MS: Principles of Management

Transcription

1 Treatment t Optimization i in MS

2 MS: Principles of Management What Is Lost Is Not Regained Delay progression to disability Cognitive and physical disability Reduce frequency and severity of relapses Treat relapses when they occur Manage symptoms Maintain functional independence Improve and facilitate an acceptable quality of life and promote Hope

3 Models of Treatment Therapeutic management needs CIS treatment Acute disease management Long-term management Symptomatic management Craig J, et al. J Neurol Neurosurg Psychiatry. 2003;74(9): Goodin DS, et al. Neurology. 2002;58(2):

4 Acute Disease Management Cornerstone: Corticosteroids Rationale Anti-inflammatory agents can reduce inflammation in brain and spinal cord Regular pulse glucocorticoids anecdotally reported to be useful in long-term management of worsening MS Benefits May relieve symptoms and reduce the severity and duration of a relapse. There does not appear to be a long-term benefit. Cohen JA, et al. Neurology. 2009;72(6):

5 High-Dose Steroid Options 1. Methylprednisolone 1 mg IV QD x 3-5 days (common)* 2. Dexamethasone mg IV QD x 3-5 days* 3. High dose oral steroids 1250 mg po QD x 6 days (Canadian protocol) 4. ACTH 80 units IM or SC x 5D in tapered dosing *With/without oral prednisone or dexamethasone taper (may be practice specific) IV=intravenous; PO=oral; IM=intramuscular; SC=subcutaneous Sellebjerg F, et al. Eur J Neurol. 2005;12(12): Filippini G, et al. Cochrane Database of Systematic Reviews. 2000(4):CD Ozakbas S, et al. J Neurol Sci. 2004;218(1-2):3-7.

6 Incomplete Recovery From Relapse in MS Recovery from acute MS relapse is variable 1 Incomplete recovery occurs in up to half of all patients and not related to gender, age, or site of lesion 2 Incomplete recovery is associated with further relapse in the following months 3 Incomplete recovery at 1 month is associated with greater residual disability More severe relapses are associated with more severe disability Risk of severe relapse is reduced in patients treated with immunomodulating agents 1. Vercellino M, et al. Acta Neurol Scand. 2009;119(2): Hirst C, et al. J Neurol. 2008;255(2): Iuliano G, et al. Eur Neurol. 2008;59(1-2):44-48.

7 Corticosteroids in the Long-term Treatment of MS Studies show insufficient evidence that long-term corticosteroid therapy delays progression of long-term disability in patients with MS Ciccione A, et al. Cochrane Database Syst Rev. 2008(1):CD

8 Corticosteroid Side Effects Side Effects During infusion: Metallic taste in mouth, flushing, headache, low back pain, anxiety Post-Infusion: Insomnia, indigestion, heartburn, nausea, fluid retention, mood changes, reduced K, increase BS, increase BP, delayed hives, psychosis Measures Suggest hard candy Slow infusion rate to decrease headache or backache Suggest OTC or RX sleep aids, recommend OTC dyspepsia agents, decrease salt intake, drink fluids, eat p y foods high in K (oranges, bananas, green vegs), consider medication for mood, modify diet, monitor blood pressure prior to infusion, monitor mental status Long-term: Osteoporosis, cataracts, irregular menses, decreased resistance to infection, skin changes Recommend calcium with vitamin D OTC=over the counter; RX=prescription

9 Long-term Management Disease-modifying therapies (DMTs) Clinically isolated syndrome (CIS) Relapsing MS Worsening disease

10 Clinically Isolated Syndrome

11 Does Treatment Soon After a CIS Delay the Second Clinical i l Event, Therefore Delaying the Onset of MS? Five large-scale clinical trials in CIS CHAMPS: 1 (Interferon [IFN] beta-1a IM) Controlled High-Risk Subjects Avonex MS Prevention Study ETOMS: 2 (IFN beta-1a SC) Early Treatment of MS IFN BENEFIT: 3 (IFN beta-1b SC) Betaseron in Newly Emerging MS For Initial Treatment PreCISe: 4 (Glatiramer acetate [GA]) Early Treatment in Delaying CDMS REFLEX: 5 (IFN beta-1a SC) REbif in FLEXible Dosing in Early MS (ongoing) 1. Jacobs LD, et al. N Engl J Med. 2000;343(13): Comi G, et al. Lancet. 2001;357(9268): Kappos L, et al. Lancet. 2007;370(9585): Comi G, et al. American Academy of Neurology Annual Meeting Chicago, IL: Serono announces initiation of the Reflex trial to evaluate new formulation of Rebif(R) in patients at risk of developing multiple sclerosis: April 10, 2009.

12 CIS Treatment Results of clinical trials in CIS provide class I evidence indicating: Treatment decreases the probability of conversion to MS following 1 demyelinating episode Treatment has beneficial effects on MRI measures in patients t with very early disease Goodin DS, et al. Neurology. 2002;58(2):

13 CIS Trials Using DMT Study Drug and Design Patients Results (Cumulative probability of conversion to MS) ETOMS ( *) Comi G, et al. Lancet. 2001;357(9268): CHAMPS ( *) Jacobs LD, et al. NE Engl ljm Med. 2000;343(13): IFN beta-1a SC vs placebo 22 mcg SC once weekly Europe (14 countries) Duration: MS (Poser) or 2 years TT MS IFN beta-1a IM vs placebo 30 mcg IM once weekly US and Canada Duration: planned 3 year TT MS N=309 Monofocal and multifocal CIS 28±6 yrs (mean) N=383 Monofocal CIS 33±7 years (mean) Sig fewer patients on IFN converted 34% vs 45% 25% difference P= Odds ratio % CI ( ) P=0.045 Sig fewer patients on IFN converted 35% vs 50% 30% difference P=N/A Rate ratio %CI ( ) P=0.002 *enrollment years; CI=confidence interval

14 CIS Trials Using DMT, continued Study Drug and Design Patients Results (Cumulative probability of conversion to MS) BENEFIT ( *) IFN beta-1b vs placebo 250 mcg SC every other N=468 Monofocal and Sig fewer patients on IFN converted Kappos L, et al. Lancet. 2007;370(9585): PreCISe ( *) Comi G, et al. American Academy of Neurology Annual Meeting Chicago, IL: day US, Canada, and Israel Duration: MS (Poser) or 2 years TT MS and TT McD Glatiramer acetate vs placebo 20 mg SC once daily Europe and US Duration: MS (Poser) or 3 years TT MS multifocal CIS 30 yrs (mean) N=481 Monofocal CIS Age NA 28% vs 45% 38% difference P=N/A Hazard ratio % CI ( ) Hazard ratio Mcd % CI ( ) 69% vs 85% conversion to MS; 19% reduction Sig fewer patients on GA converted 25% vs 43% 44% difference P< Hazard ratio % CI (unknown) P= d vs 722 d to MS (quartile) REFLEX IFN beta-1a vs placebo N=517 Data not yet available (2006-current*) 44 mcg SC 3x weekly vs Monofocal and Serono announces initiation of the once weekly multifocal CIS Reflex trial to evaluate new formulation Multinational Age NA of Rebif(R) in patients at risk of developing multiple sclerosis: duration: MS (rev McDonald) or 2 years ww/story/ / andEDATE=; April 10, *enrollment years TT MS

15 Long-term Management

16 Goals of Disease Modification in Definite MS Reduction of disease activity as measured by number of relapses, MRI findings, and disability Provide therapy that is well-tolerated and safe Affect the neurodegenerative and inflammatory components

17 The Importance of Early Effective Treatment MS may be active in the brain and spinal cord in the absence of clinical symptoms 1-4, 7 Lesions may occur early and may be associated with irreversible damage 1-6 Evidence suggests that degenerative changes can occur in normal-appearing white matter (NAWM) Damage can lead to permanent disability1, 2, 4 Starting effective treatment early may help slow the accumulation of damage 7, 8 1. Trapp BD, et al. N Engl J Med. 1998;338(5): Ruiz-Pena JL, et al. BMC Neurol. 2004;4:8. 3. Lossef NA, et al. J Neurol. 2001;248(6): De Stefano N, et al. Arch Neurol. 2001;58(1): Ferguson B, et al. Brain. 1997;120(Pt 3): Filippi M, et al. Brain. 2003;126(Pt 2): Coyle PK, Hartung HP. Mult Scler. 2002;8(1): Narayanan S, et al. J Neurol. 2001;248(11):

18 National Multiple Sclerosis Society Disease Management Consensus Statement Initiation of therapy with an immunomodulator is advised as soon as possible following a definite diagnosis of MS with a relapsing course and may be considered for selected patients with a first attack who are at high risk for MS. Medical Advisory Board of the National MS Society. Expert opinion paper: disease management consensus statement: April 10, 2009.

19 Disease-Modifying Therapies Evidence indicates DMTs Decrease frequency of relapses Reduce MRI activity Delay progression to disability Two classes of disease-modifying medications: Immunomodulators Immunosuppressants Noseworthy JH, et al. N Engl J Med. 2000;343(13):

20 Theoretical Model of Early Treatment Natural course of disease Disabili ity Diagnosis Progression Later intervention Intervention at diagnosis CIS Theoretical Model Time Adapted from Simon JH, et al. Neurology. 1999;53(1):

21 Drug Activity Is Due to Immunotherapy Properties Selective immunomodulation Glatiramer acetate Non-specific immunomodulation IFN beta-1a IFN beta-1b Selective adhesion molecule l inhibitor Natalizumab Immunosuppression Mitoxantrone Corticosteroids Cyclophosphamide

22 Disease-Modifying Therapies First-line agents for relapsing-remitting MS Interferon beta-1b IM (1993) Glatiramer acetate t (1996) Interferon beta-1a IM (1996) Interferon beta-1a SC (2002) Second-line agents Mitoxantrone (2000) Worsening relapsing-remittingremitting MS (RRMS), progressive relapsing MS (PRMS), or secondary progressive MS (SPMS) Natalizumab (2006) Relapsing MS with inadequate response to or intolerant of first-line DMTs Betaseron [package insert]. Montville, NJ: Berlex Labs; Copaxone [package insert]. Kansas City, Mo: TEVA Neuroscience Inc; Avonex [package insert]. Cambridge, Mass: Biogen, Inc.; Rebif [package insert]. Rockland, Mass: Serono Inc, and New York, NY: Pfizer Inc; Novantrone [package insert]. Rockland, Mass: Serono, Inc.; Tysabri [package insert]. Cambridge, Mass: Biogen Idec Inc.; and San Diego, Calif: Elan Pharmaceuticals; 2006.

23 First- and Second-Line Disease-Modifying Therapies Brand Name Generic Name Administration Indication Copaxone 1996 Glatiramer Acetate 20 mg daily SC injection RRMS CIS Rebif* 2002 High-dose IFN 22 mcg or 44 mcg Relapsing forms beta-1a SC tiw (3x week) Avonex* 1996 Betaseron 1993 Low-dose IFN beta -1a High-dose IFN beta-1b 30 mcg IM injection weekly Relapsing forms CIS 250 mcg SC qod Relapsing forms CIS Tysabri Natalizumab IV 300 mg gq 4 Relapsing forms 2004/2006 weeks Novantrone 2000 Mitoxantrone IV by protocol max lifetime dose Worsening RRMS, SPMS, PRMS *Delays the accumulation of physical disability 80% of all MS patients would benefit from these therapies, but only 60% of eligible patients are on treatment.

24 Mechanisms of Action

25 Potential Mechanism of Action: IFN Beta Acts in periphery (ie, does not cross BBB) Influences cytokine levels and antigen presentation May induce beneficial cytokine shifts IFN γ antagonistic Blocks T-cell activation Induces apoptosis of autoreactive ti T cells Induces antiproliferative effect Downregulates expression of costimulatory molecules Blocks IL-12 production in dendritic d cells Has antiviral effect Inhibits T-cell trafficking across BBB Decreases expression of adhesion molecules Reduces expression of several chemokines that permit transport across BBB Inhibits MMP production Noseworthy JH, et al. N Engl J Med. 2000;343(13): Yong VW. Neurology. 2002;59(6): BBB=blood-brain barrier IL=interleukin MMP=matrix metalloproteinases

26 Mechanism of Action: IFN Beta* MHC II IFN β Blood T H 1 + IFN β MMP BBB CNS (Indirectly) Myelin protein IL-10 APC T T H 1 + T H 1 + T H 1 + APC Resting T cell Activated (+) T cells T H 1 + H CAMs IFN β TNF α IL-12 IFN γ *The exact mechanisms are not fully understood. Adapted from Yong VW. Neurology. 2002;59(6): APC=antigen presenting cell MHC=major histocompatibility complex TH1+=T helper 1 cell

27 Potential Mechanism of Action: Glatiramer Acetate in MS Structurally t similar il to myelin basic protein (MBP) in the CNS and when presented to the antigenpresenting cell Induces suppressor T helper 2 cell (Th2)-polarized GA reactive CD4 + regulatory T cells (antiinflammatory) GA-induced regulatory T cells are presented to MBP in the CNS, they are stimulated to proliferate and release anti-inflammatory cytokines transforming growth factor (TGF) beta, IL-4, IL-10) GA downregulates/normalizes an accelerated Th1 differentiation of CD4 + T cells Causing a cytokine shift Weber M, et al. Neurotherapeutics. 2007;4(4):

28 Mechanism of Action: Glatiramer Acetate* Blood BBB CNS (Indirectly) GA T H 2 + Myelin protein APC T + H 2 + T H 2 T H 2 APC GA-induced T cell T H 2 + IL-4 H TGF β IL-10 Activated (+) T cells Standby suppression CNS protection *The exact mechanisms are not fully understood. T H 2 + =helper T2 + cell; IL-4=interleukin 4; IL- 10=interleukin 10; TGF β=t-cell growth factor β. Adapted from Yong VW. Neurology. 2002;59(6):

29 Potential Mechanism of Action: Natalizumab Primary mechanism related to blockade of interaction between the α4b1 integrin on inflammatory T cells and brain endothelial vascular cell adhesion molecule-1 (VCAM-1) receptors at BBB Alternative ti mechanisms Block very late antigen-4 (VLA-4) fibronectin CS-1 interaction Block VLA-4 osteopontin interaction Inhibit antigen presentation

30 Putative Mechanism of Action: Natalizumab* Blood VCAM-1 BBB CNS Natalizumab T H 1 + Antigen APC Resting T cell T Activated (+) T cells T H 1 + H α 4 Integrin T H 1 + *The exact mechanisms are not fully understood. VCAM-1=vascular cell adhesion molecule-1. Adapted from Rice GP, et al. Neurology. 2005;64(8):

31 Potential Mechanism of Action: Mitoxantrone Interferes with DNA and RNA replication; inhibits topoisomerase II to impede DNA repair 1 Actions that reduce disease progression 2 Suppresses T-cell, B-cell, and macrophage proliferation Impairs antigen presentation ti Diminishes proinflammatory cytokine secretion Enhances T-cell suppressor activity Inhibits B-cell function and antibody production Inhibits macrophage-mediated myelin degradation 1. Novantrone [package insert]. Rockland, MA; Serono, Inc; Fox EJ. Neurology. 2004;63(12 Suppl 6):S15-S18.

32 Putative Mechanism of Action: Mitoxantrone* Activated (+) T cells Blood T H 1 + BBB CNS P APC T T H 1 + T H 1 + B B Resting T ll T cell T H 1 + T H 1 + APC *The exact mechanisms are not fully understood. Fox EJ. Neurology. 2004;63(12 Suppl 6):S15-S18. Neuhaus O, et al. J Neurol Sci. 2004;223(1): TNF α IL-2 IFN γ

33 Pivotal Trials

34 Pivotal Trials Disease-Modifying Therapies Randomized, d placebo-controlled ll clinical i l trials Relapsing-remitting MS IFN beta-1b SC IFN beta-1a IM IFN beta-1a SC Glatiramer acetate Natalizumab Mitoxantrone

35 First-Line DMTs Data Based on Placebo-Controlled, ll Randomized, Controlled Trials (RCTs) How Given Effect on Relapse Rate MRI Findings IFN beta-1a IFN beta-1a IFN beta-1b Glatiramer Acetate 30 mcg IM QW 22 mcg or 44 mcg SC 250 mcg SC 3x/week 20 mg SC daily QOD 18% 27%-33% 30% 32% (annualized) (2 years) (5 years) (long-term) lesions risk for progression of disability active lesions disability rate of new lesions rate of severe relapses lesions loss of brain tissue IFNB MS Study Group. Neurology. 1995;45(7): PRISMS Study Group. Neurology. 2001;56(12): Stone LA, et al. Neurology. 1997;49(3): Jacobs LD, et al. Ann Neurol. 1996;39(3): Ge Y, et al. Neurology. 2000;54(4):

36 Pivotal Trials Summary Class I evidence from randomized control trials (RCTs) in RRMS indicates immunomodulating therapies Reduced relapse rate Delayed progression of disability Had a beneficial effect on MRI measures of disease burden In addition, a dose response has been observed with IFN beta Results from pivotal trials cannot be directly compared Goodin DS, et al. Neurology. 2002;58(2):

37 Direct Comparison Trials

38 Why Direct-Comparison Trials Are Important Provide an alternative to assessing therapies due to the difficulties in comparing one placebo-controlled trial against another Compare one therapy with another in a fixed study setting Depending on study design, conclusions may be drawn about each therapy s effect on endpoint and which had a better effect on the endpoint Can provide a forum for comparing a therapy considered standard of care against a new therapy Offer an avenue of study when placebo is not an appropriate option Reinforce the value of study design importance Not all comparison trials are designed to show superiority or equivalence Study design and methodology impact study result interpretation

39 Direct Comparison Trials INCOMIN EVIDENCE REGARD BECOME BEYOND Treatment IFN beta-1b IFN beta-1a SC IFN beta-1a SC IFN beta-1b IFN beta-1b SC (250 mg) Arms SC vs IFN beta-1a IM vs IFN beta-1a IM vs glatiramer acetate SC vs glatiramer acetate vs glatiramer acetate Study Randomized Randomized Randomized Randomized Randomized design N=188 N=677 N=764 RRMS RRMS RRMS N=36 24 mos RRMS N= mos RRMS Key results Higher relapse-free rate with IFN beta-1b IM (51%) compared with IFN beta- 1a IM (36%) (P<0.03) Higher relapsefree rate with with IFN beta- 1a SC (56%) vs IFN beta-1a IM (48%) (P=0.023) No significant difference in time to relapse No significant difference in cumulative active lesions per scan between groups Similar decline in relapse risk (78%-79% decline with IFN and GA, respectively)

40 Direct Comparison Trials Relapsing-remitting g MS INCOMIN: IFN beta-1b SC vs IFN beta-1a IM EVIDENCE: IFN beta-1a SC vs IFN beta-1a IM REGARD: IFN beta-1a SC vs glatiramer acetate BECOME: IFN beta-1b SC vs glatiramer acetate BEYOND: IFN beta-1b SC vs glatiramer acetate

41 INCOMIN Trial in RRMS: IFN Beta-1a IM vs IFN Beta-1b SC Parameter Criteria Design RD, NB (clinical), SB (MRI) Patients Diagnosis Prior exacerbations N=188, IFN beta naïve RRMS 2 in 2 years Baseline EDSS INCOMIN=Independent Comparison of Interferons; RD=randomized; NB=not blinded; SB=single-blinded. Durelli L, et al. Lancet. 2002;359(9316):

42 INCOMIN Trial: Clinical Results at 2 Years* Primary Endpoint IFN beta-1a IM IFN beta-1b SC Proportion relapse free 36% 51% 0.03 Secondary Endpoint IFN beta-1a IM IFN beta-1b SC Annualized exacerbation rate Mean change in EDSS Proportion of patients with progression in disability 30% 13% P P *Not blinded. Durelli L, et al. Lancet. 2002;359(9316):

43 EVIDENCE Trial in RRMS: IFN Beta-1a IM vs IFN Beta-1a SC Parameter Design Patients Diagnosis Prior exacerbations Criteria RD, SB (clinical and MRI) N=677 IFN beta naïve RRMS 2 in 2 years Baseline EDSS EVIDENCE=Evidence of Interferon Dose-Response: European North American Comparative Efficacy. Panitch H, et al. Neurology. 2002;59(10): Panitch H. Int J MS Care. 2003;5(3):80.

44 EVIDENCE Trial: Results at 64 Weeks Primary Endpoint IFN beta-1a IM n=319 IFN beta-1a SC n=315 Proportion relapse free 48% 56% Secondary Endpoint IFN beta-1a IM IFN beta-1a SC Annualized exacerbation rate Time to first relapse (mo) Mean proportion of active T2 scans per patient 44% 27% P P Panitch H. Int J MS Care. 2003;5(3):80.

45 REGARD Trial in RRMS: IFN Beta-1a SC vs Glatiramer Acetate Purpose was to compare the efficacy and safety of IFN beta-1a SC and GA in RRMS Parameter Design Patients Diagnosis Prior exacerbations Criteria RD, open-label, comparative assessor-blinded (96 weeks) N=386 IFN beta-1a SC; N=378 GA (N=764) RRMS Baseline EDSS in past 12 mos REGARD=Comparison of Interferons; RD=randomized. Mikol DD, et al. Lancet Neurol. 2008;7(10):

46 REGARD Study: IFN Beta-1a SC vs Glatiramer Acetate in RRMS Outcomes No significant difference between treatment groups for time to first relapse (primary endpoint) Planned MRI subgroup analysis No significant difference between treatment groups in number of new or enlarging T2 lesions (secondary endpoint) Significant (P<0.001) difference favoring IFN beta-1a SC in number of T1 Gd-enhancing lesions (secondary endpoint) Significant difference favoring IFN beta-1a SC in number of combined unique active lesions (P=0.010) and proportion of scans with combined unique active lesions (P=0.009) (tertiary endpoint) No significant ifi difference between treatment t t groups for ARR: 0.30 for IFN beta- 1a SC and 0.29 for glatiramer acetate (tertiary endpoint) Patients discontinuing treatment 20.9% of IFN beta-1a SC group, 13.6% of glatiramer acetate group Patients experiencing adverse events ents 90.8% of IFN beta-1a SC group, 85.3% of glatiramer acetate patients No unexpected safety issues ARR=absolute risk reduction Mikol DD, et al. Lancet Neurol. 2008;7(10):

47 BECOME Trial in RRMS: IFN Beta-1b SC vs Glatiramer Acetate t Purpose: Compare the efficacy of IFN beta-1b with GA for the treatment of RRMS using MRI protocol Parameter Design Patients Diagnosis Criteria RD, open-label, comparative, assessor-blinded study (24 mos) N=36 IFN beta-1b; N=39 GA RRMS Cadavid D, et al. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Prague, Czech Republic: October 12, Wolansky L, et al. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Prague, Czech Republic: October 12, 2007.

48 BECOME Trial in RRMS: IFN Beta-1b vs Glatiramer Acetate Outcomes There was no statistically significant difference between treatment groups with regard to: CAL per scan per patient (primary endpoint) 078IFNbeta1b; 0.78 beta-1b; 0.56 GA (P=0.70) CAL per month (secondary outcome) NEL per scan (secondary outcome) There was a statistically significant drop in the mean number of CAL for IFN beta-1b but not for GA when comparing pre-rx to on-rx IFN beta-1b (P=0.001); GA (P=0.14) CAL=cumulative active lesions; NEL=number of enhancing lesions Cadavid D, et al. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Prague, Czech Republic: October 12, Wolansky L, et al. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Prague, Czech Republic: October 12, 2007.

49 BEYOND Trial in RRMS: IFN Beta-1b vs Glatiramer Acetate t Purpose: Compare the efficacy, tolerability, and safety of IFN beta-1b (two doses) with GA for the treatments of RRMS Parameter Design Patients Diagnosis Criteria Phase III, RD, comparative study using 3 arms (3.5 years) N=897 IFN beta-1b 250 mcg N=899 IFN beta-1b 500 mcg N=448 GA RRMS Comi G. The European Charcot Foundation Symposium. Fiuggi, Italy: O'Connor P, et al. American Academy of Neurology Annual Meeting. Chicago, IL: 2008.

50 BEYOND Study: IFN Beta-1b (250 mcg) vs Glatiramer Acetate Outcomes 250 mg IFN beta-1b arm vs glatiramer acetate arm Study designed to assess 500 mcg IFN beta-1b every other day vs 250 mg IFN beta-1b every other day vs 20 mg GA once daily After study s conclusion, research on 500 mcg dose halted No difference between standard-dose IFN beta-1b and standard-dose glatiramer acetate for/in: Relapse risk (primary endpoint) T1-hypointense lesion volume (secondary endpoint) Number of T1 gadolinium (Gd)-enhancing lesions Similar reduction in relapse rate for pre-study to study period: -78% for standard-dose IFN beta-1b, -79% for glatiramer acetate Significant differences between treatment groups for T2 burden of disease (BOD) Cumulative number of new T2 lesions: 4.8 for standard-dose IFN beta-1b vs 6.4 for glatiramer acetate (P=0.017) Change in T2-lesion volume: +9.9% for standard-dose IFN beta-1b vs +17.3% for glatiramer acetate (P<0.001) 001) No unexpected safety outcomes Comi G. The European Charcot Symposium. Fiuggi, Italy: 2007.

51 Summary of Direct Comparison Trials Two randomized head-to-head trials comparing different IFN beta products: Higher dose and more frequent administration are associated with better treatment outcomes Unclear if higher dose or frequency of administration is the key factor or if both are equally important Three randomized head-to-head trails comparing GA with IFN beta: None of the high-dose interferons studied were shown to work earlier or more effectively than GA on primary endpoints Goodin DS, et al. Neurology. 2002;58(2):

52 Suboptimal Responses With First-Line Treatments Assessing Therapeutic Response Courses of Action

53 Rationale for Defining the Suboptimal Responder Response to DMTs is highly variable DMTs may become ineffective as the disease progresses; why? MS is a heterogeneous disease with great variability in clinical presentation and underlying pathology One DMT might work while others may not Freedman MS, et al. Can J Neurol Sci. 2004;31(2):

54 Signs of Worsening MS Increasing disability without relapses Increasing relapses without return to baseline Decreased cognitive function Increasing MRI activity Increased use of MS-related medicines to control symptoms Decline in activities of daily living and quality of life

55 Determining Patient Responsiveness: Outcomes to Consider Clinical relapses Frequency/severity and extent of recovery Disease progression Expanded Disability Status Scale progression MRI activity Increased disease burden or activity Freedman MS, et al. Can J Neurol Sci. 2004;31(2):

56 Assessing Therapeutic Response Relapses Frequency, severity, and extent of recovery MRI Activity Degree of lesion burden and new disease activity Level of Disability Progression on the EDSS Quality of Life Activities of daily living

57 Determining Patient Responsiveness: Outcome Concern Levels Clinical i l relapses, disability progression, and MRI activity An MS patient would be a suboptimal responder if all 3 outcomes show low level of concern OR any 2 outcomes show medium level of concern OR a single outcome shows high level of concern Freedman MS, et al. Can J Neurol Sci. 2004;31(2): Bashir K, et al. Int J MS Care. 2002(suppl):1-7.

58 Relapse Assessment Concern Low Medium High Rate Severity Moderate reduction (>75%, <100%) vs baseline Modest reduction Minimal reduction (35%-75%) vs baseline (<35%) vs baseline Mild Corticosteroids t id Moderate Corticosteroids t id Severe Corticosteroids/ t id not required Minimal effect on ADL 1f functional required Moderate effect on ADL >1 functional domain hospitalization required Severe effect on ADL >1 functional domain domain affected No or mild motor/cerebellar involvement affected Moderate motor/cerebellar involvement affected Severe motor/ cerebellar involvement Recovery Prompt recovery Incomplete recovery at 3 months Incomplete recovery at 6 months ADL=activities of daily living Freedman MS, et al. Can J Neurol Sci. 2004;31(2): ; Bashir K, et al. Int J MS Care. 2002(suppl):1-7.

59 MRI Assessment Change in MRI Categories Low Medium New Gd-enhancing lesions New T2 lesions Enlarging T2 (burden of disease) New T1-hypointense lesions Enlarging T1-hypointense lesions Atrophy Any new lesion Increase in >2 MRI categories Freedman MS, et al. Can J Neurol Sci. 2004;31(2):

60 Disability Progression Assessment Concern Low Medium High EDSS 3.5 <2 points 2 points confirmed at 6 months EDSS 4-5 <1 point 1 point confirmed at 6 months EDSS point confirmed at 6 months >2 points confirmed at 6 months 2 points confirmed at 12 months >1 point confirmed at 6 months 1 point confirmed at 12 months >0.5 point confirmed at 6 months Clinically No motor, Some motor, Pronounced motor, documented minor sensory progression cerebellar, or cognitive; multiple domains affected cerebellar, or cognitive; multiple domains affected Freedman MS, et al. Can J Neurol Sci. 2004;31(2):

61 Therapeutic Approach to a Suboptimal Responder: Rationale of Options Increase dose of current DMT Lack of adequate controlled studies measuring benefit of increasing the dose of DMTs after worsening MS Switch to a different DMT agent Lack of adequate controlled studies measuring benefit of switching DMTs after worsening MS Mitoxantrone is the only FDA-approved drug for worsening MS Natalizumab is a second-line monotherapy to be considered for use when first-line response is inadequate Other agents include methotrexate, IV methylprednisolone, cyclophosphamide Cohen BA, et al. Neurology. 2004;63(12 suppl 6):S33-S40. Stuart WH, Vermersch P. Neurology. 2004;63(11 suppl 5):S28-S34.

62 Therapeutic Approach to a Suboptimal Responder: Rationale of Options, continued Initiate combination therapy Evidence suggests benefit with some drugs, such as mitoxantrone MS is a heterogeneous disease (patients respond in variable degrees to different therapies) Combination of agents may have a synergistic therapeutic effect Combination therapy has been used successfully in other chronic diseases Cohen BA, et al. Neurology. 2004;63(12 suppl 6):S33-S40. Stuart WH, Vermersch P. Neurology. 2004;63(11 suppl 5):S28-S34. Confavreux C. In Multiple Sclerosis Therapeutics. 2003:524. Weiner HL. Can J Neurol Sci. 1998;25(2): Jeffery D. Neurology. 2004;63(Suppl 6):S41-S46.

63 Therapeutic Approach to a Suboptimal Responder: Evaluate Need to Change Treatment Patient must be on therapy for a minimum time period (6 months) before concluding it is an inadequate response Comorbidities and alternate diagnoses must be taken into consideration as reason for inadequate response Contribution of side effects to apparent lack of response should be considered

64 Summary Suboptimal responders can be identified based on relapse outcomes, disability and progression outcomes, and MRI-related outcomes Identifying suboptimal responders is essential to modify and optimize i treatment t t in patients with progressive MS Most MS patients t will experience increased disease activity; DMTs will slow but not stop it

65 Active or Worsening Disease

66 Mitoxantrone in Worsening MS: Clinical and MRI Results Number of Relapses Gd-Enhancing Lesions Number of Relaps ses Placebo * Mitoxantrone 12 mg/m 2 Patie ents With Gd d+ Lesions (%) Placebo Mitoxantrone 12 mg/m Baseline Year 1 Year 2 0 *P<0.0002; P=0.02. Data from Hartung HP, et al. Lancet. 2002;360: Drugs at FDA:

67 Mitoxantrone in Clinical Trials (Summary) Improved clinical outcome based on 5 components: EDSS Ambulation index Number of treated relapses Time to first treated relapse Neurologic status Delayed time to first treated relapse Improved MRI measures of disease activity Adverse events observed Leukopenia, decreased d left ventricular ejection fraction (LVEF), therapy-related acute leukemia (TRAL), cardiac failure, leukemia Hartung HP, et al. Lancet. 2002;360(9350):

68 Natalizumab in RRMS: Clinical and MRI Results at 2 Years AFFIRM Trial Clinical Endpoints Natalizumab Placebo P Annualized relapse rate <0.001 Percent sustained increase in disability 17% 29% MRI Endpoints Natalizumab Placebo P New or newly enlarging g T2-hyperintense lesions proportion 43% 85% <0.001 Proportion Gd-enhancing lesions 3% 28% <0.001 SENTINEL Trial Clinical Endpoints Natalizumab + IFN beta-1a IM Placebo IFN beta-1a + IM P Annualized relapse rate <0.001 Percent sustained increase in disability 23% 29% MRI Endpoints Natalizumab + IFN beta-1a IM Placebo IFN beta-1a + IM P Proportion new or newly enlarging T2-hyperintense lesions 34% 69% <0.001 Proportion Gd-enhancing lesions 4% 25% <0.001 Tysabri [package insert]. Cambridge, Mass: Biogen Idec Inc.; and San Diego, Calif: Elan Pharmaceuticals, Inc.; 2006.

69 Clinical Trials in RRMS: Summary Treatment optimization Disease-modifying therapies offer effective intervention for patients with RRMS In the event of suboptimal response, improved outcomes may be achieved by using another drug or combining interventions Tailoring therapy for each patient is key to optimizing therapeutic outcomes in RRMS

70 Side Effects, Tolerability, and Safety y y of Disease-Modifying Therapies

71 Trade Name Reference Trade Name Avonex Betaseron Copaxone Novantrone Rebif Tysabri Generic Name Interferon beta-1a (IM formulation) Interferon beta-1b (SC formulation) Glatiramer acetate (subcutaneous formulation) Mitoxantrone (intravenous [IV] formulation) Interferon beta-1a (subcutaneous formulation) Natalizumab (intravenous formulation)

72 Safety and Tolerability of DMTs Available DMTs improve outcomes in patients with RRMS Most of these drugs are relatively safe and dtolerable, but all llhave AEs that t potentially interfere with adherence; some AEs may be life threatening Adherence to drug therapy balanced against AE risk is key to successful pharmacologic management of MS Poor adherence limits it efficacy of the DMT

73 Adverse Events Associated With DMTs Shortterm IFN Beta Glatiramer Mitoxantrone Natalizumab Acetate Injection site reactions, flu- like symptoms, hepatic injury, lymphopenia, depression Injection site reactions, vasodilation, tachycardia, chest pain, nausea, asthenia, anxiety, infection Fatigue, nausea, infection, cytopenia, hair thinning Fatigue, headache, arthralgia, depression Longterm Seizures, cardiomyopathy, thyroid disorders, anaphylaxis Leukemia, cardiotoxicity risk Risk of fatal PML (1 in 1000 patients), liver toxicity PML=progressive multifocal leukoencephalopathy McDonagh M, et al. Drug class review on disease-modifying drugs for multiple sclerosis

74 DMTs and Pregnancy Risks Treatment Pregnancy Effects on Pregnancy Category Interferon beta C Low birth weight, spontaneous abortions Glatiramer acetate B No adverse effects found, same as general population Natalizumab C Animal studies: anemias, endocrine abnormalities, spontaneous abortions Mitoxantrone D Birth defects A: No risk to fetus; B: No evidence of harm to animal fetuses, limited studies in pregnant women; C: Serious adverse effects in animal studies, no studies in pregnant women; D: Serious risk to fetus Betaseron [package insert]. Montville, NJ: Berlex Labs; Copaxone [package insert]. Kansas City, Mo: TEVA Betaseron [package insert]. Montville, NJ: Berlex Labs; Copaxone [package insert]. Kansas City, Mo: TEVA Neuroscience Inc; Avonex [package insert]. Cambridge, Mass: Biogen, Inc.; Rebif [package insert]. Rockland, Mass: Serono Inc, and New York, NY: Pfizer Inc; Novantrone [package insert]. Rockland, Mass: Serono, Inc.; Tysabri [package insert]. Cambridge, Mass: Biogen Idec Inc.; and San Diego, Calif: Elan Pharmaceuticals; 2006.

75 Antibody Formation and DMTs Reactive antibodies any antibody formed in response to the presence of the DMT agent Neutralizing antibodies (NAbs) antibodies that t block or neutralize the biological i l effects of the protein or polypeptide, potentially decreasing the therapeutic effects of these agents Binding antibodies (binding Ab or BAb) antibodies that simply bind to the drug with no subsequent effect on function

76 DMTs and Antibody Formation Type of Antibody Clinical Impact Reported Incidence IFN beta-1b SC neutralizing Decreased clinical effect Increased disease progression 12 28%-42% 1,2 IFN beta-1a IM neutralizing Decreased clinical effect 2%-22% 22% 3-5 Increased disease progression 12 IFN beta-1a SC neutralizing Decreased clinical effect Increased disease progression 12 Glatiramer acetate reactive/binding Impact not observed in 3 clinical trials Mitoxantrone not reported NA NA Natalizumab neutralizing Presence of NAb correlated with serum drug levels; persistent presence associated with drug effectiveness 13%-24% % of pts in clinical had IgG levels above baseline at 12 mos IgG=Immunoglobulin G 1. Lancet. 1998;352(9139): The IFNB MS Study Group. Neurology. 1993;43(4): Jacobs LD, et al. N Engl JMed Med. 2000;343(13): Jacobs LD, et al. Ann Neurol. 1996;39(3): Panitch H, et al. Neurology. 2002;59(10): PRISMS Study Group. Lancet. 1998;352(9139): SPECTRIMS Study Group. Neurology. 2001;56(11): Brenner T, et al. J Neuroimmunol. 2001;115(1-2): Teitelbaum D, et al. Mult Scler. 2003;9(6): Copaxone [package insert]. Kansas City, Mo: TEVA Neuroscience Inc; Tysabri [package insert]. Cambridge, Mass: Biogen Idec Inc.; and San Diego, Calif: Elan Pharmaceuticals; Namaka M, et al. Curr Med Res Opin. 2006;22(2): % 11

77 IFN Beta: Long-term Considerations Flu-like symptoms (fever, chills, headache, fatigue) Experienced by up to 75% of patients taking an IFN beta Usually diminish over time Injection-site it reaction Pain, erythema, swelling Exacerbation of dermatologic conditions: eczema, psoriasis Liver function and bone marrow abnormalities Depression Neutralizing antibodies Pregnancy Category C PRISMS Study Group. Lancet. 1998;352(9139): Neurology. 1995;45(7):

78 IFN Beta: Laboratory Testing and Monitoring Obtain baseline complete blood count and differential and liver function values before initiating therapy Monitor laboratory test t values at regular intervals after initiating therapy Every 6 to 12 weeks the first year Every 6 months the second year Annually Consider dose adjustment or discontinuation of treatment if abnormalities persist

79 IFN Beta: Flu-Like Symptoms Begin 3-6 hours after injection May last up to 24 hours or longer Management Injection at bedtime NSAIDs or acetaminophen as co-medications Dose titration Individualized Walther EU, Hohlfeld R. Neurology. 1999;53(8):

80 Glatiramer Acetate: Long-term Considerations Post-injection reaction Injection-site reaction Erythema, swelling Pain Itching Lipoatrophy Necrosis Fibrosis Rare allergic reactions Pregnancy category B Ziemssen T, el al. Drug Saf. 2001;24: Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2000.

81 Safety of Mitoxantrone: Cardiotoxicity and TRAL Cardiotoxicity 1 TRAL 2 Changes in EKG, asymptomatic in LVEF, or symptomatic CHF LVEF <50%: 17 of 779 patients with MS (2.18%) CHF: 2/1378 patients (<0.20%) Monitoring: 2D echocardiogram or MUGA at baseline and prior to each dose Cumulative dose: Not greater than 140 mg/m 2 Characterized by short latency, acute onset, cytogenic changes similar to de novo leukemia Usually responds to therapy Reported incidence: 5 of 2336 treated MS patients (0.21%) Risk likely not dose-related Monitoring: 3 WBC count prior to each dose and weeks post-infusion EKG=electrocardiogram; WBC=white blood cell; LVEF=left ventricular ejection fraction; CHF=congestive heart failure; MUGA=multiple-gated acquisition. TRAL=therapy-related acute leukemia 1. Ghalie RG, et al. Neurology. 2002;59(6): Gauthier SA, et al. Neurol Clin. 2005;23(1): Voltz R, et al. Mult Scler. 2004;10(4):

82 Natalizumab and PML PML is an opportunistic viral infection of the brain, potentially leading to death or severe disability Absolute risk for PML cannot be assessed with current data No prevention or treatment known Plasmapheresis Patients with immune system dysfunction should not receive natalizumab Patients must be registered in special prescribing program Only authorized prescribers, infusion centers, and pharmacies associated with infusion centers can distribute and administer the drug Patient enrollment approval required Patients must meet strict criteria Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc; South San Francisco, CA: Elan Pharmaceuticals, Inc; 2008.

83 Minimizing and Managing Site Reactions

84 Layers of the Skin Subcutaneous layer Subcutaneous Layer Deepest layer Connects dermis to underlying organs Composed of fibrous connective tissue and fat cells interlaced with blood vessels Function: insulation, storing lipids, cushioning, temperature t regulation

85 Reported SC Injection Site Reactions (ISRs) Interferons Transient pain or burning Erythema Inflammation Granulomas Swelling Abscess Skin necrosis Fibrosis Glatiramer Transient pain Erythema Swelling Pruritis Induration Lumping Fibrosis Panniculitis Lipoatrophy Granuloma: chronic inflammatory lesion on epidermis Fibrosis: proliferation of fibrous connective tissue scar tissue replacing normal tissue lost from injury or infection

86 Minimizing ISRs Warm DMT to room or body temperature Avoid expelling air bubble from syringe prior to injection Dry needle Prepare site Clean site with mild soap, rinse, and dry well before injecting Shower first Correct needle depth selection (autoinjector) Subcutaneous tissue, not dermis Vertical needle penetration Inject into healthy tissue Rotate sites If ISR occurs, avoid site until reaction has completely resolved

87 Managing g ISRs Painful injections/erythema/painful sites Warm compress before and after injection: seconds Limit use of ice to no more than 30 seconds Ice may constrict blood vessels and decrease absorption of drug Topical anesthetic 30 minutes before injection (site pain) Short-term use of topical anti-inflammatory creams (skin irritation) OTC vs Rx Non-steroidal anti-inflammatory drugs (oral) Avoid excessive sunlight/ultaviolet rays Skin toughens, dryness Avoid smoking: chronic nicotine use results in vasoconstriction

88 Managing g ISRs, continued For itching Topical antihistamines Systemic antihistamines Zyrtec: usually can reduce use in days For recurrent lumping Warm site before and after injection seconds Gentle massage of site immediately post injection Avoid excessive pressure (trauma) Necrosis: Tissue death Requires special attention for debridement Wound management support team Patient and family education Dermatology evaluation

89 Lipoatrophy p Defined as a breakdown and loss of subcutaneous fat Considered to occur most often with repeated SC injections at the same site leading to areas of inflammation Results in areas of skin depression

90 Lipoatrophy p Lipoatrophy occurs in patients treated with insulin, glatiramer acetate, and less often with SC IFN beta Reported more frequently in women Prevention requires meticulous skin care and surveilance Discontinue SC injections in areas of lipoatrophy If extensive, consider discontinuing medication to preserve injection sites Contributing factors Injecting same site frequently Injecting into areas of lumping Smoking Skin trauma: may induce macrophages, cytokines that enhance lypocytic catabolism, and inhibit lipogenesis Panniculitils

91 Lipoatrophy p With Glatiramer Acetate Skin depressions, cm in area and 1-2 cm deep Patient education on rotating injection site improves management Copaxone Medical Information, March 2003 Hwang 2001

92 Sustaining Adherence to Complex Protocols

93 Global Adherence Project: Reasons for Non-adherence Forgot to administer injection Duration of treatment Cost Complexity, duration of disease Devonshire V. The Global Adherence Project. Presented at: 22 nd ECTRIMS Congress; September 28, 2006; Madrid, Spain.

94 Promoting Adherence Clarify realistic expectations Advocate for the patient Assist with reimbursement Identify resources Involve family Educate about the critical role of adherence in outcomes Recognize and address barriers to adherence Consider ethnocultural barriers

95 Considerations for Adherence Medical Considerations Burden of disease Enhancing lesions Disease course Number of relapses Patient Considerations Lifestyle Expectations Capabilities Support system

96 Clinical Case: Mary A 43-year-old Caucasian woman with a 7-year history of MS. Treatment: self-injected interferon beta-1a SC weekly for 3 years but stopped when she moved to a different state. t She has not been on DMTs since 2001 and has not felt the need as she does not believe she has had any bad exacerbations. In the year prior to diagnosis and through the first 2 years following diagnosis, she had 4 exacerbations, including AON OD, weakness of the right leg, weakness of the right arm and leg, and weakness of both legs. Since 2001, she has had 2 untreated exacerbations by history. The first in 2003 was mild vertigo with diplopia that lasted about 2 weeks and disappeared. The second was in 2004 and involved a band-like sensation around her torso that t lasted about 3½ weeks and resolved. Over 7 years of having MS, she developed increased difficulty with walking, described as tripping over her right foot and diminished walking stamina that increases over the course of the day. She has bladder urgency and nocturia.

97 Mary, continued Overall, her general energy level has diminished. She is under a lot of stress as she just received a poor performance review and is worried she will lose her job. She thought she was doing a good job and is convinced the poor review is because her new boss does not like her. She presents to the MS clinic because her family insisted she see someone. MRI of her brain revealed 2 periventricular enhancing lesions and significant brain atrophy. The neurologist has suggested a course of mitoxantrone, but the patient feels it would not do any good and no one is listening to her problems. The nurse is asked to counsel the patient.

98 What is the nurse s assessment of Mary? a. Non-adherence to medications b. Lack of understanding of her disease c. Determination to work d. Cognitive impairment due to her MS

99 What would be the nurse s best approach for this patient? a. Present her with information about mitoxantrone b. Address her problems at work c. Encourage her to identify her priority for this visit d. Refer e her to a NMSS support group

100 Patient states she does not want to get worse and would like to resume self-injection rather than chemotherapy. What information from her history can support her decision? a. Her MS is worsening b. MRI still shows enhancing lesions c. She has requested this treatment d. b and c

101 The patient requests information about resources for her family so they can understand what is happening to her. What would be the best plan for this patient since she has had MS for a long time and the nurse is unsure of the family s understanding about her disease? a. Refer her to a support group b. Provide her with information about MS to bring home c. Suggest some Internet resources d. Plan a family meeting to discuss their concerns

102 The patient begins injectable therapy and one month later calls you complaining about vision loss in her right eye. She is seen by an ophthalmologist and is diagnosed with optic neuritis. Intravenous steroids are prescribed for 5 days, and her vision returns to about 80%. The patient calls crying that the injectable treatment is not working and her MS is getting worse. She is very frightened. What can the nurse do to help her stay on therapy? a. Refer her to the long-term data published about her treatment b. Tell her to seek counseling for her anxiety c. Facilitate the initiation of an antidepressant medication d. Have her return for follow-up education

103 Two weeks later, the patient calls with another attack. Her symptoms consisted of weakness in her right leg, tremor in her right hand, and blurring of vision. The nurse asks about other symptoms, including urination, and she reports that she is going more frequently and her urine is darker than usual. What can the nurse do to help? a. Send her to her primary care physician b. Fax a prescription for urinary analysis and culture and sensitivities to a laboratory c. Talk to the neurologist about a course of oral steroids d. Bring her to the office for a neurologic examination

104 The patient has been feeling well during the past 2 months and returns for a follow-up visit. She reports that she is selfinjecting regularly but would really like to decrease injection frequency since that routine is interfering with her normal routine. What strategies can sustain adherence in this patient? a. Provide her with information from the clinical trial b. Have her speak to another person on this therapy c. Ask her to clarify her expectations from treatment d. Ask the neurologist to discuss this with her during the visit

105 Mary Conclusions Because multiple sclerosis is a disease with no cure, the availability of disease-modifying dif i therapies has raised the hopes and expectations of people with MS. These may be unrealistic and should be clarified in a supportive, educative fashion by the health care team. Fostering the nurse-patient relationship has provided the patient with a stable base of support and has resulted in a collaborative relationship with her neurologist and MS team. It is important for the nurse to recognize factors, such as infection and other environmental issues, that cause increased MS symptoms and functional change and either address them appropriately or provide that patient with resources and support. Educating the patient involves discussing what MS is, how we can help, and what symptoms may or may not persist during a lifetime with the disease.

106 References Halper J, Holland NJ. Comprehensive Nursing Care in Multiple Sclerosis. New York: Demos Medical Publishing; Becker MH. The health belief model and personal health behavior. Health Education Monographs.1974;2: Medical Advisory Board of the National MS Society. Expert opinion paper: disease management consensus statement: April 10, 2009.