the foundation role of immunomodulation therapy for long-term efficacy safety, outcome measures, and...

The Foundation Role of The Foundation Role of Immunomodulation Therapy Immunomodulation Therapy

for Long-Term Efficacy for Long-Term Efficacy

Safety, Outcome Measures, and Disability MitigationSafety, Outcome Measures, and Disability Mitigation

Investigations • Innovation • Clinical ApplicationInvestigations • Innovation • Clinical Application

Program ChairmanProgram ChairmanBruce A. Cree, MD, PhD, MCRBruce A. Cree, MD, PhD, MCR

Assistant Professor of NeurologyAssistant Professor of NeurologyDepartment of NeurologyDepartment of Neurology

University of CaliforniaUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco Multiple Sclerosis Center

San Francisco, CaliforniaSan Francisco, California

OverviewOverview

► Mechanisms of action of first line Mechanisms of action of first line therapiestherapies

► Outcome measures in clinical trialsOutcome measures in clinical trials

► Comparison of landmark trialsComparison of landmark trials

► Longitudinal studies: what do they tell Longitudinal studies: what do they tell us?us?

Goals of TreatmentGoals of Treatment

► Reduce frequency of relapseReduce frequency of relapse

► Slow progression of disabilitySlow progression of disability

► Reduce MRI activityReduce MRI activity

► Prevent morbidity from symptoms and Prevent morbidity from symptoms and provide palliative careprovide palliative care

► Maintain adherenceMaintain adherence

► Provide long-term efficacy and safety Provide long-term efficacy and safety

TregTh2/Th3

MO

IL-4IL-5IL-6

IL-13TGF

B

HistamineProteases

TNFNAA, ATP

NOO2

5-HT

Mast Cell

IL-12

APC

Thp

CD4

CD40LCD40

IL-4 & IL-10

CD4APCThp

CD28B7

Th2/Th3

B7

CD40

MicrogliaCD40L

CD28

Th1Th17

B

Glutamate

TCD8

MMP-2/9

VCAM-1ICAM-1 VCAM-1

IFNTNFIL-17

IL-10TGF

Ab+C9neo

CD8

Mast Cell

T

Granutocyte

Complement

Monocyte

Pl

Figure courtesy of Dhib-Jalbut S, 2008

Immunopathogenesis of the MS LesionImmunopathogenesis of the MS Lesion

IFNTNFTh17

NOOi

TNFaMMP

LFA-1VLA-4Th1

Th17

Oligo

BBB

MCP-1MIP-1P-10

RANTES

Astrocyte

IL-23

Treg

CD4+CD25+

Myelin AgMicrobial Ag

HLA

Virus

TCR

IFN-IFN-: Activity: Activity

TH1+

RestingT cell

MMP

Activated (+)T cells

TH1+

TH1+

MMP

BBBBlood CNS

TNF-α IFN-γ

IL-2

TH1APC APC

IFN-β

IFN-β

MyelinproteinAntigen

TH1+

Adapted from Yong VW. Adapted from Yong VW. NeurologyNeurology. 2002;59:802-808.. 2002;59:802-808.

Glatiramer Acetate: ActivityGlatiramer Acetate: Activity

Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.

BBB

GA-specificT cell

APC

GA

ther

apy

TH1 TH2

APC

Microglia

MHC

CNS Ag

TCR

Macrophage

Periphery CNS

TH2

MHC

GA

TCR

Neuroregeneration

Bystandersuppression

effect

Anti-inflammatory cytokines

Neurotrophins+ +

TCRIL-4

IL-10

BDNF

Low (0-1 attacks in 2 years)Low (0-1 attacks in 2 years)

Intermediate (2-4 attacks in 2 years)Intermediate (2-4 attacks in 2 years)

High (High (>> 5 in 2 years) 5 in 2 years)

Weinhenker B et al. Brain. 1989;112:1422Weinhenker B et al. Brain. 1989;112:1422

Long-Term DisabilityLong-Term DisabilityEffect of Early RelapsesEffect of Early Relapses

50504040303020201010

2020

00

00

4040

6060

8080

100100

Time from onset of MS (years)Time from onset of MS (years)

Per

cent

Pts

DS

S <

6P

erce

nt P

ts D

SS

< 6

p < 0.0001p < 0.0001

Number of Attacks, 1Number of Attacks, 1stst 2 years 2 years p <0.001p <0.001

Interval Between 1Interval Between 1stst 2 Attacks 2 Attacks p <0.001p <0.001

DSS at 2 yearsDSS at 2 years p < 0.001p < 0.001

DSS at 5 yearsDSS at 5 years p < 0.001p < 0.001

Development of DisabilityDevelopment of DisabilityEffect of Early Clinical Course Effect of Early Clinical Course

Clinical CharacteristicClinical Characteristic Significance*Significance*

* Controlled for age at onset, remitting at onset, cerebellar, cerebral* Controlled for age at onset, remitting at onset, cerebellar, cerebral

Weinshenker B et al. Weinshenker B et al. Brain. 1991;114 ( Pt 2):1045-56.Brain. 1991;114 ( Pt 2):1045-56.

Relapses in MSRelapses in MS

► Relapses are the most obvious evidence of Relapses are the most obvious evidence of inflammatory disease activity in RRMS inflammatory disease activity in RRMS

► Relapse frequency in typical untreated Relapse frequency in typical untreated RRMS populations enables treatment effect RRMS populations enables treatment effect to be rapidly assessable in a 12-month to be rapidly assessable in a 12-month clinical studyclinical study

Total number of relapses during the study periodTotal in-study person-years

Effect on Annualized Relapse Rates: Summary Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-studyof Phase III Trials – 2 years in-study

35

% R

educ

tion

in r

elap

se r

ates

% R

educ

tion

in r

elap

se r

ates

30

25

20

15

10

5

0

31%

8 MIU qod8 MIU qodIFN beta-1bIFN beta-1b

P=0.0001

29%

4.4 MIU tiw4.4 MIU tiwIFN beta-1aIFN beta-1a

P<0.001

32%


P<0.0001

29%

20 mg qd20 mg qdglatiramer acetateglatiramer acetate

P=0.055P=0.055

6 MIU qw6 MIU qwIFN beta-1aIFN beta-1a

P=0.04

18%

N.B.: Results are from separate clinical trialsJacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert.

Is MS All About Relapses? Is MS All About Relapses?

► Hypothesis: if relapses cause long-term Hypothesis: if relapses cause long-term disability then patients with frequent disability then patients with frequent relapses should be at higher risk for relapses should be at higher risk for disabilitydisability

► From the London Ontario natural history From the London Ontario natural history studies patients with frequent attacks studies patients with frequent attacks are at highest risk for future ambulatory are at highest risk for future ambulatory disabilitydisability

► Assumption: modifying the relapse rate Assumption: modifying the relapse rate will influence long-term disabilitywill influence long-term disability

Weinshenker et al. 1989 Brain 112:1419Weinshenker et al. 1989 Brain 112:1419

Proportion of Placebo Groups Proportion of Placebo Groups with Clinical Activity with Clinical Activity

Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498.

RelapsesRelapses EDSS EDSS ProgressProgress

IFNIFNββ-1b (3 year)-1b (3 year) 86%86% 39%39%

IFNIFNββ-1a (QW) (2 year)-1a (QW) (2 year) 77%77% 35%35%

IFNIFNββ-1a (TIW) (2 year)-1a (TIW) (2 year) 84%84% 38%38%

Glatiramer acetate (2 year)Glatiramer acetate (2 year) 73%73% 25%25%

How is Sustained Progression How is Sustained Progression Measured?Measured?

► Most clinical trials define progression by Most clinical trials define progression by comparing the change in EDSS from comparing the change in EDSS from baseline to study conclusion, and then baseline to study conclusion, and then confirmconfirm the change in EDSS at 3 or 6 the change in EDSS at 3 or 6 monthsmonths

► Does this measure of confirmed Does this measure of confirmed progression reflect permanent disability?progression reflect permanent disability?

► If so, then confirmed changes in EDSS If so, then confirmed changes in EDSS during the course of the trial should be during the course of the trial should be sustainedsustained by the end of the study by the end of the study

Does Sustained Disability Measure Does Sustained Disability Measure Permanent Disability?Permanent Disability?

► 50% of patients with a 1 point change, 50% of patients with a 1 point change, confirmed at 3 months will improve to a lower confirmed at 3 months will improve to a lower EDSSEDSS

► 33% of patients with a 1 point change, 33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower confirmed at 6 months, will improve to a lower EDSSEDSS

► More stringent measures of change are harder More stringent measures of change are harder to demonstrate in 2-year trials because to demonstrate in 2-year trials because relatively few MS patients will progress relatively few MS patients will progress

► Conclusions: Conclusions: 6 months sustained EDSS change 6 months sustained EDSS change is more rigorous than a 3-month sustained is more rigorous than a 3-month sustained change, but neither is a good predictor of long change, but neither is a good predictor of long term disabilityterm disabilityLiu C & Blumhardt LD Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000J Neurol Neurosurg Psychiatry. 2000;;68:450-7.68:450-7.

**1 EDSS point sustained for 1 EDSS point sustained for 6 months in 6 MIU qw phase III trial6 months in 6 MIU qw phase III trial and for and for 3 months 3 months in all other in all other phase III trials.phase III trials.

Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701PRISMS Study Group. Lancet. 1998;352:1498

Effect on Sustained Disability*: Effect on Sustained Disability*: Summary of Phase III TrialsSummary of Phase III Trials

40

Reduct

ion in

R

educt

ion in

su

stain

ed d

isabili

ty

sust

ain

ed d

isabili

ty

pro

gre

ssio

n (

%)

pro

gre

ssio

n (

%)

12%

22%

30%

NS

30

20

10

0



20 mg qd20 mg qdglatiramer acetateglatiramer acetate

p<0.05

p<0.05

p=NSp=NS

37%

6 MIU qw6 MIU qwIFN beta-1aIFN beta-1a

p=0.0229%

8 MIU qod8 MIU qodIFN beta-1bIFN beta-1b

p=NSp=NS

SummarySummary

► Relapses and disability progression represent Relapses and disability progression represent different but complimentary aspects of MS natural different but complimentary aspects of MS natural historyhistory

► Relapse rate reduction and the mean change in Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome EDSS are the most sensitive clinical outcome measures in MS trialsmeasures in MS trials

► The generally accepted sustained change in EDSS The generally accepted sustained change in EDSS measure is not a reliable marker of long term measure is not a reliable marker of long term disability disability

► Phase III trials results showed:Phase III trials results showed: The interferons and glatiramer acetate modestly reduce the relapse The interferons and glatiramer acetate modestly reduce the relapse

raterate IFN beta-1a has a statistically significant impact on sustained IFN beta-1a has a statistically significant impact on sustained

disability progression over two yearsdisability progression over two years IFN beta-1a and glatiramer acetate have a statistically significant IFN beta-1a and glatiramer acetate have a statistically significant

impact on the mean EDSS over two yearimpact on the mean EDSS over two year

Are direct comparator studies Are direct comparator studies needed in MS or can we make needed in MS or can we make

valid conclusions from cross trial valid conclusions from cross trial comparisons?comparisons?

Cross Trial ComparisonsCross Trial ComparisonsRelative Efficacy (RR)Relative Efficacy (RR)

IFNIFNββ-1a-1a30 30 µµgg qwqw

IFNIFNββ-1b, -1b, 250 250 µµgg

qodqod

IFN IFN ββ-1a -1a 44 44 µµgg

tiwtiw

GA GA 20 mg20 mg

qdqd

Relapse rate (annualized)Relapse rate (annualized) -18%-18% -34%-34% -32%-32% -29%-29%

Relapse-Free (2 years)Relapse-Free (2 years) +42%+42% +95%+95% +100%+100% +36%+36%

Progression free Progression free -37%-37% -29%-29% -30%-30% -12%-12%

New T2 LesionsNew T2 Lesions -36%-36% -83%-83% -78%-78% -38%-38%

Gd+ LesionsGd+ Lesions -42%-42% -- -88%-88% -33%-33%

BODBOD - 4%- 4% -17%-17% -15%-15% -8%-8%

672 days (96 weeks)

IFNβ-1a

GA

Time to first relapse (days)Time to first relapse (days)

Hazard ratio (95% CI): 0.943 (0.74, 1.21) p = 0.643

0 100 200 300 400 500 600 700

0.00

0.25

0.50

0.75

1.00

Sur

viva

l dis

trib

utio

n fu

nctio

nS

urvi

val d

istr

ibut

ion

func

tion

The REGARD TrialThe REGARD TrialTime to First Relapse (1Time to First Relapse (1oo endpoint) endpoint)

The BEYOND TrialThe BEYOND TrialRelapse Risk (1Relapse Risk (1oo Endpoint) Endpoint)

►No significant difference in relapse risk between any groupNo significant difference in relapse risk between any group

Interferon beta-1bInterferon beta-1b 500 500 vs. vs. Interferon beta-1bInterferon beta-1b 250 250

Interferon beta-1b Interferon beta-1b 500500vs. Glatiramer acetatevs. Glatiramer acetate

Interferon beta-1b Interferon beta-1b 250250vs. Glatiramer acetatevs. Glatiramer acetate

Primary AnalysisPrimary Analysis

Sensitivity Analysis Sensitivity Analysis (no major protocol violations, (no major protocol violations,

100% of doses, post-hoc)100% of doses, post-hoc)

P-valuesP-values(one-sided)(one-sided)

P-valuesP-values(one-sided)(one-sided)

P=0.16P=0.16

P=0.73P=0.73

P=0.43P=0.43

P=0.29P=0.29

P=0.30P=0.30

P=0.18P=0.18

0.50.5 1.0 1.5 1.0 1.50.50.5 1.0 1.5 1.0 1.5

What can be learned from What can be learned from long-term follow up studies?long-term follow up studies?

Long-Term Follow UpLong-Term Follow Up

► Do long-term follow up studies Do long-term follow up studies adequately address medication safety?adequately address medication safety?

► Do long-term studies adequately Do long-term studies adequately address longitudinal efficacy?address longitudinal efficacy?

► Have methods of analysis for Have methods of analysis for longitudinal studies been optimized?longitudinal studies been optimized?

BiasBias ImpactImpact StrategyStrategy

AscertainmentAscertainmentModified therapeutic effect dependent Modified therapeutic effect dependent

on characteristics of participating on characteristics of participating patients.patients.

F/U must be as complete as possible F/U must be as complete as possible Directly compare baseline and on-Directly compare baseline and on-RCT characteristics of those RCT characteristics of those patients in LTF to those not in LTFpatients in LTF to those not in LTF

Informed Informed Therapeutic Therapeutic DecisionsDecisions

Inflated estimate of therapeutic benefit Inflated estimate of therapeutic benefit because patients doing well because patients doing well continue therapy whereas failing continue therapy whereas failing patients switch or stop therapy.patients switch or stop therapy.

MPR: Use percent of total possible MPR: Use percent of total possible time on therapy instead of time on therapy instead of absolute time to assess exposure.absolute time to assess exposure.

Treatment Treatment SelectionSelection

Modified therapeutic effect dependent Modified therapeutic effect dependent on patient selection characteristics.on patient selection characteristics.

Propensity Scoring: Adjust for the Propensity Scoring: Adjust for the propensity (i.e., likelihood) that a propensity (i.e., likelihood) that a particular treatment will be particular treatment will be selected based on available selected based on available patient characteristicspatient characteristics

Multiple TestingMultiple TestingIncreased risk of Type 1 error from the Increased risk of Type 1 error from the

use of multiple predictor variables use of multiple predictor variables and weighting schemesand weighting schemes

Create a single model and apply Create a single model and apply adjustments to p-values according adjustments to p-values according to the number of predictors tested to the number of predictors tested in the model.in the model.

Sources of Bias in LTFU StudiesSources of Bias in LTFU Studies

Glatiramer Acetate 15 year LTFUGlatiramer Acetate 15 year LTFU

Ford C et al. Mult Scler. 2010;16:342-50. Ford C et al. Mult Scler. 2010;16:342-50.

Glatiramer Acetate 15 year LTFUGlatiramer Acetate 15 year LTFU

► In a small cohort of patients followed for In a small cohort of patients followed for 15 years, glatiramer acetate was safe and 15 years, glatiramer acetate was safe and well toleratedwell tolerated

► 65% of continuously treated patients did 65% of continuously treated patients did not progress to SPMSnot progress to SPMS

► 41% of patients withdrawing from the 41% of patients withdrawing from the study did so because of disease study did so because of disease progressionprogression● Propensity scores were used to try to adjust Propensity scores were used to try to adjust

for differences between ongoing and for differences between ongoing and withdrawing patientswithdrawing patients

► EDSS at baseline predicts EDSS at 15 EDSS at baseline predicts EDSS at 15 yearsyears

IFN IFN ββ-1a (QW) LTFU Disposition-1a (QW) LTFU Disposition

Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]

Complete 2-year follow-up(n=172)

Unascertained(n=36)

Ascertained for ASSURANCE(n=136; 79%)

Able to locate,Unable to contact

(n=13)

Unable to locate(n=23)

Living(n=122; 90%)

Deceased(n=14; 10%)

ICF and question booklet

completedLOCF

IFN IFN ββ-1a QW LTFU Outcomes-1a QW LTFU Outcomes

Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]

Currently receiving IM IFN ß-1a (n=56)Currently receiving IM IFN ß-1a (n=56)Not currently receiving IM IFN ß-1a (n=66)Not currently receiving IM IFN ß-1a (n=66)

Pat

ient

s, %

Pat

ient

s, %

Pat

ient

s, %

Pat

ient

s, %

P=0.062P=0.062

EDSS MilestoneEDSS Milestone

P=0.326P=0.326P=0.114P=0.114

P=0.006P=0.006

IFN IFN ββ-1a QW LTFU Conclusions-1a QW LTFU Conclusions

► 79% of eligible patients were located for the 15 79% of eligible patients were located for the 15 year follow upyear follow up

► At 15 years, patients currently on IFN At 15 years, patients currently on IFN ββ-1a had -1a had less progression in EDSS scores than patients less progression in EDSS scores than patients not on IFN not on IFN ββ-1a -1a

► However, patients not currently on IFN However, patients not currently on IFN ββ-1a had -1a had higher baseline EDSS scores suggesting more higher baseline EDSS scores suggesting more severe baseline MSsevere baseline MS● Propensity scores were used to adjust for these Propensity scores were used to adjust for these

differencesdifferences

► Inferences with regard to association with lower Inferences with regard to association with lower EDSS and ongoing treatment were not made EDSS and ongoing treatment were not made

Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]

124124

125125

123123

5252

5858

5656IFNβ-1b 250 µg

IFNβ-1b 50 µg

Placebo

1988 1993

Pivotal Study (n=372)Pivotal Study (n=372)

LTF

2005

Cross-sectional investigation of:- clinical outcomes (disability, relapse rate)- imaging (brain and spinal MRI)- cognition and mood- QoL, resource use- lab parameter including NAb's and PgX

Patients under regular medical care - no trial

1990

IFN IFN ββ-1b LTFU Design-1b LTFU Design

Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at AAN, October 2006: M-3Ebers G et al. presented at AAN, October 2006: M-3

Event Rates and Long-Term EfficacyEvent Rates and Long-Term EfficacyClinical and Radiological EndpointsClinical and Radiological Endpoints

1.1. Need to demonstrate that the short-Need to demonstrate that the short-term event-rates are correlated with term event-rates are correlated with long-term outcome.long-term outcome.

2.2. Need to demonstrate that the short-Need to demonstrate that the short-term event-rates contribute term event-rates contribute independently to predicting outcome.independently to predicting outcome.

3.3. Need to demonstrate that therapies Need to demonstrate that therapies which reduce the event-rates, are also which reduce the event-rates, are also associated with improved long-term associated with improved long-term outcome.outcome.


IFN IFN ββ-1b LTFU Adjusted OUtcome-1b LTFU Adjusted OUtcome

Any Variable + Any Exposure Weighting – Any Negative Outcome

EDSSp<0.001

1

Exposurep<0.001

2

HighLow


Event Rates and Long-Term EfficacyEvent Rates and Long-Term EfficacyConclusionsConclusions

1.1. The LTF study demonstrates that the short-term The LTF study demonstrates that the short-term event-rate is correlated with long-term outcome.event-rate is correlated with long-term outcome.

2.2. The LTF study also demonstrates that the short-The LTF study also demonstrates that the short-term event-rate contributes independently to term event-rate contributes independently to predicting long-term outcome.predicting long-term outcome.

3.3. The LTF study provides convincing evidence that The LTF study provides convincing evidence that early initiation and sustained use of IFNearly initiation and sustained use of IFNββ-1b has a -1b has a beneficial impact on long-term outcome in MS.beneficial impact on long-term outcome in MS.

4.4. The analysis strategy employed provides a The analysis strategy employed provides a methodological framework for mitigating bias in methodological framework for mitigating bias in assessing long-term efficacy in other clinical trials assessing long-term efficacy in other clinical trials having similar non-randomized data.having similar non-randomized data.

► Disease modifying therapy seems favorably effect the Disease modifying therapy seems favorably effect the long-term course of MSlong-term course of MS

► Propensity score adjusted analysis and other statistical Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, methods for controlling biases inherent in long term, unblinded studies are important statistical advances for unblinded studies are important statistical advances for interpreting these studiesinterpreting these studies

► Once the MS community agrees on the relevant Once the MS community agrees on the relevant covariates, these methods can be used to sort out some covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials.posed by long-term placebo-controlled trials.

ConclusionsConclusions

the foundation role of immunomodulation therapy for long-term efficacy safety, outcome measures, and...

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