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New Frontiers and Landmark Practice Advances Optimizing Neurotherapy for Multiple Sclerosis and Parkinson’s Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines Patient Care Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine Welcome and Program Overview CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Teva Neuroscience, Inc. Faculty disclosures: Listed in program syllabus Program Faculty Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine Douglas R. Jeffery, MD, PhD Associate Professor Department of Neurology Wake Forest University Baptist Medical Center Winston-Salem, NC Howard L. Zwibel, MD Founding Medical Director, Emeritus Neuroscience Consultants Comprehensive Multiple Sclerosis Center in affiliation with the National Multiple Sclerosis Center Coral Gables, Florida Baptist Health Doctors Hospital MS Center Coral Gables, FL New Frontiers and Landmark Practice Advances Parkinson’s Disease and Multiple Sclerosis Two Diseases in Need of a Neuroprotective Therapy Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine Parkinson’s Disease and Multiple Sclerosis ► Two important neurological disorders ● ● ► Both have surrogate imaging markers ● ● ► Primarily affect older individuals (PD) Primarily affect younger individuals (MS) FD-PET (PD) MRI (MS) Treatments are available for both diseases ● ● Benefit symptoms (PD) Reduce relapse rate (MS) Parkinson’s Disease and Multiple Sclerosis ► Both result in unacceptable disability for many patients despite available treatments ► Disease-modifying or neuroprotective therapies are urgent priorities ► Both offer many candidate diseasemodifying agents based on laboratory work Parkinson’s Disease and Multiple Sclerosis ► Development of a disease modifying therapy in each condition would be enhanced by: ● ● ● ► Insight into the precise cause of the disease Better animal models Better clinical trial designs with endpoints reflecting the underlying disease process Advances in these areas will be reviewed in the current session New Frontiers and Landmark Practice Advances Attempts to Obtain Neuroprotection for Parkinson’s Disease Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine Current Therapies for PD ► Primarily dopaminergic ► Highly effective for the classic motor features ● ► Do not satisfactorily control non-dopaminergic features ● ► Tremor, rigidity, bradykinesia Gait dysfunction, freezing, postural instability, falling, autonomic dysfunction, mood disorders, sensory problems, cognitive impairment, dementia Do not stop disease progression The Sydney Long Term PD Study ► 149 PD patients were entered ► 52 survivors after 15 years ► None were still employed ► 40% were in a nursing home ► 95% had levodopa-induced dyskinesia and wearing off ► Non-dopaminergic features (falling, dementia) were the primary cause of disability and of nursing home placement Neuroprotective (Disease-Modifying) Therapy For PD A treatment intervention that slows, stops or reverses disease progression Neuroprotective Trials in PD Negative Studies Agent Mechanism Endpoint Anti-oxidant Time to L-dopa Anti-glutamate Time to L-dopa Minocycline Anti-Inflammatory Δ UPDRS Imunophilin Trophic Time to L-dopa GDNF/Neurturin Trophic factors Δ UPDRS TCH346 Anti-apoptotic Time to L-dopa CEP1347 Anti-apoptotic Time to L-dopa Cell replacement Δ UPDRS/QOL Vitamin E Riluzole DA Cell Transplant Obstacles to Finding a Neuroprotective Therapy for PD ► We do not know the precise etiology or pathogenesis of PD—we don’t know what to target ► We do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PD ► We do not have a good method for determining the optimal dose to use in a clinical trial Neuroprotective Trials in PD Positive Studies Agent Mechanism Endpoint Selegiline (DATATOP) Anti-apoptotic Time to L-dopa Selegiline (SINDEPAR) Anti-apoptotic Wash Out Co-Q10 Bio-energetic Δ UPDRS Creatine Bio-energetic Δ UPDRS Ropinirole Anti-apoptotic Β-CIT-SPECT Pramipexole Anti-apoptotic F-DOPA PET Obstacles to Finding a Neuroprotective Therapy for PD We do not know the precise etiology or pathogenesis of PD –we don’t know what to target ► We do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PD ► We do not have a good method for determining the optimal dose to use in a clinical trial ► We do not have a clinical trial design that can reliably detect a disease-modifying agent ► Trial Designs for Neuroprotection in PD ► Time to a milestone of disease progression ► Washout design (change from untreated baseline to final visit performed after drug washout) ► Change from baseline to final visit in UPDRS score ► Neuroimaging of surrogate biomarker of dopaminergic function Delayed Start Design Period I Placebo Early Start Early Start Intervention Delayed Start Design Period I Period II Delayed Start Placebo Early Start Early Start Intervention Delayed Start Intervention Symptomatic Effect Delayed Start Design Period I Period II Delayed Start Placebo Early Start Early study Intervention Delayed Start Intervention Possible Disease Modifying Effect Delayed Start Study Principal Statistical Analyses Mean UPDRS change from baseline Improvement Worsening I. Superiority of Early Start vs Placebo (UPDRS Slope weeks 12 – 36) II. Superiority of Early Start vs Delayed Start (UPDRS change from baseline to week 72) II III I 12 24 36 42 48 54 60 66 72 Week III. Non-Inferiority of Early Start vs Delayed Start (UPDRS slope weeks 48 – 72;) Delayed Start (Placebo-Rasagiline) Early Start (Rasagiline-Rasagiline) Adapted from Olanow et al. Mov Disord. 2008. Issues That Must Be Addressed in a Delayed-Start Study ► Duration of period 1 and period 2 ● ● ● Long enough for protective effect to occur Long enough for full symptomatic effect to occur Not so long that patients withdraw ► Drop outs ► Missing data ● ► Need for sensitivity and imputation analyses Sufficient numbers of visits to permit slope analysis in period 1 and 2 The ADAGIO Study ADAGIO Study Design 1 mg/day 1 mg/day Untreated PD patients Placebo 2 mg/day 2 mg/day Week 0 4 12 24 36-week (9-month) Double Blind PlaceboControlled Phase Olanow et al. Mov Disord. 2008 36 42 48 54 60 66 72 36-week (9-month) Double Blind ActiveTreatment Phase ADAGIO – Baseline Characteristics Patients randomised (n) Male patients (n, %) 1,176 718 (61.1%) Age, years (mean, SD) 62.2 (9.6) PD duration, months (mean, SD) 4.5 (4.6) UPDRS-Total score (mean, SD) Motor ADL 20.4 (8.5) 14,2 (6.4) 5.2 (2.8) Hoehn & Yahr score (mean, SD) 1.5 (0.5) Olanow et al. Mov Disord 2008 Rasagiline 1mg: Early vs Delayed Start Olanow et al. NEJM; 2009 Rasagiline 2mg: Early vs Delayed Start Olanow et al. NEJM; 2009 The ADAGIO Study Summary and Conclusions ► Rasagiline 1 mg/day met all 3 primary outcomes of the delayed start study ● ► Is this a false positive? Rasagiline 2 mg/day failed to meet all primary outcomes of the delayed start study ● Is this a false negative? ADAGIO – Clinical Significance of Positive Result with Rasagiline 1 mg ► UPDRS difference of 1.7 units ► 38% reduction in rate of decline of UPDRS score ► Reflects only 9 months of active treatment ADAGIO Trial Clinical Significance ► Delayed-start study designed to determine if a study intervention has benefits that cannot be accounted for by symptomatic effects alone ► Long-term studies are required to assess effect of drug on cumulative disability ● ● ● Extension study Long-term simple study Endpoints that include measures of motor and nonmotor function - UPDRS gait, cognitive function, and quality of life New Dimensions and Landmark Practice Advances The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs) From Mechanisms to Therapy-Landmark Trials, LongTerm Safety Data, and Clinical Experience Howard L. Zwibel, MD Founding Medical Director, Emeritus | Neuroscience Consultants | Comprehensive Multiple Sclerosis Center in affiliation with the National Multiple Sclerosis Center Coral Gables, Florida | Baptist Health Doctors Hospital MS Center | Coral Gables, FL New Dimensions and Landmark Practice Advances The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs) From Mechanisms to Therapy-Landmark Trials, LongTerm Safety Data, and Clinical Experience NOTE: Both trade and chemic names are used in the presentation to establish clarity, and because many trials use acronyms that employ the brand name. The use of brand names should not be construed as endorsements for these products. MS: Immune Dysfunction Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cell Blood-brain barrier T cells 1. Ziemssen T. J Neurol. 2005;252:V/38-V/45. 2. Yong VW, et al. Neurology. 2007;68:S32-S37. 3. DhibJalbut S. Neurology. 2007;68:S13-S21. 4. Tzartos JS, et al. Am J Pathol. 2008;172:146-155. Diagnosis of MS Based on modifications to McDonald Criteria CSF = cerebrospinal fluid Polman CH, et al. Ann Neurol. 2005;58:840-846. Compston A, Coles A. Lancet. 2008;372:15021517. Figure 1. Differentiating MS Lesions Using MRI A B Note: Scans are not from the same patient. T2 with FLAIR T2 C T1 Precontrast Black Holes FLAIR = Fluid Attenuated Inversion Recovery Slide courtesy of JS Wolinsky. D T1 Post-Gd Contrast Active Inflammation Clinically Isolated Syndrome (CIS) ► ► Clinical episode consistent with demyelination ● Characterized by MRI and lab data ● Patient may or may not develop clinically definite MS (CDMS) Features of CIS suggestive of a first MS attack include: ● Appropriate age; female gender ● Abnormal brain MRI ● Optic neuritis • Typically unilateral, retrobulbar, and painful ● Brainstem/cerebellar dysfunction • Most commonly ocular motor syndromes (INO, nystagmus), ataxia, dysarthria, sensory or motor signs ● Myelitis • Partial sensory more common than partial motor • Bowel and bladder dysfunction common INO: Internuclear ophthalmoparesis Frohman, et al. Neurology. 2003;61:602-611. Clinically Isolated Syndrome (CIS) ► The challenge for physician is to determine the likelihood that person experiencing this type of demyelinating event is going to experience a second demyelinating event in the future, thereby meeting the criteria for a definite diagnosis of MS. ► When the CIS is accompanied by MRI-detected brain lesions consistent with those seen in MS, there is a high risk of a second neurologic event and diagnosis of clinically definite MS within several years. ► Individuals who experience CIS with no evidence of MRIdetected lesions are at relatively low risk of developing MS. National MS Society. Clinically isolated syndrome. http://www.nationalmssociety.org/about-multiplesclerosis/diagnosing-ms/cis/index.aspx. Accessed 12/08. CIS: MRI Lesions at Baseline Associated with Development of CDMS Over Next 20 Years 82% 85% 81% 21% (n = 34) Fisniku LK, et al. Brain. 2008;131:808-817. (n = 22) (n = 20) (n = 31) CIS or First Demyelinating Event: Phase III, Placebo-Controlled Studies Acronym Full name Primary Endpoint(s) Status PreCISe Study to Evaluate the Effect of Early Glatiramer Acetate (GA, Copaxone®) Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CIS Time to clinically definite MS (CDMS) Completed BENEFIT Betaferon® (IFNb-1b) in Newly Emerging MS for Initial Treatment Time to CDMS Time to McDonald MS Completed CHAMPS Controlled High-Risk Subjects (IFNb-1a) Avonex® Multiple Sclerosis Prevention Study Probability of developing CDMS Changes in MRI Completed ETOMS Early Treatment of MS Study (IFNb-1a) Conversion to CDMS Completed REFLEX Rebif® (IFNb-1a) FLEXible Dosing in Early MS Time to conversion to MS (McDonald criteria) Ongoing Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name. Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9. Kappos L, et al. Neurology. 2006;67(7):1242-1249. Jacobs LD, et al. N Engl J Med. 2000;343(13):898-904. Comi G, et al. Lancet. 2001;357:1576-1582. Completed CIS Clinical Trials: Demographics and Key Results PreCISe (GA) BENEFIT (IFNb-1b SC) CHAMPS (IFNb-1a IM) ETOMS (IFNb-1a SC) 3 yrs (stopped early) 2 yrs 3 yrs (stopped early) 2 yrs Patients (N) 481 468 383 308 Patient age 31 ± 7 yrs 30 yrs 33 ± 7 yrs 28 ± 6 yrs EDSS (mean) NA 1.5 NA 1.17 ± 1.2 % Reduction in CDMS Risk 45% 50% 44% 39% 0.0005 < 0.0001 0.002 0.047 Parameter Duration P-value NA = not available EDSS= expanded disability status score Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9. Kappos L, et al. Neurology. 2006;67(7):1242-1249. Jacobs LD, et al. N Engl J Med. 2000;343(13):898-904. Comi G, et al. Lancet. 2001;357:1576-1582. BENEFIT 5-Year Extension Data: Early Versus Delayed IFNβ-1b 57% 46% HR 0.63, 95% Cl 0.48–0.83; P = 0.003 Kappos L, et al. Lancet. 2009; published online September 11, 2009 DOI:1016/S1474-4422(09)70237-6 37% reduction in risk of developing CDMS CDMS = clinically definite multiple sclerosis CHAMPIONS (CHAMPS Open-label Extension): Early Versus Delayed IFNβ-1a Incidence of CDMS by Treatment Group: 10-year extension data Delayed Treatment (n = 190) Immediate Treatment (n = 193) Univariate HR (95% CI) = 0.64 (0.47–0.86), P = 0.003 Adjusted HR (95% CI) = 0.60 (0.44–0.81), P < 0.001 Kinkel RP, et al. Presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Düsseldorf, Germany, September 9-12, 2009. Poster # 446. 40% reduction in risk of developing CDMS ► “Initiation of treatment with an interferon beta medication or glatiramer acetate should be considered as soon as possible following a definite diagnosis of MS with active, relapsing disease, and may also be considered for selected patients with a first attack who are at high risk of MS.” National Clinical Advisory Board of the National Multiple Sclerosis Society (2007). http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/download.aspx?id=8. Accessed 01/14/09. Summary ►Early treatment of CIS with DMTs (GA, IFNβ formulations) delays progression to CDMS ►Early treatment of CIS or MS • Reduces rate of relapses • Delays the development of disability • May reduce the overall cost of care Current MS Therapies Immunosuppressants or Immunomodulators? ► ► Generally considered to be immunomodulators ● Glatiramer acetate [GA] injection ● IFNβ products ● Natalizumab (?) Uses of these immunomodulators ● ● GA and IFNβ products are first-line therapies for the long-term treatment of CIS and RRMS Natalizumab for patients who are unresponsive or who cannot tolerate first-line DMTs, first-line use in very active RRMS Chan A, et al. J Neuron. 2008;255(suppl 6):22-27. Glatiramer Acetate ► Dose: 20 mg sc daily (pre-filled syringes) ► Pregnancy Category: B ► Drug Interactions: None noted in clinical trials ► Laboratory monitoring: None needed ► Adverse events: Injection site reaction, immediate post-injection reaction Presumed MOA of Glatiramer Acetate: Immunomodulation Proinflammatory immune cells Proinflammatory cytokines Regulatory T-cell types Anti-inflammatory cytokines Antigen-presenting cell Neurotrophic factors T cells Blood-brain barrier ● ● ● Weber MS, et al. Neurotherapeutics. 2007;4:647-653. Aharoni R, et al. Proc Natl Acad Sci U S A. 2008;105:1135811363. Induces a population of regulatory T-cell types (Th2,Treg) Anti-inflammatory cytokines and neurotrophic factors are released May prevent nerve damage and lead to remyelination* * It is not known if these effects play an important role in the observed clinical activity of COPAXONE® in MS. T cells derived from MS patients receiving therapy with COPAXONE® have been shown to produce neurotrophic factors, including brain-derived neurotrophic factor, and to prevent nerve damage and enhance in situ remyelination and repair in animal models. Interferons Avonex®, Betaseron®, Rebif® ► Doses: ● ● ● Avonex ® : 30 mcg IM once weekly Betaseron ® : 250 mcg SC every other day Rebif ® : 22 mcg, or 44 mcg, SC TIW ► Pregnancy Category: C ► Drug Interactions: Possible with hepatically active drugs ► Laboratory monitoring: CBC, LFT, thyroid ► Adverse events: Flu-like symptoms, injection site reaction, depression, hepatic injury Presumed MOA of IFNβ: Immunomodulation Proinflamatory immune cells Proinflammatory cytokines Eliminated immune cell T cells Antigen-presenting cell Blood-brain barrier ● ● Betaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc. Reduces proinflammatory cytokine levels Reduces lymphocyte trafficking into the central nervous system (CNS) Monoclonal Antibody Natalizumab ► Dose: ● 300 mg iv infusion monthly ► Pregnancy Category: C ► Drug Interactions: Immunosuppressants, corticosteroids ► Safety Issues: ● ● ● ● ● Progressive Multifocal Leukoencephalopathy (PML) Hypersensitivity Reaction / NAbs Melanoma / Other Cancers Liver Injury Reactivation of Latent Viruses Presumed MOA of Natalizumab: Reduction of Cell Trafficking Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cells Blood-brain barrier T cells ● ● Tysabri® (natalizumab) prescribing information. Biogen Idec Inc. Inhibits the α4-mediated adhesion of leukocytes to vascular cell adhesion molecule-1 Strongly reduces proinflammatory cell recruitment to the CNS Head to Head Clinical Trials Head to Head Clinical Studies EVidence of Interferon Dose-response: European North American Comparative Efficacy (The EVIDENCE Trial) Results : Primary Endpoint Proportion Relapse Free at 64 Weeks % Relapse Free 56.3% Panitch H, et.al. J Neurol Sci. 2005;239:67-74. P = 0.023 48.2% Results : Mean T2 Active Lesions at 64 Weeks Secondary Endpoint 1.4 Mean T2 Lesions P < 0.001 0.9 Panitch H, et.al. J Neurol Sci. 2005;239:67-74. Head to Head Clinical Studies REbif® vs. Glatiramer Acetate in Relapsing MS Disease (The REGARD Study) Phase IV Multicenter, Open Label, Randomized Study of Rebif® 44 µg Administered Three Times Per Week by Subcutaneous Injection Compared with Copaxone® 20 mg Administered Daily by Subcutaneous Injection in the Treatment of RRMS Time to First Relapse Survival distribution function (Primary Endpoint) 672 days (96 weeks) IFNβ-1a Hazard ratio (95% CI): 0.943 (0.74, 1.21) GA p = 0.643 Time to first relapse (days) Adapted from an analyst report by Bernstein Research, October 15, 2007. Head to Head Clinical Studies Betaseron Efficacy Yielding Outcomes of a New Dose (The BEYOND Study) Annualized Relapse Rate 1 Year Before and During Treatment 2.0 IFNβ-1b 500 ug IFNβ-1b 250 ug GA 1.5 1.0 -79% -78% -79% 0.5 *No significant differences 0 Before During Comi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007; Fiuggi, Italy. Head to Head Clinical Studies BEtaseron® vs. COpaxone® in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (The BECOME Study) The BECOME Study ► Study Design ● ● ● ● ● Investigator-initiated study (single site) N = 75 RRMS (61) and CIS (14) patients Triple dose Gd with 40 min post-injection delay 3-Tesla MRI • “This protocol is optimized to detect enhancement…” ● ► Sponsored by Berlex/Schering AG Primary Outcome Measure ● The mean number of combined active lesions (CALs) per scan • CALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with enhancement Wolansky L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. BECOME: Summary ► Primary Outcome (CAL Count) ● ► No significant differences on the following secondary outcomes ● ● ● ► “The primary outcome of the BECOME study demonstrates that IFNβ-1b and GA have similar efficacy and onset of action for suppression of blood–brain barrier (BBB) breakdown in MS” New enhancing lesions Black Holes (acute hypointensities and persistent black holes) Clinical: ARR, sustained disability progression, cognitive function It is difficult to generalize from one set of cohorts, however, the implication of the BECOME trial is that “the superiority of IFNβ1b over GA for reducing the incidence of active inflammation in MS may have been overestimated” Wolansky L, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic. Cheriyan J, et al. Presented at: 132nd Annual Meeting, American Neurological Association; October 7-10, 2007; Washington, D.C. Cadavid D, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic. % Reduction in ARR vs Baseline Trends Across Clinical Trials: % Reduction in ARR – ~2 Years 100 85 79 80 60 71 69 GA Rebif 44 REGARD 2007 REGARD 2007 79 78 GA Betaseron 84 86 GA Betaseron 59 51 44 42 40 20 0 GA Johnson 1995 Avonex Betaseron Rebif 44 Jacobs 1996 IFNβ-1b study PRISMS-2 group,1993 1998 FTY720 Tysabri Kappos Polman ECTRIMS 2006, 2006 NEJM 2006 BEYOND 2007 BEYOND 2007 BECOME 2007 BECOME 2007 Trends Across Clinical Trials: Annualized Relapse Rate – ~2 Years Annualized Relapse Rate – 2-yrs 1.00 0.84 0.87 0.80 0.67 0.60 0.59 0.40 0.20 0.29 0.30 GA Rebif 44 0.34 0.35 0.32 0.28 0.23 0.20 0.00 GA Johnson 1995 Avonex Bet aseron Jacobs IFNB-1b study 1996 group,1993 Rebif 44 FTY720 PRISMS-2 Kappos 1998 ECTRIMS 2006 Tysabri Polman 2006 REGARD 2007 REGARD 2007 GA BEYOND 2007 Bet aseron BEYOND 2007 GA BECOME 2007 Bet aseron BECOME 2007 Long Term IMT Data Long-term Study Design in RRMS Copaxone® (glatiramer acetate injection)20,21 N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort included 108 patients at 10 years and 100 patients at 15 years. Avonex® (IFNβ-1a)9,23 Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2 years. 15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year 15. Up to 2 Tysabri® (natalizumab)27 N=942; Tysabri® 300 mg (n=627) or placebo (n=315). years 5 Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo. 16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but included in the study as identified patients). LTFU data were obtained in an observational study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients were not taking Betaseron®. N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was continued to year 4. LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8 years after enrollment. 15 yrs Betaseron® (IFNβ-1b)24,25 Rebif® (IFNβ-1a)26 15 years 16 yrs 4 yrs 3 yrs years 7-8 years Key Prospective study design Retrospective follow-up 9. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 20. Ford C, et al. WCTRIMS 2008. Abstract P44. 21. Ford CC, et al. Mult Scler. 2006;12:309-320. 23. Bermel RA, et al. WCTRIMS 2008. Abstract P14. 24. IFNβ Study Group. Neurology. 1995;45:1277-1285. 25. Ebers G, et al. AAN 2006. P01.079. 26. Kappos L, et al. Neurology. 2006;67:944-953. 27. O’Connor PW, et al. AAN 2007. P06.082. Pivotal Trial and Extension-Phase Study Design 2008 EDSS assessment 3 6 Ongoing 6-month assessments • 15-year analysis for Ongoing cohort • Mean disease duration: 22 years 9 12 15 18 21 24 27 30 33 36 13.6 years glatiramer acetate injection mITT†‡ (n=232) 8.6 years placebo 4.8 years Double-blind, placebo-controlled phase 0 Open-label extension phase 35* 60 120+ 180 Months *Due to staggered enrollment, the duration of the trial was 35 months in order to obtain 2-year results for all participants. The mean time on treatment was 30 months. †19 placebo patients of 251 in original pivotal trial chose not to enter open-label extension. ‡1 patient in the Withdrawn without long-term follow-up (LTFU) cohort withdrew before an on-treatment neurologic evaluation; therefore, 231 patients were included in the efficacy evaluable modified intent-to-treat (mITT) cohort. 29. Johnson KP, et al. Neurology. 1995;45:1268-1276. 51. Ford C, et al. WCTRIMS 2008. Abstract P44. 52. Ford CC, et al. Mult Scler. 2006;12:309-320. 56. Johnson KP, et al. Neurology. 1998;50:701-708. Yearly Relapse Rate While on GA Mean Relapse Rate 1.25 1 0.75 0.5 0.25 0 * 1 2 3 4 5 6 7 8 9 10 Year # of pts†: 232 231 208 196 175 163 149 143 11 12 † 138 125 64 57 51 *ARR in the 2 years before GA start †After year 9, mITT data included only those of patients randomized to GA in the double-blind phase of the study. Crossovers from placebo group had not yet received GA Ford CC, et al. Mult Scler. 2006;12:309-320. Demonstrated Long-term Benefits EDSS levels at 15-year follow-up 100 Patients (%) 80 60 40 38% 18% 20 0 EDSS of 4 or higher EDSS of 6 or higher 3% EDSS of 8 or higher After an average of 22 years with RRMS and a mean of 14 years of COPAXONE ® (glatiramer acetate injection) therapy, the majority of patients still in the study had not reached EDSS 4, 6, or 8 The labeling for COPAXONE® does not include an indication for slowing progression of disability. Ford C, et al. WCTRIMS 2008. Abstract P44. ASSURANCE ► 15-year long-term follow-up of pivotal IM IFNβ1a relapsing trial (MSCRG) ● ● Involved 2-year completers Open label, retrospective, patient reported ► N=136 (of 172) participated ► 46% currently on IM IFNβ1a (median duration 13.3 years) Rudick et al. MS 11:626, 2005 ASSURANCE ► Those on IM IFNβ1a showed ● ● ● ● ● ↓ Mean EDSS change (2.3 vs. 3.3, p=0.011) ↓ EDSS 4 (64% vs. 83%, p=0.06) ↓ EDSS 6 (32% vs. 62%, p=0.008) ↓ EDSS 7 (9% vs. 33%, p=0.008) Better physical score on SF36 (p<0.0001), greater independence (p=0.0019; p=0.031) Rudick et al. MS 11:626, 2005 16 Year Follow-Up Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 IFNβ-1b 50 µg 125 52 Placebo 123 58 1988 1990 Patients under regular medical care - no trial 1993 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 Goodin et al., Multiple Sclerosis; 2008: 14 (Suppl 1), P52 LTF 2005 16-Year LTF: Patient Disposition in the Intent-to-Treat Population Proportion of Patients 16.3% 7.2% 13.6% 11.4% 4.8% 10.5% Deceased 84.7% Not found 79.2% Alive 72.4% Placebo n = 123 Ebers G. Presented at ECTRIMS 2006, Madrid, Spain. INFB-1b 50 µg n = 125 IFNB-1b 250 µg n = 124 16-Year LTF: Other Findings ► The most important predictors for better long-term outcomes from the IFNB-1b 16-year LTF study were ● ● Low EDSS (<2) at study entry High exposure to IFNB-1b • The risk of any negative outcome* was reduced by 60% with high compared to low exposure ► Safety and tolerability ● ● No new or unexpected side effects Flu-like symptoms , injection site reactions and NAbs continued at a low level *EDSS 6; SPMS; EDSS 6/SPMS, Wheelchair Goodin et al. Multiple Sclerosis; 2008: 14 (Suppl 1), P52 PRISMS Long Term Follow-up ► ► 8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial 382 of 560 subjects (68.2%) evaluated ● 275 (72%) still receiving IFNβ1a ● ► Subjects initially randomized to 44mcg showed best EDSS, relapse rate, T2 burden of disease at 8 years -no brain atrophy difference 19.7% progressed to SPMS Neurology 2006;67:944 Natalizumab Monotherapy Trial: ARR 0.81† 0.73‡ 68% reduction* 68% reduction* 0.26† 0.23‡ *P<0.001. †Preplanned interim analysis. ‡Final analysis. Polman CH et al. N Engl J Med. 2006;354:899-910. Natalizumab Monotherapy Trial: Time to Sustained Progression Proportion of Patients with Sustained Progression of Disability 0.4 Placebo Natalizumab 0.3 P<0.001. 0.2 0.1 0 0 12 24 36 48 60 72 84 96 Weeks Adapted with permission from Polman CH et al. N Engl J Med. 2006;354:899-910. 108 120 Natalizumab: AFFIRM Gd-Enhancing Lesions P<0.001 between groups for all time intervals. 92% 92% Miller DH et al. Neurology. 2007;68:1390-1401. 92% Natalizumab: AFFIRM T2 Lesions P<0.0001 83% Miller DH et al. Neurology. 2007;68:1390-1401. Summary GA and interferons ► Efficacy data documented from initial event to long-term ► GA long-term data is prospective ► Interferon data long-term is retrospective ► No long-term safety signalling with GA or interferons Natalizumab ► Efficacy data short term ► Safety signalling for development of PML New Dimensions and Landmark Practice Advances The Evolution of Chemotherapeutic Agents in the Treatment of Multiple Sclerosis Douglas R. Jeffery, MD, PhD Associate Professor Department of Neurology Wake Forest University Baptist Medical Center Winston-Salem, NC “Chemotherapeutic” ► Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment of cell division ► Usually mediated by an effect on DNA or RNA synthesis ► Through this mechanism such agents kill T-cells, B-cells, and macrophages thus impairing an immune response against a wide variety of stimuli ► Immunosuppressive agents that also increase the risk of infection through the nonspecific suppression of immune function The Search for a Treatment ► Early on there were no treatments for MS ► Other disciplines (rheumatology) adopted the use of chemotherapeutic agents to treat autoimmune diseases ► MS thought by many to be autoimmune in nature ► Investigators in the MS field considered the use of these agents ► Early study designs were flawed and some doubted the effectiveness of these agents Benefits vs. Risk of Chemotherapuetuc Agents ► Chemotherapies are nonspecific immunosuppressive agents ► Many have well known and very serious side effects ● ● ● ● ► Immunosuppression Infection Hepatoxicity Secondary malignancy In the absence of other effective treatments the benefits outweighed the risks in those with worsening disability Agents that have Been Studied in MS ► Azathioprine ► Methotrexate ► Cyclophosphamide ► Mycophenylate ► Mitoxantrone ► Cladribine ► Cyclosporine Azathioprine ► Earliest studies date back to 1971 ► Small poorly controlled trials suggested a modest effect on relapses ► Later controlled trials confirmed an effect on relapse rate but not disability progression ► Cochrane meta analysis suggested an effect on relapse rate ► Odds ratio of remaining relapse free on azathioprine was 1.51 at yr 1, 2.04 at yr 2, and 1.97 at yr 3 Yudkin et. al. 1991 Azathioprine ► Used widely in Europe prior to the introduction of IFNβs ► Less popular in the modern era of immunomodulatory therapy ► Studied and used widely as a combination therapy in those with a suboptimal response to IFNβs and galtiramer acatete (GLAT) ► Use as a monotherapy felt to be suboptimal given potential for longterm toxicity Azathioprine in Multiple Sclerosis ► 354 patients randomized to azathioprine vs. placebo ► Double blinded, 3 yr duration ► At 3 yrs mean EDSS decreased 0.80 in the placebo and 0.62 in the treated group ► At 3yrs the placebo group had an average of 2,5 relapse while the azathioprine group had an average of 2.2 relapses (ns) ► Results showed a very small benefit ► Could not be recommended for most patients with MS Lancet. 1988; 23:179-183 Effect of Azathioprine on MRI Metrics ► 14 patients with at least three gd(+) lesions within 6 months ► Azathioprine dosed up to 3mg/kg daily depending on lymphocyte counts ► Evaluation for six months before treatment and six months of treatment ► Reduction of greater than 50% observed in 12 of 14 patients ► Reduction of greater than 50% or more in new T2 lesions ► Azathioprine reduced new MS brain lesions Massacesi, et. al. 2005 Toxicity of Azathioprine ► Bone marrow suppression ● ● ● Leukopenia Lymphopenia Thrombocytopenia ► Increased risk of infection ► Hepatotoxicity ► Malignancy risk increased with duration of exposure ● Solid organ tumors, myelodysplastic syndromes, epitheliomas, skin cancer La Mantia 2007, Confravreux 1996 Cyclophosphamide ► Early studies suggested a possible effect in secondarily progressive MS and rapidly progressive MS ► Conflicting results of several trials led to controversy as to whether it was effective at all ► Some believed it was highly effective and others felt it to be ineffective and dangerous ► Both were right. It depended on whether the extent of the inflammatory process present Hauser et. al. Weiner et. al. 1993 Northeast Cooperative MS Treatment Group ► Randomized ● ● Standard vs modified induction Induction only vs induction + maintenance IV CTX (700 mg/m2) bimonthly ► Induction ● ● ► IV CTX (600 mg/m2) days 1, 2, 4, 6, 8 IV ACTH for 14 days Maintenance ● Weiner et. al. 1993 IV CTX (700 mg/m2) bimonthly NE Cooperative Study Percentage Stable/Improved on DSS Months on Study 6 12 18 24 30 36 Induct (20) 75% 56% 46% 24% 17% 15% Boosters (127) 71% 55% 48% 38% 27% 20% P value 0.76 0.71 0.61 0.04 0.04 0.14 NE Cooperative Study Months on Study, with Maintenance 6 12 18 24 30 36 Younger (<41) 81% 62% 57% 42% 40% 28% Older (>41) 60% 47% 40% 34% 14% 21% P value 0.02 0.13 0.10 0.18 0.01 0.05 Cytoxan ► Factors effecting response to therapy ● ● ● ● ● Younger age Rapidly progressive course Relapses in the year before therapy <2yrs in the progressive phase Enhancing lesions on T1+Gd Canadian Cooperative Trial ► CP-MS ► EDSS 4.0-6.5 and increase >1.0 step prior 1 year ► Randomized ● ● ● ► IVCTX + prednisone PlEx + POCTX + prednisone Sham PlEx + placebo po meds Blinded examining neurologist Lancet 337:441, 1991 55 57 56 Canadian Cooperative Trial ► Randomized, placebo-controlled ► Clin-def, CP MS ► EDSS 4.0-6.5 ► Worsening on EDSS >1.0 steps prior 12M ► Non-blinded monitoring neurologist ► Blinded examining neurologist Lancet 337:441, 1991 Canadian Cooperative Trial ► CTX group (n=55) ● ● ► PlEx group (n=57) ● ● ● ► IV CTX 1 gm QOD until WBC<4.5 up to 9 gm Prednisone 40 mg qD x 10 then taper over 6 d PlEx qW for 20 wk PO CTX 1.5-2.0 mg/kg/d for 22 wk Prednisone 20 mg QOD Placebo group (n=56) ● Sham PlEx, PO CTX placebo, Prednisone placebo Lancet 337:441, 1991 Canadian Cooperative Trial Results No significant differences in: ► Rate of failure (increase in EDSS >1.0 sustained for 6 months) ► Proportions improved, stable, worse at each visit up to 36 months ► Mean change in EDSS Lancet 337:441, 1991 Canadian Cooperative Trial Results ► Proportion of treatment failures ● ● ● ► CTX PlEx Plac 35% 32% 29% Mean time to treatment failure (months) ● ● ● Lancet 337:441, 1991 CTX PlEx Plac 24.8 + 7.6 29.3 + 10.9 20.6 + 9.5 Canadian Cooperative Trial Results M12 vs. baseline Improved Stable Worse IVCTX 3 (6%) 38 (79%) 7 (15%) PIEx 4 (8%) 39 (81%) 5 (10%) Placebo 1 (2%) 35 (73%) 12 (25%) CTX vs placebo p=0.295 Lancet 337:441, 1991 Canadian Cooperative Trial Results M24 vs. baseline Improved Stable Worse IVCTX 2 (6%) 13 (42%) 16 (52%) PIEx 1 (3%) 25 (81%) 5 (16%) 0 20 (67%) 10 (33%) Placebo CTX vs placebo p=0.088 Lancet 337:441, 1991 Canadian Cooperative Trial Results M36 vs. baseline Improved Stable Worse IVCTX 2 (4%) 24 (44%) 28 (52%) PIEx 1 (2%) 34 (59%) 22 (39%) Placebo 1 (2%) 32 (59%) 21 (39%) CTX vs placebo p=0.290 Lancet 337:441, 1991 Kaiser Study ► CP-MS (EDSS 3.0-8.0) ► Increased EDSS or AI >1 step prior 1 year ► Randomized ● ● ► IV CTX Placebo Single-blind Likosky WH et al. JNNP 54:1055, 1991 22 20 Kaiser Study Results EDSS Stable or Improved* CTX Placebo 12 Months 14/22 (64%) 14/20 (70%) 24 Months 9/19 (47%) 9/17 (53%) * based on EDSS change of >1.0 step Likosky WH et al. JNNP 54:1055, 1991 Kaiser Study Results Mean DEDSS Placebo-CTX (95% CI) Month CTX Placebo 0 to 12 0.50 0.53 0.03 (-0.60 to 0.65) 0 to 18 0.38 0.73 0.35 (-0.40 to 1.10) 0 to 24 0.58 0.97 0.39 (-0.45 to 1.23) Likosky WH et al. JNNP 54:1055, 1991 Spectrum of Disease Activity ► Early inflammatory process with frequent relapse and “apparent” progression may appear “progressive” ► Usually accompanied by numerous enhancing lesions and rapidly increasing T2 lesion burden ► Late stage secondary progression related to a poorly understood degenerative process ► Infrequent enhancing lesions and little evidence of progression on MRI ► These forms of disease differ in their response to treatment Natural History of MS Measures of brain volume Relapses and impairment MRI burden of disease MRI activity Preclinical Secondary-progressive Relapsing-remitting Time Reconciliation of Early Studies on the Use of Cyclophosphamide and Mitoxantrone in MS ► Many early studies probably included patients with very active inflammation that led to the appearance of progressive disease ► The reality was that the dynamics of disease in these patients was characterized by active inflammation ► The Canadian cooperative trial and the Kaiser trial probably included a greater proportion of patients with primary progressive MS and true secondary progression ► CPM was effective in those with an active inflammatory component but not in those with slowly progressive degeneration observed in true secondary progression Cyclophosphamide Potential Adverse Effects Acute: Chronic: Nausea / malaise Infertility Alopecia Pulmonary fibrosis Hemorrhagic cystitis Myocarditis Myelosuppression Malignancy Infection Mitoxantrone ► An anthracenedione related to dauxorubicin with potent immunosuppressive effects ► Intercalates DNA and blocks the synthesis of RNA ► Inhibits topoisomerase ► Potent effects on B-cell and T-cell function ► Inhibits both passive and active EAE Clinical Trials of Mitoxantrone in MS ► Early trials produced slightly conflicting results and employed dose regimens that differed considerably ► This may have been due to the patient populations studied ► What emerged was a marked reduction in relapse rate and a reduction in enhancing lesion frequency ► Suggesting that MITX might be useful in rapidly progressive forms of MS characterized by active inflammatory disease Methylprednisolone and Mitoxantrone in MS (MP+M): Trial Design Randomized Treatment Triage M1 M2 M3 M4 M5 M6 M5 M6 Mitoxantrone 20 mg/mo IV + Methylprednisolone 1 g/mo IV M -2 M -1 M0 M1 M2 M3 M4 Methylprednisolone 1 g/mo IV MP+M: Lower Incidence of New MRI Lesions Percentage of Patients Developing New Gd-Enhancing Lesions MP (N = 21) 100 MP+M (N = 21) * Patients (%) 80 *P = .009 †P = .030 ‡P = .033 §P = .001 † ‡ § 60 40 86% Reduction 20 0 -1 Edan et al. 1997. 0 1 2 3 Months 4 5 6 MP+M: Slower Progression of Neurologic Disability Confirmed EDSS 1-Point Variation* Between Patient Inclusion and End of Study P<.01 Patients (%) (N = 12) (N = 12) (N = 8) (N = 6) (N = 3) (N = 1) *EDSS changes from 6.0-6.5 and from 6.5-7.0 were considered equivalent to 1-point change. The 1-point variation was measured for 2 months running at the end of the study. Edan et al. 1997. Mitoxantrone and IVMP in RPMS Relapse Assessment IVMP (n=21) Mito + IVMP (n=21) P-value Baseline annualized relapse rate 2.9 3.1 NS On study annualized relapse rate 3.0 0.7 0.003 7 (33%) 14 (67%) 0.031 Patients free of relapses on study Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:112-118. MP+M: Conclusions ► Addition of mitoxantrone to methylprednisolone significantly ● ● ● Reduced new MRI lesions Slowed the progression of neurologic disability Reduced relapse rate Edan et al. 1997. Mitoxantrone in Multiple Sclerosis (MIMS): Study Design ► 2-year, double-blind, multicenter, placebo controlled ► 194 patients, 18-55 years, EDSS 3-6 ► Treatment arms ● ● ● Mitoxantrone 5 mg/m2, IV, q3mo Mitoxantrone 12 mg/m2, IV, q3mo Placebo MIMS Design R A N D O M I Z E Placebo Mitoxantrone 5 mg/m2 Mitoxantrone 12 mg/m2 Rx every 3 months x 24 months Follow up at Month 36 Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 MIMS Study Inclusion and Exclusion Criteria Inclusion Criteria ► ► ► ► ► Age 18 to 55 Definite MS (Poser’s criteria) Secondary progressive or remitting progressive MS (worsening RRMS) EDSS progression 1 point in preceding 18 months Baseline EDSS from 3.0-6.0 Exclusion Criteria ► ► ► ► ► ► Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 Benign or primary progressive MS Relapse or treatment with corticosteroids in preceding 8 weeks Prior treatment with NOVANTRONE® Immunosuppressive therapy in preceding 9 months Cardiac risk factors Major medical illness MIMS Baseline Demographics* (1) Placebo Mitox 5 Mitox 12 (n=64) (n=64) (n=60) Male/Female (%) 52/48 39/61 53/47 Mean age (years) 40 40 40 Remittent progressive (%) 45 58 47 Secondary progressive (%) 55 42 53 Type of MS * No significant differences between the 3 groups Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 Mitoxantrone Efficacy at 2 Years: Primary Efficacy Variables Placebo (n=64) Mitoxantrone 12 mg/m2 (n=60) Multivariate primary efficacy criterion P-value Mitoxantrone 12 mg/m2 vs. Placebo <0.0001 EDSS change (mean) 0.23 -0.13 0.0194 Mean no. of treated relapses 1.20 0.40 0.0002 Time to first treated relapse (median months) 14.2 NR 0.0004 SNS change (mean) 0.77 -1.07 0.0269 NR=not reached within 24 months. Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 Changes in EDSS (m24 - Baseline) Mean Change in EDSS p = 0.0194 † † Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 EDSS >1.0 Point Deterioration from Baseline % of patients (N=16) p = 0.036 † (N=5) † Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 Time to First Treated Relapse Placebo Mitox 12 1.00 0.75 Mitox 12mg not reached 0.50 Placebo =14.19 m. 0.25 p=0.0004† 0.00 0 † 3 6 9 Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet 2002. v360 2018-2025 12 Months 15 18 21 24 MIMS: Patients With New Gd-Enhancing Lesions (N = 110) 19% (N = 7) P = .02 at Month 24 Placebo Mitoxantrone 12 mg/m2 16% (N = 5) Patients (%) 12% (N = 4) (N = 0) 0% Month Significantly Reduced the Change in the Number of T2-Weighted Lesions vs Placebo Mean Change in Number of T2-Weighted Lesions at 24 Months 85% reduction Mitoxantrone 12 mg/m2 (n=28) Placebo (n=32) Potential Adverse Effects of Mitoxantrone ► Acute ● Alopecia ● Myelosupression ● Infection ● Nausea/vomiting ● Malaise ● Discoloration of sclera ● Arrhythmia ► Chronic ● Cardiac toxicity ● Malignancy ● Amenorrhea ● Infertility ● Fetal malformation Mitoxantrone ► Approved by the FDA for worsening RR MS, SP MS with relapse, and PR MS ► Recognized as a rescue therapy ► More dangerous than A,B,C,R ► Useful in those failing conventional therapy or with aggressive disease from the outset The “Evolution” ► Much has changed since the advent of mitoxantrone ► Our understanding of the disease process and the importance of the inflammatory process has grown substantially ► Not much has changed regarding the profiles of the chemotherapeutic agents used and being developed ► Cladribine is a perfect example Cladrbine Synthetic purine analogue product (adenosine analogue) Deoxycytidine kinase (phosphorylation) Affect cellular metabolism, induce DNA damage and apoptosis in dividing and non dividing cells Reduction of CD4 and CD8 T cells, B cells but also other immune cells such as neutrophils and monocytes Background ► Approved by FDA for: ● ● Hairy cells leukemia Malignant lymphoma ► A few phase 1 and 2 studies have been conducted in MS with cladribine iv or s/c. ► Pregnancy category D The FDA has a categorization of drug risks to the fetus that runs from: "Category A" (safest) to "Category X" (known danger--do not use!) Category A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. Category B Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Category C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Category D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Category X Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. CLARITY - Treatment Regimen ► Annual short-course treatment ● ● Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive days per month Courses given for 2 or 4 consecutive months in Year 1 and for 2 consecutive months in Year 2 First 48 weeks XXXX Second 48 weeks XX Placebo Screening 1326 randomized (1:1:1) •• XX •• Cladribine tables: 4 courses, total dose 3.5 mg/kg •••• •• X Placebo course • Cladribine course Cladribine tables: 6 courses, total dose 5.25 mg/kg Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Primary Outcome Reduction in Relapse Rates (ITT) Annualized relapse rate 54.5% reduction (P < 0.001) 57.6% reduction (P < 0.001) 0.4 0.33 0.3 0.2 0.14 0.15 Cladribine 3.5 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) 0.1 0 Placebo (n = 437) ITT = intent-to-treat population; error bars indicate upper limit of 95% confidence interval. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Secondary Outcome Reduction in Disability Progression (ITT) Hazard ratio vs placebo (95% CI)* Proportion with 3-month confirmed EDSS progression (%) Placebo Cladribine 3.5 mg/kg 0.67 (0.48, 0.93); P = 0.018 Cladribine 5.25 mg/kg 0.69 (0.49, 0.96); P = 0.026 Number of patients at risk: Placebo 437 424 3.5 mg/kg 433 424 5.25 mg/kg 456 447 33% 31% Relative reduction 399 407 425 373 389 404 355 379 388 333 364 375 315 355 363 304 347 350 304 347 350 Time to sustained change for 3 months in EDSS of 1 point (or 1.5 point if baseline EDSS was 0, or 0.5 point if baseline EDSS was 5); CI = confidence interval; *Cox proportional hazards model. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Secondary Outcome Improvement in MRI Parameters (ITT) Placebo Cladribine 3.5 mg/kg –87.9%* Cladribine 5.25 mg/kg –76.9%* –77.9%* Mean ± SE lesions/patient/scan 2.00 –86.8%* –74.6%* –73.4%* 1.72 1.50 1.43 *P < 0.001 *P < 0.001 *P < 0.001 1.00 0.91 0.50 0.12 0.11 0.38 0.33 0.43 0.38 0 T1 Gd+ lesions Active T2 lesions Combined unique lesions SE = standard error. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Secondary Outcome Safety Overview Placebo Cladribine 3.5 mg/kg (n = 435) (n = 430) Any treatment-emergent AE 73.3 80.7 83.9 82.4 AEs leading to discontinuation 2.1 3.5 7.9 5.8 AEs leading to withdrawal 1.1 1.2 2.0 1.6 Serious AEs 6.4 8.4 9.0 8.7 0.5 (n = 2) 0.5 (n = 2) 0.4 (n = 2) 0.4 (n = 2) Patients with AE (%) Deaths* Cladribine Cladribine 5.25 mg/kg overall (n = 454) (n = 884) *Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardiorespiratory arrest. AEs = adverse events Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Cladribine Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMS CD4+ (helper T cells) CD8+ (cytotoxic T cells) CD19+ (B cells) Placebo Cladribine 0.7 mg/kg Cladribine 2.1 mg/kg CD19+/CD56+ (natural killer cells) Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55]. Cladribine: Effect after 3-5 years on Naïve (CD45RA+) and Memory (CD45RO+) - CD4+ Tcells Hairy Cell Leukemia patients were treated with Cladribine (1 mg/kg c.i. for 7 days) At 3-5 years post dose, there was a decrease in CD4+/CD45RA+ cells while CD4+CD45RO+ cells slightly increased These findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of cladribine Raspadori D, et al. Leukemia. 1999;13:1254-1257. Subject with Resolved Grade 3 and 4 Toxicity Hematology (resolved = returning to Grade 1 or 0) ► ► App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~ 24 wks Almost all other Grade 3 and 4 toxicities resolved on study Laboratory test Haemoglobin WBC Neutrophils Lymphocyte Statistics Cladribine 5.25 Cladribine 3.5 mg/kg (n=454) mg/kg (n=430) n (%) n (%) Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 0 (1 total) Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) Placebo (n=435) n (%) 3 (5 total) 2 (3 total) 17.5 (6.8) 18.1 10.4;24.0 13.0 (8.3) 13.0 7.1;18.9 8 (10 total) 6 (6 total) 2 (2 total) 11.8 (10.3) 9.0 1.4;29.1 3.7 (1.9) 3.4 1.6;6.0 2.8 (0.9) 2.8 2.1;3.4 Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 17 (17 total) 12 (12 total) 17 (18 total) 8.1 (9.6) 5.9 1.1;42.1 5.2 (3.8) 4.9 1.0;12.1 4.8 (3.1) 4.3 1.1;12.1 Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 108 (203 total) 52 (110 total) 2 (2 total) 29.4 (20.8) 24.1 2.9;88.0 25.4 (19.8) 23.4 0.9;92.7 4.6 (0.6) 4.6 4.1;5.0 PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472. Adverse Events of Special Interest Herpes Zoster Preferred term, n (%) patients Placebo (n=435) Herpes zoster 0 Herpes zoster oticus 0 Varicella ► 1 (0.2) Cladribine 3.5 mg/kg (n=430) Cladribine 5.25 mg/kg (n=454) Cladribine overall (n=884) 8 (1.9) 11 (2.4) 19 (2.1) 1 (0.2) 1 (0.1) 1 (0.2) 2 (0.2) 0 1 (0.2) Herpes zoster was reported more frequently with cladribine tablets than placebo ● 20 patients had 21 zoster events in the cladribine tablets groups ● All 21 cases were self-limiting and dermatomal S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009. Adverse Events of Special Interest Malignancies Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cervix carcinoma Stage 0 0 0 0.2 (1) 0.1 (1) Malignant melanoma 0 0.2 (1) 0 0.1 (1) Ovarian cancer 0 0.2 (1) 0 0.1 (1) Pancreatic cancer, metastatic 0 0.2 (1) 0 0.1 (1) 0 0 0.2 (1) 0.1 (1) Preferred term, % (n) Cladribine Cladribine 5.25 mg/kg overall (n = 454) (n = 884) During study During post-study surveillance Choriocarcinoma Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Cladribine Cladribine Summary ► Efficacy is comparable to high dose IFN ► Toxicity is considerable ● ● ● ● ● ● Risk of malignancy Long-term immunosuppression Increased risk of herpes infections Infertility Fetal malformation Graft vs. host ► How long can it be used with CD-4 counts markedly reduced ► What do you do if patients are worsening? Evolution? ► There has been no evolution! ► Chemotherapeutic agents remain nonselective, broad spectrum cytotoxic agents that suppress the immune system in a nonspecific fashion ► They all have considerable risk of adverse events that include secondary malignancy, infection, infertility, fetal malformation, and other end organ toxicity ► Newer monoclonal antibodies and other innovative therapies appear equally or more effective and have manageable risk Case Studies Challenging Cases in the Management of Multiple Sclerosis and Parkinson’s Disease Multiple Sclerosis Case #1 ► 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual ► Back in Houston another ophthalmologist called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral steroids ► 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia UPIN 4804 06/06/08 UPIN 4804 06/06/08 Multiple Sclerosis Case #1 ► 4 days later continued double vision on looking to the right ► Extensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoning ► Nystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normal ► CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs ► Intravenous methylprednisolone course started UPIN 4804 07/02/08 UPIN 4804 07/02/08 Multiple Sclerosis Case #1 The Issues ► The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this? ► When you have CIS and can’t diagnose more than suspect MS by McDonald’s or Swanton’s, do you just treat, use Frohman? ► When asked about the familial risk of MS in the company of the patients twin sister, what is the best course? Multiple Sclerosis Case #2 ► 30-year-old Caucasian female presented initially with right optic neuritis. ► Vision improved after high dose intravenous methylprednisolone treatment ► T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter. ► No disease modifying therapy was started at that time. Multiple Sclerosis Case #2 ► 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. ► MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. ► MRI brain- one new periventricular white matter lesion without enhancement in comparison to last year’s. ► Motor symptoms improved with high dose corticosteroid therapy ► Residual numbness in the feet and bladder control difficulties. Multiple Sclerosis Case #2 ► Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. ► 6 months later she complained of markedly increased fatigue and “fuzzy thinking.” ► Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. ► Disease modifying therapy was changed to a high dose subcutaneous interferon beta. Multiple Sclerosis Case #2 ► Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. ► After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. ► MRI scan showed additional Gd+ enhancing lesions. ► A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100. Multiple Sclerosis Case #2 ► The same interferon treatment was continued but after several months she complained of ongoing problems with memory. ► Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged. Multiple Sclerosis Case #3 ► Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. ► 18 months later, follow-up MRI shows unchanged cyst but single periventricular nonenhancing white matter lesion. ► Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities. Is it Multiple Sclerosis? ► While hiking with physician husband on hot afternoon, she notes numbness in left foot. ► Spinal cord MRI shows enhancing lesion at T17. ► Is it MS? ► Treatment recommendations? Multiple Sclerosis Case #4 ► 32-year-old healthy female post-doc researcher who participated in an MRI study as a volunteer. ► Subject has no family history of MS or immune-mediated diseases. No personal past medical history. ► No neurological symptoms except rare migraine headaches and no signs on her neurological exam. Multiple Sclerosis Case #3 Research Brain MRI Parkinson’s Disease Case #1 ► A 56-year-old male in good health presents with slight, intermittent rest tremor of the left (nondominant) hand. Tremor worse with stress and when he walks. Wife has noticed decreased arm swing on the left. ► He notes some stiffness on the left side and some constipation. He states that symptoms are only minimally bothersome and not interfering with job or home life. The couple is troubled that the condition will become apparent to coworkers and interfere with career. Parkinson’s Disease Case #1 ► ► ► ► Family History: No family history of Parkinson’s disease Medical History/Medications: Wife noticed that for the past three years the patient moves about during sleep. No current medications Examination: Reveals normal mental status and eye movements. He has slight bradykinesia on repetitive alternating movements in the left hand and a slight rest tremor is noted. Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy Parkinson’s Disease Case #2 ► 58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. ► Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day. Parkinson’s Disease Case #2 ► ► ► ► Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopa Medical History/Medications: No significant medical or surgical history. No current medications Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Decision making: Patient diagnosed with Parkinson’s disease with some disability and he wishes to start treatment. Parkinson’s Disease Case #3 ► 68-year-old woman with a 4-year history of Parkinson’s disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. ► Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working. Parkinson’s Disease Case #3 ► ► ► ► Family History: no relatives with PD Medical History: No significant medical or surgical history Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopalevodopa Decision making: treatment of motor fluctuations, non-motor features of PD Parkinson’s Disease Case #4 ► ► 82-year-old woman has a history of Parkinson’s disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pillrolling tremor of the right hand. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently. Parkinson’s Disease Case #4 ► ► ► ► Family History: 87-year-old sister diagnosed with Alzheimer’s disease and Parkinson’s disease Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Decision making: management of advanced PD motor and non-motor features