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Investigations • Innovation • Clinical Application

Investigations • Innovation • Clinical Application. The Foundation Role of Immunomodulation Therapy for Long-Term Efficacy Safety, Outcome Measures, and Disability Mitigation. Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology

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Investigations • Innovation • Clinical Application

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  1. Investigations • Innovation • Clinical Application The Foundation Role of Immunomodulation Therapy for Long-Term Efficacy Safety, Outcome Measures, and Disability Mitigation Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

  2. Overview Mechanisms of action of first line therapies Outcome measures in clinical trials Comparison of landmark trials Longitudinal studies: what do they tell us?

  3. Goals of Treatment Reduce frequency of relapse Slow progression of disability Reduce MRI activity Prevent morbidity from symptoms and provide palliative care Maintain adherence Provide long-term efficacy and safety

  4. Immunopathogenesis of the MS Lesion Pl IL-10 TGFb Astrocyte B B CD8 Ab+C9neo gdT MO Oligo NO Oi TNFa MMP Virus Histamine Proteases TNFa NAA, ATP NO O2 5-HT IFNg TNF Th17 Th2/ Th3 Treg Glutamate CD28 B7 MCP-1 MIP-1a IP-10 RANTES CD4+CD25+ Th1 Th17 Microglia Mast Cell CD40 CD40L BBB VCAM-1 Mast Cell ICAM-1 VCAM-1 MMP-2/9 Treg Th2/ Th3 IL-4 IL-5 IL-6 IL-13 TGFb Complement LFA-1 VLA-4 gdT Th1 Th17 IFNg TNF IL-17 IL-23 Monocyte IL-4 & IL-10 CD8 Granutocyte IL-12 B7 CD28 CD4 CD4 APC HLA APC TCR Thp Myelin Ag Microbial Ag Thp Figure courtesy of Dhib-Jalbut S, 2008 CD40 CD40L

  5. Blood BBB CNS MMP TH1+ IFN-β IFN-β Myelinprotein Antigen TH1+ TH1+ TH1 APC APC MMP IL-2 TH1+ RestingT cell TNF-α IFN-γ Activated (+)T cells IFN-: Activity Adapted from Yong VW. Neurology. 2002;59:802-808.

  6. APC Glatiramer Acetate: Activity BBB Periphery CNS Macrophage Microglia Bystandersuppressioneffect APC MHC GA TCR MHC CNS Ag TCR GA therapy IL-4 IL-10 BDNF TCR Anti-inflammatory cytokines + + Neurotrophins GA-specificT cell Neuroregeneration TH1 TH2 TH2 Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.

  7. Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (> 5 in 2 years) Long-Term DisabilityEffect of Early Relapses 100 80 60 Percent Pts DSS < 6 40 p < 0.0001 20 0 0 10 20 30 40 50 Time from onset of MS (years) Weinhenker B et al. Brain. 1989;112:1422

  8. Development of Disability Effect of Early Clinical Course Significance* Clinical Characteristic * Controlled for age at onset, remitting at onset, cerebellar, cerebral Weinshenker B et al. Brain. 1991;114 ( Pt 2):1045-56.

  9. Relapses in MS • Total number of relapses during the study period • Total in-study person-years Relapses are the most obvious evidence of inflammatory disease activity in RRMS Relapse frequency in typical untreated RRMS populations enables treatment effect to be rapidly assessable in a 12-month clinical study

  10. 31% 29% 32% 29% P=0.0001 P<0.001 P<0.0001 P=0.055 8 MIU qod IFN beta-1b 20 mg qd glatiramer acetate 4.4 MIU tiw IFN beta-1a 8.8 MIU tiw IFN beta-1a Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study 35 30 25 20 % Reduction in relapse rates 18% 15 P=0.04 10 5 0 6 MIU qw IFN beta-1a N.B.: Results are from separate clinical trials 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; Rebif package insert.

  11. Is MS All About Relapses? Weinshenker et al. 1989 Brain 112:1419 Hypothesis: if relapses cause long-term disability then patients with frequent relapses should be at higher risk for disability From the London Ontario natural history studies patients with frequent attacks are at highest risk for future ambulatory disability Assumption: modifying the relapse rate will influence long-term disability

  12. Proportion of Placebo Groups 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.

  13. How is Sustained Progression Measured? Most clinical trials define progression by comparing the change in EDSS from baseline to study conclusion, and then confirm the change in EDSS at 3 or 6 months Does this measure of confirmed progression reflect permanent disability? If so, then confirmed changes in EDSS during the course of the trial should be sustained by the end of the study

  14. Does Sustained Disability Measure Permanent Disability? Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7. 50% of patients with a 1 point change, confirmed at 3 months will improve to a lower EDSS 33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower EDSS More stringent measures of change are harder to demonstrate in 2-year trials because relatively few MS patients will progress Conclusions: 6 months sustained EDSS change is more rigorous than a 3-month sustained change, but neither is a good predictor of long term disability

  15. NS Effect on Sustained Disability*: Summary of Phase III Trials 37% 40 30% 29% p=0.02 30 22% Reduction in sustained disability progression (%) p<0.05 20 p=NS p<0.05 12% 10 p=NS 0 20 mg qd glatiramer acetate 8 MIU qod IFN beta-1b 6 MIU qw IFN beta-1a 4.4 MIU tiw IFN beta-1a 8.8 MIU tiw IFN beta-1a *1 EDSS point sustained for 6 months in 6 MIU qw phase III trial and for 3 months in all other phase III trials. 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

  16. Summary • Relapses and disability progression represent different but complimentary aspects of MS natural history • Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome measures in MS trials • The generally accepted sustained change in EDSS measure is not a reliable marker of long term disability • Phase III trials results showed: • The interferons and glatiramer acetate modestly reduce the relapse rate • IFN beta-1a has a statistically significant impact on sustained disability progression over two years • IFN beta-1a and glatiramer acetate have a statistically significant impact on the mean EDSS over two year

  17. Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?

  18. Cross Trial ComparisonsRelative Efficacy (RR)

  19. The REGARD TrialTime to First Relapse (1o endpoint) 1.00 672 days (96 weeks) IFNβ-1a 0.75 GA Hazard ratio (95% CI): 0.943 (0.74, 1.21) p = 0.643 Survival distribution function 0.50 0.25 0.00 0 100 200 500 300 400 600 700 Time to first relapse (days)

  20. The BEYOND TrialRelapse Risk (1o Endpoint) Sensitivity Analysis (no major protocol violations, 100% of doses, post-hoc) Primary Analysis P-values (one-sided) P-values (one-sided) Interferon beta-1b 500 vs. Interferon beta-1b 250 P=0.29 P=0.30 P=0.18 P=0.16 P=0.73 P=0.43 Interferon beta-1b 250vs. Glatiramer acetate Interferon beta-1b 500vs. Glatiramer acetate 0.5 1.0 1.5 0.5 1.0 1.5 No significant difference in relapse risk between any group

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

  22. Long-Term Follow Up Do long-term follow up studies adequately address medication safety? Do long-term studies adequately address longitudinal efficacy? Have methods of analysis for longitudinal studies been optimized?

  23. Sources of Bias in LTFU Studies

  24. Glatiramer Acetate 15 year LTFU Ford C et al. MultScler. 2010;16:342-50.

  25. Glatiramer Acetate 15 year LTFU Ford C et al. MultScler. 2010;16:342-50.

  26. Glatiramer Acetate 15 year LTFU • In a small cohort of patients followed for 15 years, glatiramer acetate was safe and well tolerated • 65% of continuously treated patients did not progress to SPMS • 41% of patients withdrawing from the study did so because of disease progression • Propensity scores were used to try to adjust for differences between ongoing and withdrawing patients • EDSS at baseline predicts EDSS at 15 years

  27. IFN β-1a (QW) LTFU Disposition 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 completed LOCF Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print]

  28. IFN β-1a QW LTFU Outcomes Currently receiving IM IFN ß-1a (n=56) Not currently receiving IM IFN ß-1a (n=66) P=0.006 P=0.062 P=0.114 P=0.326 Patients, % Patients, % EDSS Milestone Bermel R et al. MultScler. 2010 Feb 18. [Epub ahead of print]

  29. IFN β-1a QW LTFU Conclusions Bermel R et al. Mult Scler. 2010 Feb 18. [Epub ahead of print] • 79% of eligible patients were located for the 15 year follow up • At 15 years, patients currently on IFN β-1a had less progression in EDSS scores than patients not on IFN β-1a • However, patients not currently on IFN β-1a had higher baseline EDSS scores suggesting more severe baseline MS • Propensity scores were used to adjust for these differences • Inferences with regard to association with lower EDSS and ongoing treatment were not made

  30. IFN β-1b LTFU Design Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 Patients under regular medical care - no trial IFNβ-1b 50 µg LTF 125 52 Placebo 123 58 1988 1990 1993 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 Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

  31. Event Rates and Long-Term Efficacy Clinical and Radiological Endpoints • Need to demonstrate that the short-term event-rates are correlated with long-term outcome. • Need to demonstrate that the short-term event-rates contribute independently to predicting outcome. • Need to demonstrate that therapies which reduce the event-rates, are also associated with improved long-term outcome. Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

  32. IFN β-1b LTFU Adjusted OUtcome Any Variable + Any Exposure Weighting – Any Negative Outcome 1 EDSS p<0.001 2 Exposure p<0.001 High Low Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

  33. Event Rates and Long-Term Efficacy Conclusions • The LTF study demonstrates that the short-term event-rate is correlated with long-term outcome. • The LTF study also demonstrates that the short-term event-rate contributes independently to predicting long-term outcome. • The LTF study provides convincing evidence that early initiation and sustained use of IFNβ-1b has a beneficial impact on long-term outcome in MS. • The analysis strategy employed provides a methodological framework for mitigating bias in assessing long-term efficacy in other clinical trials having similar non-randomized data.

  34. Conclusions • Disease modifying therapy seems favorably effect the long-term course of MS • Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, unblinded studies are important statistical advances for interpreting these studies • Once the MS community agrees on the relevant covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials.

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