Disability Progression in MS: Why Bother? What Have We Learned? - - PowerPoint PPT Presentation

2/15/2018 1

Disability Progression in MS: What Have We Learned?

Bruce Cree, MD, PhD, MAS Weill Institute for Neurosciences University of California San Francisco

Clinical Trials and Long Term Follow-up: Why Bother?

• Clinical trials offer meticulously curated data

– Standardized data collection – Data undergoes quality control

• External study monitors review data
• Data acquisition can include imaging, biometric assessments and

even biological samples

– Rarely if ever obtained in natural history studies

– Treatment is standardized during the randomized controlled study period – Treatment is typically open-label during the LTFU

Expectations from Long Term Follow-up Studies

• Long term medication safety

– Sample is limited to size of original cohort

• Longitudinal assessment of efficacy

– Lack of reference group

• Identification of predictors of long-term outcomes

– Assumes data on predictors are collected at baseline or during the study

• Caveat: extent of attrition and baseline sample size

limits interpretation of all of the above Some Long-term Follow up Study Interpretations

• “Multiple sclerosis patients with mean disease duration of 22 years administering GA

for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS.” Ford C. Mult Scler 2010;16:342-350

• “Disease activity despite treatment with IFNb is associated with unfavorable long-term
• utcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNb

therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNb-treated patients with MRI, and for changing therapy in patients with active disease.” Bermel RA. Annal Neurol 2013;73:95– 103

• “This study provides class III evidence that long-term treatment with teriflunomide is

well-tolerated and efficacy of teriflunomide is maintained long-term.” O’Connor P. Neurology 2016;86:920-930

• “These findings suggest that higher cumulative exposure to sc IFN β-1a may be

associated with better clinical outcomes.” Kappos L. J Neurol Neurosurg Psychaitry 2015;86:1202-1207

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Long-term Follow-up Studies from Clinical Trials

Medication Clinical Trial Duration of LTFU Ascertainment Interferon β-1b Pivotal Trial 16 years 70% Pivotal Trial- mortality 21 years 98% Secondary Progressive MS 10 years 50% BENEFIT (CIS) 11 year 59% Interferon β-1a IM MSCRG 15 years 40% CHAMPS (CIS) 10 years 33% Glatiramer Acetate Pivotal Trial 15 years 43% Interferon β-1a SC PRISMS 15 years 52% Teriflunomide TEMSO 9 years 63% Fingolimod FREEDOMS/TRANSFORMS 7 years 30% Goodin DS. J Neurol Neuorsurg Psychiatry 2012;83:282-287. Goodin DS. Neurology. 2012;78:1315-22. Kuhle J. Mult Scler 2016;22:533-43. Kappos L. Neurology 2016;87:978-87. Bermel RA. Mult Scler 2010;16:588-96. Kinkle RP. Arch Neurol 2012;69:183-90. Ford C. Mult Scler. 2010;16:342-50. Kappos L. J Neurol Neurosurg Psychiatry 2015;86:1202-1207. O’Connor P. Neurology 2016;86:920-930. Cohen JA. AAN2016 [P3.057]

Attrition and Informative Censoring

• Subject attrition in long-term studies occurs for multiple reasons

– Subject factors: relocation, loss of interest, life-changes – Center factors: some centers chose not to or are unable to participate – Disease factors: some subjects drop out or switch treatment because or worsening MS

• This last feature known as informative censoring plagues interpretation of

all studies with substantial drop-out making accurate assessment of efficacy nearly impossible

– For example in the glatiramer acetate (GA) long term follow up study subjects who stayed in the cohort experienced less progression than subjects who discontinued GA – A substantial proportion of subjects who discontinued GA did so due to worsening MS – Therefore, those retained in the study are positively selected to remain in the study as “GA responders”

Interferon β-1b LTFU and Mortality:

Example of nearly complete LTFU ascertainment

Goodin DS. Neurology. 2012;78:1315-22.

Interferon β-1b LTFU and Mortality

Goodin DS. Neurology. 2012;78:1315-22.

Survival from Randomization Survival from Clinical Onset

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Interferon β-1b LTFU and Mortality

• Nearly complete ascertainment: 366/372 (98.4%)
• 21 year “hard” outcome of all cause mortality
• Comparison of placebo versus interferon beta-1b assignment without regard

to later treatments

• Follow-up analysis found death was could be attributed to MS in 54/69

subjects (78.3%), especially from pulmonary infections related to MS

• Study provided evidence that treatment with interferon β-1b has an impact
• n MS related mortality
• Provides evidence based rationale for early versus delayed initiation of

treatment

• Results recently replicated in observational cohorts from Rennes France and

British Columbia, Canada (N=7009, 30% treated with IFN beta)

Goodin DS. Neurology. 2012;78:1315-22. Goodin DS. BMJ Open. 2012;2(6). Kingwell E. ECRTIMS 2017 abstract 2178 Bias Impact Strategy

Ascertainment/Attrition Modified therapeutic effect dependent on characteristics of participating patients. F/U must be as complete as possible Compare baseline and on-RCT characteristics

• f those patients in LTF to those not in LTF

Sensitivity analysis of those lost to f/u assuming worse outcomes Informed Therapeutic Decisions Inflated estimate of therapeutic benefit because patients doing well continue therapy whereas failing patients switch or stop therapy. MPR: Use percent of total possible time on therapy instead of absolute time to assess exposure. Treatment Selection Modified therapeutic effect dependent on patient selection characteristics. Propensity Scoring: Adjust for the likelihood that a particular treatment will be selected based

• n available patient characteristics

(assumes that such characteristics are relevant) Multiple Testing Increased risk of Type 1 error from the use of multiple predictor variables and weighting schemes Create a single model and apply adjustments to p-values according to the number of predictors tested in the model.

Sources of Bias in LTFU Studies

Long-term follow up in EPIC

• EPIC originally conceived of as a 5 year genotype-phenotype correlation study

– Emphasis on genetics and brain MRI

• Collaborative effort with MS centers in Amsterdam Netherlands and Basel

Switzerland and Glaxo Smith Kline, formerly known as GENE-MSA

• Long-term follow up of cohort proposed as a means of predicting disability

progression

• Anticipated observations:

– brain volume change, new lesions, EDSS change and active disease on treatment would be predictive of long-term disability outcomes – Escalation to high potency therapy based on clinical and MRI activity would be associated with improved outcomes

Cree B. Ann Neurol 2016; 80:499-510

P ro po rtio n

• f In

S tu d y P a tie n ts

Baseline Y ear 1 Y ear 2 Y ear 3 Y ear 4 Y ear 5 Y ear 6 Y ear 7 Y ear 8−10 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

In Study Patients 517 505 489 484 479 472 461 460 456 Withdrawn Patients 9 24 28 31 36 47 48 49 Deceased (Not MS) 3 4 4 5 7 7 7 8 Deceased (MS) 1 2 2 2 2 4

EPIC Subject Retention

• Data available on 471/517 (91%) of subjects at

the last follow up visit 10 years after baseline

• Rigorous analysis conducted on

subjects lost to follow up with comparisons to subjects retained and sensitivity analyses assuming worst outcomes

Cree B. Ann Neurol 2016; 80:499-510

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Baseline EDSS scores of subjects with long-term follow up RMS (N=407) vs. PMS (N=64)

Time to Cane Dependency (EDSS=6)

Kaplan Meier survival curves for time to EDSS=6 (ambulatory impairment requiring a cane to walk 100 meters). Disease duration in years is graphed on the X-axis and the percentage of the cohort at each time point that has not met the failure events is depicted on the y-axis.

Disease Duration Pr

• p
• rtio

n

• f Su

bje cts

• No. Subjects

10 20 30 40 .0 .2 .4 .6 0.8 1 .0

A) Time to EDSS 6

Censored Data 406 379 144 53 14 subjects developing EDSS greater than or equal to 6 by 10 years: 4.7% 95% CI: [2.6%, 6.8%] subjects developing EDSS greater than or equal to 6 by 20 years: 16.2% 95% CI: [11.5%, 20.7%]

London Ontario Canada Lyon France British Columbia Canada Nova Scotia Canada

Cree B. Ann Neurol 2016; 80:499-510

Is NEDA Nada?

• From LTFU study of IFN β-1a disease activity (relapses or new lesion

formation) was predictive of worse long term outcomes

• MSBase found that high frequency relapse rates, especially on treatment,

were predictive of worse long term outcomes

• Hypothesis: those with NEDA-3 (relapse, EDSS increase and new lesion free)
• ver 2 years should fare better over the long term
• However, in EPIC, NEDA had no predictive value for long-term worsening of

any clinical outcome

• Result is inconsistent with IFN β-1a IM LTFU study
• Maybe annual MRI scans are not as useful for detecting sub-clinical disease

activity as we like to think?

Bermel RA. Annal Neurol 2013;73:95-103 Jokubaitis VG. Ann Neurol. 2016;80:89-100

Increase in EDSS at last visit by baseline EDSS

Better/ Same

A) RMS Patients (N=401) B) PMS Patients (N=61)

Worse 1 1.5 2 2.5 3 3.5 4 >4 1.5 2 2.5 3 3.5 4 >4

20 (23.3%) 66 (76.7%) 1 40 (42.1%) 55 (57.9%) 1.5 36 (58.1%) 26 (41.9%) 2 32 (46.4%) 37 (53.6%) 2.5 11 (50%) 11 (50%) 3 13 (61.9%) 8 (38.1%) 3.5 15 (65.2%) 8 (34.8%) 4 6 (40%) 9 (60%) >4 3 (37.5%) 5 (62.5%) EDSS Better/Same Worse 1.5 0 (0%) 2 (100%) 2 0 (0%) 6 (100%) 2.5 0 (0%) 2 (100%) 3 2 (40%) 3 (60%) 3.5 3 (33.3%) 6 (66.7%) 4 1 (33.3%) 2 (66.7%) >4 7 (20.6%) 27 (79.4%)

For the subjects who died of MS, an EDSS score of 10 was assigned. For subjects who became disabled due to non-MS causes, the last EDSS score was carried forward. There is 1 patient with a visit at year 10 for whom an EDSS score is missing. For the 8 subjects who died due to non-MS causes, year 10 EDSS scores were not available. The width of the bar represents the proportion of subjects in the cohort with each baseline EDSS score. The height of the black and grey bars represents the relative proportion of subjects with worse scores (black) versus stable or improved scores (grey).

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Clinical Radiographic and Genetic Correlates of Relapse

Cree BAC. ECTRIMS 2017 P1859

Silent Progression is Associated with Brain Volume Loss

Cree BAC. ECTRIMS 2017 P1859

Does Treat-to-Target Work?

• Intuitive hypothesis that escalating therapy based on disease activity

results in improved outcomes

• Standard practice in rheumatology
• One might expect that those who escalate therapy from so-called platform

treatments (e.g. IFN or GA) to high efficacy treatments (e.g. natalizumab, mitoxantrone, cyclophosphamide or rituximab) would have better long term outcomes

• In EPIC, clinical relapses (OR=2.15, 95% CI 1.14, 4.19, p=.02) and loss of

brain volume (OR=2.45, 95% CI 1.29, 4.93, p=.008) were predictors of therapeutic escalation during the first 3 years of the study

Treatment Escalation and EDSS worsening

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Escalation Therapy- Too Little Too Late?

• In EPIC escalation therapy was not associated

with more favorable long-term outcomes

– Escalation was associated with some worse outcomes

• Patients treated with escalation therapy might

have faired worse had they been maintained on either no treatment or platform therapy

– Confounding by indication to treat – No control arm limits interpretation

Summary

• Long term follow up studies from clinical trials and observational

cohorts provide limited insights into long-term safety and possibly efficacy

• Appropriate methods to account for major sources of bias such as

attrition are rarely applied

• Conclusions from LTFU studies of clinical trials may not be accurate

due to uncontrolled sources of bias, especially attrition

• All long-term studies are limited by a lack of an untreated reference

group

• Natural history studies might provide important bench-marks for

contextualizing datasets of actively treated patients

Biotin: Targeting Two Mechanisms That May Underpin Progressive MS

ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP ATP

Myelinated axon

Demyelinated axon

TCA cycle

increases ATP

Malonyl CoA Fatty acids Acetyl CoA

ACC

BIOTIN

Oligodendrocyte Group 1: MD1003 (103 patients) Group 2: Placebo (51 patients)

MS-SPI: a placebo-controlled double-blind study in progressive MS

• Patients with progressive MS (primary or secondary)

– EDSS between 4.5 and 7 – Progression in the past 2 years – Without disease inflammatory activity

M0

Extension phase: all patients are treated with MD1003

M24 M12

Proportion of patients with improved EDSS or TW25 at M9 confirmed at M12*

*EDSS : at least 1 point if baseline EDSS 4.5-5.5 and 0.5 point if baseline EDSS 6-7

TW25 : at least 20% compared to baseline Baseline definition: best EDSS and TW25 out of M-1 and M0

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2 4 6 8 10 12 14 16

Proportion of patients improved on EDSS or TW25

24-month-treatment with-MD1003 (high doses of biotin) in progressive multiple sclerosis: results of the MS-SPI trial extension phase % patients with improvement at M9 confirmed at M12

Double-blind phase

p=0.005

MD1003 N=103 Placebo N=51

0%

12.6 %

• 4

1 6 11 16

2 4 6 8 10 12 14 16 Extension phase

% patients with improvement at M18 confirmed at M24

7.1% 13.2%

MD1003 N=91 Placebo / MD1003 N=42

11.9% 15.4%

Extension phase

% patients with improvement at M24

SPI2 Study Design

26

• Signature of the

consent form

• Inclusion
• TW25
• EDSS
• C-SSRS
• Laboratory testing
• Biotin blood test

M-1 M0 Months M3 M24

• 600 patients with criteria of progressive MS and 3.5≤EDSS≤6.5 with pyramidal subscore ≥2
• Evidence of progression during the past 2 years
• TW25 < 40 seconds
• No relapse in the year prior to inclusion
• No fampridine, other treatments allowed if introduced at least 3 months prior to inclusion

Extension phase: all patients are treated with MD1003, 300 mg/day Group 1: 300 patients Placebo Group 2: 300 patients on MD1003, 300 mg/day M18 Randomization M6 M9 M12

• EDSS
• TW25
• C-SSRS
• MRI
• EDSS
• TW25
• C-SSRS
• SDMT
• MSQOL54
• ECG
• MRI
• Randomization
• Treatment onset
• EDSS
• TW25
• C-SSRS
• EDSS
• TW25
• C-SSRS
• SDMT
• CGI/SGI
• MSQOL54
• MRI
• Laboratory testing
• ECG

M15 M27

• EDSS
• TW25
• C-SSRS
• Laboratory testing
• Biotin blood test
• EDSS
• TW25
• C-SSRS
• Laboratory

testing

• Biotin blood

test

• EDSS
• TW25
• C-SSRS
• EDSS
• TW25
• C-SSRS
• EDSS
• TW25
• C-SSRS
• SDMT
• CGI/SGI
• MSQOL54
• MRI
• Laboratory testing
• ECG

Proportion of patients with decreased EDSS at M12 confirmed at M15 or with improved TW25 of at least 20% at M12 and M15 compared to the best EDSS and