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Clinical Challenges of MS

Clinical Challenges of MS A State-of-the-Discipline Overview and Lessons Learned from Landmark Trials Focused on Immune-Modulating Agents Jerry S. Wolinsky, MD Bartels Family and Opal C. Rankin Professor of Neurology University of Texas Health Science Center at Houston.

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Clinical Challenges of MS

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  1. Clinical Challenges of MS A State-of-the-Discipline Overview and Lessons Learned from Landmark Trials Focused on Immune-Modulating Agents Jerry S. Wolinsky, MDBartels Family and Opal C. RankinProfessor of NeurologyUniversity of Texas Health Science Centerat Houston

  2. Major Challenges of MS Therapeutics • If relapse rates are truly falling, what should now be regarded as a treatment effect? • Why are relapse rates falling? • What is the basis for phase shift? • Can it be prevented? • Can it be treated? • How can it be recognized? • What is primary progressive disease?

  3. Better Treatment Effects or Shifting Disease

  4. Annualized Relapse Rates: Proportional Treatment Effects 1992 – 2001 2002 - 2008 43.3% ▼ 57% ▼ Annualized Relapse Rate

  5. Are we entering a even better placebo era? • The two cladribine tablet treatment groups of the study, assessing different dose regimens, demonstrated a statistically significant reduction in the annualized rate of relapses compared to placebo. • Patients from the lower total dose group experienced a 58% relative reduction in annualized relapse rates with respect to placebo (0.14 versus 0.33 for the placebo group; p<0.001). • Patients from the higher total dose group experienced a 55% relative reduction in annualized relapse rates with respect to placebo (0.15 versus 0.33; p<0.001). http://www.emdserono.com/cmg.emdserono_us/en/images/20090123_en_tcm115_34944.pdf

  6. Will Rogers Phenomena: The joke’s on us • “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.” • MRI replaced CT and arguably CSF for diagnostic support • McDonald’s replaced Poser and we are moving towards Swanton and RIS Sormani et al. Ann Neurol 64:428, 2008

  7. Gender Creep: Importance for Therapeutics • No apparent change in sex ratio among PPMS – remains near 1:1 • If female predominance is evident for CIS through RR and SPMS does this account for changing features of recent clinical trial cohorts? • Should it influence decisions to start therapy? Orton et al. Lancet Neurol 5:932, 2006

  8. Gender Effect on Annualized Relapse Rates: Meta-analysis RRMS Annualized Relapse Rate Wolinsky et al. J NeurolSci (in review)

  9. Gender Effect on Progression: Meta-analysis RRMS of Confirmed Accumulated Disability Both males and females benefited Females Odds Ratio 0.58, 95% CI 0.33-1.00 Males Odds Ratio 0.62, 95% CI 0.29-1.32 Proportion of with ≥1 point increase in EDSS sustained for 3 months Wolinsky et al. J NeurolSci (in review)

  10. Gender Effect on Progression: Post Hoc Sensitivity Analyses PPMS Trial Cumulative Proportion of Patients Progressing Months Male Patients on Study Drug, N/ Population at Risk, N; (% ITT)PBO: 163/163 (100%) 118/122 (75%) 82/88 (54%) 14/23 (14%) Female Patients on Study Drug, N/ Population at Risk, N; (% ITT)PBO: 151/151 (100%) 121/122 (81%) 93/97 (64%) 16/23 (15%) Wolinsky et al. J NeurolSci (in review)

  11. Phase Shift More of the Same or an Alternative Process

  12. Frequency of MS Clinical Trial Endpoints Laboratory-based biomarkers of Drug Activity Gadolinium Enhancements Unique Active Lesions Early Detected Laboratory-based Adverse Events Increased Lesion Volume Relapses Common Clinical Adverse Events T1 hypointense Lesion Resolution Accumulated Disability Evolution of Atrophy Rare Clinical Adverse Events Phase shift reduction Deceasing Event Frequency

  13. SPMS atrophy disability Matrix Destructive Phase T2 burden Inflammatory Phase Late RR black holes Early RR CIS Subclinical Gd Course of Relapsing MS Occurrence, Extent, or Severity Time

  14. Effects of glatiramer acetate on disease activity:Effects on an Early Phase Shift PBO GA Proportion Converting from ‘CIS’ to ‘CDMS’ Hazard Ratio = 0.55 [CI 0.40, 0.77] p = 0.0005 Comi et al. AAN, 2008

  15. Effects of natalizumab on disease activity:Effects on Phase Shift? Havrdova et al. Lancet Neurol 8:254, 2009

  16. Effects of natalizumab on disease activity:Effects on Phase Shift? Havrdova et al. Lancet Neurol 8:254, 2009

  17. What is PPMS? Different Course - Sorry

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