2 years NAT, FIN, or INJ treatment reported

GA=glatiramer acetate; IFN=interferon-beta

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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 6

Participant disposition

NAT for 2 years with ≥1 follow-up, N=604 PDDS at start of NAT, N=594 PDDS ≥6 months after 2 years

  • f NAT, N=537

Only NAT treatment N=406 FIN treatment N=50 INJ (no other DMTs) N=71 Additional treatments 40 FIN only 7 FIN + INJ 3 FIN + non-DMT Additional treatments 64 INJ only 7 INJ + non-DMT No PDDS at baseline N=10 No PDDS after 2 years of NAT N=57 DMTs other than NAT, FIN, INJ N=10

Exclusions

DMT=disease modifying therapy

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Characteristics at start of natalizumab

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NAT N=406 FIN N=50 INJ 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, mean (SD) 36.4 (9.4) 36.6 (9.0) 36.5 (9.0) 0.9614 Relapse in prior 6 months, % Yes 20.4 16.0 19.7 0.9570 PDDS, mean (SD) median (range) 3.4 (2.1) 3 (0-8) 3.6 (2.0) 4 (0-7) 3.9 (2.3) 4 (0-7) 0.1334

SD=standard deviation

Total follow-up time

  • 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.

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NAT N=406 FIN N=50 INJ N=71 p-value Total follow-up, months, mean (SD) median (range) 45.6 (16.2) 48 (12-72) 52.9 (14.4) 54 (18-72) 57.7 (12.4) 60 (24-72) <0.0001 Follow-up after treatment transition, months, mean (SD) median (range) NA NA 13.8 (10.0) 12 (0-42) 20.4 (13.9) 18 (0-54) 0.0123

NA=not applicable

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Mean PDDS increase was lower in the NAT treatment group

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Mean PDDS increase from NAT start Mean PDDS increase NAT

(N=406)

FIN

(N=50)

INJ

(N=71)

0.0 0.2 0.4 0.6 0.8 0.3 0.5 0.6 p = 0.0141

Group differences in PDDS increase remained after covariate adjustment

NAT

(N=406)

FIN

(N=50)

INJ

(N=71)

0.0 0.2 0.4 0.6 0.8 Covariate-adjusted mean PDDS increase from baseline 0.3 0.6 0.7 Mean PDDS increase p = 0.0036

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  • Predictors of increased PDDS

worsening were:

  • Older age (p = 0.0014)
  • Male sex (p = 0.0235)
  • Lower baseline PDDS (p < 0.0001).
  • Follow-up time was not significantly

related to PDDS change (p = 0.6930).

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INJ

(N=71)

FIN

(N=50)

NAT

(N=406)

PDDS increase occurred in a smaller proportion

  • f participants in the NAT group

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Proportion of participants with ≥ 1 point PDDS increase 10 20 30.8 46.0 42.3 p = 0.0296 30 40 50 % with PDDS increase

SF-12 PCS worsened significantly in FIN and INJ

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INJ

(N=71)

FIN

(N=50)

NAT

(N=406)

  • 5.0
  • 4.0
  • 3.0
  • 2.0
  • 1.0

0.0 Mean change in SF-12 PCS from NAT start

  • 1.3
  • 4.2
  • 4.3

p = 0.1279 Mean SF-12 PCS worsening

SF= short form; PCS= physical component score

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Covariate adjusted group differences in mean SF-12 PCS change

NAT

(N=406)

FIN

(N=50)

INJ

(N=71)

Covariate-adjusted mean SF-12 PCS worsening from baseline

  • 1.4
  • 2.8
  • 4.6

Mean SF-12 PCS worsening p = 0.0476

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  • Predictors of SF-12 PCS

worsening were:

  • Older age (p < 0.0001)
  • Higher baseline SF-12 PCS

(p < 0.0001).

  • Follow-up time (p = 0.53) and

sex (p = 0.44) were not significantly related to SF-12 PCS change.

  • 5.0
  • 4.0
  • 3.0
  • 2.0
  • 1.0

0.0

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.

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Characteristic NAT, N=50 FIN, N=50 NAT, N=45 INJ, N=45 PDDS, n (%): 0-2 3-5 6-7 15 (30) 24 (48) 9 (18) 15 (30) 24 (48) 9 (18) 11 (24) 21 (47) 12 (27) 11 (24) 21 (47) 12 (27) Relapse in prior 6 months, n (%): No Yes 34 (68) 8 (16) 34 (68) 8 (16) 33 (73) 7 (16) 33 (73) 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)

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NAT

(N=45)

INJ

(N=45)

NAT

(N=50)

FIN

(N=50)

Observed lower mean PDDS increase in the NAT group

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p-values are not significant after correcting for multiple comparisons

0.1 0.5 0.2 0.7 Mean PDDS increase 0.0 0.2 0.4 0.6 0.8 Mean PDDS increase 0.0 0.2 0.4 0.6 0.8 Mean PDDS increase for paired NAT-FIN participants Mean PDDS increase for paired NAT-INJ participants p = 0.0584 p = 0.0216 INJ

(N=45)

NAT

(N=45)

FIN

(N=50)

NAT

(N=50)

Observed fewer participants with PDDS increase in the NAT group

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% with PDDS increase 10 20 30 40 50 % with PDDS increase 10 20 30 40 50 24.0 46.0 33.3 46.7 Proportion of paired NAT-FIN participants with PDDS increase Proportion of paired NAT-INJ participants with PDDS increase p = 0.1967 p = 0.0211

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Mean SF-12 PCS worsening Mean SF-12 PCS worsening

Observed less mean SF-12 PCS worsening in the NAT group

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INJ

(N=45)

NAT

(N=45)

FIN

(N=50)

NAT

(N=50)

  • 2.1
  • 4.2
  • 5.1
  • 6.6

p = 0.6335 p = 0.4282

  • 5.0
  • 4.0
  • 3.0
  • 2.0
  • 1.0

0.0

  • 2.0

0.0

  • 4.0
  • 6.0
  • 8.0

Mean change in SF-12 PCS for paired NAT-FIN participants Mean change in SF-12 PCS for paired NAT-INJ participants

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.

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