Switching Therapy in Multiple Sclerosis:

Switching Therapy in Multiple Sclerosis: Evidence & Challenges

2016Presenter: Dr Divya Moderator: Prof R Bhatia

Table of contentsCase ScenarioMeasures of disease activity and progression When to switch therapy?What are the options?Evidence and challenges Take home message

PATIENT PRESENTATION

37 YEAR OLD HOUSE WIFE , Mrs S D

Patient Presentation (cont)

Mrs S DMrs S DWhat will be the next step?? Switch to a DMT ?? Which one?? What is the evidence ??

DMT

Changing the course of multiple sclerosis: the need for earlytreatment optimizationT. Ziemssen et al. / Multiple Sclerosis and Related Disorders 4 (2015) 460469

clinical course of MS consists of twomajor phases: one early, inammatory phase and one later, progressive,inammatory-independent phase. The widely used rst-line therapies beta-interferon (IFN ) andglatiramer acetate (GA) have only demonstrated partial efcacy inthe treatment of MS . Considering theearly window of opportunity to inuence the accumulation of ir-reversible long-term damage (Leray et al., 2010; Freedman, 2011),early switching to a high-efcacy therapy that targets both focaland diffuse pathology may impact favorably on long-term outcomes(Bermel et al., 2013; Ro et al., 2009). 5

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Criteria that should be considered for the evaluation of clinically relevant and measurable NEDA in patients with relapsing remitting MS that should be considered for treatment adjustment (modified from Gold et al. [2012])Relapse activityThe occurrence of one of the following events during therapy should in most cases result in a therapeutic change: 1 relapse with incomplete remission 1 severe relapse with necessity of escalating acute therapy [ultra high steroid treatment (i.e. 2 g/day for 5 days) or plasma exchange] 2 clinically objectified relapses without residual symptoms in 1 year whenever possible, with evidence of a correspondingly localized lesion in the MRI

M Stangel, IK Penner et alTherapeutic Advances in Neurological Disorders 8(1). Disability progressionDepending on the individual patient situation, even slight impairments represent a significant impairment in the working ability and quality of lifeThe EDSS value should categorically be kept under 3 for as long as possibleHowever, the EDSS is not sensitive enough particularly in its lower rangesFatigue and cognitive parameters are not considered enough in the EDSSMRI parametersThe decision on treatment change should not be based solely on MRI findingsThe detection of multiple new or enlarged T2 lesions or gadolineum-enhancing inflammatory lesions can, however, serve as an additional criterion

thereis no clear definition of treatment failure and nostandardized method of how to follow patientswith MS in order to detect clinical worsening anddisease activity in everyday practice. Although thecrude definition of NEDA including relapse,EDSS, and MRI parameter represents a goodstarting point, this does not completely reflect theneed in clinical practice. In particular, in the lowEDSS ranges, slight clinical worsening and neuropsychologicalaspects are not taken into consideration. Neuropsychologicalaspects as well as individual working ability andquality of life should also be included. A switchshould be performed in due time in any case,particularly in order to extend the time in thelower EDSS range (up to 3), since progressionmay be more difficult to stop thereafter

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The multi factorial model: the domains of disease activity and their rating to assess disease progression (MSDM points)

Theinterpretation of the total MSDM score may help in decision making for the optimization of immunomodulatory treatments13

Debras Risk Factors

RISK FACTORS & CLINICAL COURSE IN OUR PATIENT

Debras 2009 FLAIR MRI

2009

2010

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Rationale for Switching

MS involves diverse damage mechanismsMS is heterogenousNo DMT cures MSVariability in how well a treatment is toleratedMS generally results in disabilityDMT efficacy may differ

Switching to a theoretically more effective agent is logical for breakthrough disease activity

Data are limited because there have been so few randomized prospective head-to-head trials

General indications for changing therapy

When to SwitchIntolerable side effectsCategoryExamplesAdverse reactionsInjection site reaction, infusion reaction, infectionsPersistent symptomsFlu-like symptoms, headache, nauseaSignificant and persistent laboratory abnormalityIncreased liver enzymes, low WBCDetection of antibodiesJC virus antibody positivityPertinent for natalizumab usePersistent neutralizing antibodiesPertinent for natalizumab and IFN (high titer antibodies)Unacceptable breakthrough activityClinical activityRelapses, disability, cognitive status, transition to progressive diseaseNeuroimaging activityBrain MRI, spinal cord MRI abnormalities

CNS DrugsApril 2013,Volume 27,Issue 4,pp 239-247

SUMMARY OF MS THERAPY

Unapproved: off-labelAzathioprine (purine antimetabolite)ImuranPODailyCladribine (purine antimetabolite)Cladribine, Leustatin (IV)SC, IVEpisodicCyclophosphamide (alkylating agent)Cytoxan, CyreviaIVEpisodic; single high dose course over four daysMethotrexate (antifolate antimetabolite)Rheumatrex, TrexallPO, intrathecal, IVWeekly (PO), episodicMycophenolate (purine antimetabolite)Cellcept, MyforticPODailyGlucocorticoidsPrednisone/Deltasone, Methylprednisolone/Solumedrol, Dexamethasone/DecadronIV or POEpisodic

CNS DrugsApril 2013,Volume 27,Issue 4,pp 239-247Intravenous immunoglobulinGammagard, Gamunex, Privigen, Octagam, Carimune, Gamaplex, Flebogamma, HizentraIV or SCEpisodicPlasma exchange/plasmapheresisPlasma exchange/plasmapheresisIVEpisodicAnti-CD20 monoclonalRituximab/Rituxan (chimeric), Ofatumumab/Arzerra (human)IVEpisodicAnti-CD25 monoclonalDaclizumab/ZenapaxIV or SCEpisodicAnti-CD52 monoclonalcAlemtuzumab/Lemtrada, CampathIVAnnuallyAnti-CD20 monoclonalOcrelizumab (humanized)IVEpisodicLaquinimod (quinoline 3-carboximide)LaquinimodPODaily

FINGODMFNZAZMITO

TREATMENT LADDER

RECOMMENDATIONS FOR PATIENTS WITH SUBOPTIMAL THERAPEUTIC RESPONSES

Increasing the Frequency of IFN-beta TherapySwitching From IFN to GA in Patients With Suboptimal ResponseSwitching From IFN or GA to Natalizumab TherapySwitching From IFN or GA to Chemotherapeutic AgentsOral Fingolimod/ BG12Combination therapy

Randomized, controlled, multicenter trialCompared the efficacy and safety of IFNbeta-1a (Rebif) 44 mcg s/c thrice weekly & IFNbeta-1a (Avonex) 30 mcg IM once weekly 677 patients with RRMS, at least 2 exacerbations of MS in the prior 2 years, and EDSS scores of 05.5The primary endpoint: The proportion of patients who were relapse free at 24 weeksMRI endpoint: Number of active lesions per patient per scan at 24 weeks74.9% (254/339) of patients receiving IFNbeta-1a 44 mcg tiw remained relapse free compared with 63.3% (214/338) of those given 30 mcg qwNeurology.2002 Nov 26;59(10):1496-506 Increasing the Frequency of IFN-beta TherapyRandomized, comparative study of interferon -1a treatment regimens in MS: The EVIDENCE Trial

Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage23

Randomized, comparative study of interferon -1a treatment regimens in MS: The EVIDENCE Trial

The odds ratio for remaining relapse free: 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeksPatients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks)at 48 weeksNeutralizing antibodies: 25% of 44 mcg tiw p and 2% of patients receiving 30 mcg qwIFNbeta-1a 44 mcg s/c tiw was more effective than IFNbeta-1a 30 mcg IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatmentNeurology.2002 Nov 26;59(10):1496-506

. However, the difference was primarily seen for the first 24 weeks, whereas during the subsequent 24 weeks, the relapse rate was similar for the 2 groups, suggesting a possible faster clinical induction of IFN activity with the higher frequency dosing during the initial 24-week period. Similarly, the disability measures were not different at the end of the 1-year study period

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Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicenter study (INCOMIN)

2-year, prospective, randomised, multicentre studyCompared the clinical & MRI benefits of on-alternate-day IFN beta-1b 250 mcg with once-weekly interferon beta-1a 30 mcg 188 patients with relapsing-remitting MSIFN beta-1b (n=96), IFN beta-1a (n=92)Primary outcome measures: Proportion of patients free from relapses & Patients free from new proton density/T2 lesions at MRI assessmentLancet.2002 Apr 27;359(9316):1453-6049 (51%) of IFN beta-1b remained relapse-free compared with 33 (36%) given IFN beta-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03)42 (55%) compared with 19 (26%)remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; 0.45-0.8; por= 2 yearsOutcomes at 1 and 2 years : Change from baseline EDSS score, percentage of progression-free patients (< 1.0 EDSS point), annualized relapse rate (RR), percentage of relapse-free patients, and reasons for therapy changeQuality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosisJ Neurol.2007 Jan;254(1):67-77. Epub 2007 Feb 1. Of 4754 patients, 3991 (84%) received IFN-beta as initial therapyNo significant differences among IFN-beta products when used as initial or follow-up therapy on almost all outcome variablesRelapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapyThese results call into question the benefit of switching between IFN-beta preparations/dosing regimens

Switching From IFN to GA in Patients With Suboptimal ResponsePopulation: 85 consecutive RRMS patients who received weekly IFN beta-1a 6 MU i.m. for at least 18 monthsBaseline ARR for the 2 years prior to initiating therapy with IFN beta-1a was obtained from chartsTreatment duration 18 to 24 months (mean 19.7 months)Treatment with IFN beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005)All 85 patients were then switched to glatiramer acetate (GA) 20 mg s.c. daily

Clinical course after change of immuno modulating therapy in relapsing-remitting multiple sclerosisEur J Neurol. 2006; 13(5):471-4(ISSN: 1351-5101)Prospectively followed up for 36-42 months (mean 37.5 months)Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001) In patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001)In patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN beta-1a to 0.47 on GA (P, non-significant) Clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice

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Efficacy of treatment of MS with IFN-1b or glatiramer acetate by monthly brain MRI in the BECOME studyObjective: To compare the efficacy of IFN-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI75 patients with relapsing-remitting MS or clinically isolated syndromesRandomization to standard doses of IFN-1b or GA and followed by monthly brain MRI for up to 2 yearsPrimary outcome: Number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/FLAIR lesionsD. Cadavid, MD et al. NEUROLOGY APRIL 2009Secondary outcomes : Number of new lesions and clinical exacerbations over 2 yearsThe primary outcome showed similar median (75th percentile) CAL per patient per scan for months 112, 0.63 (2.76) for IFN- 1b, and 0.58 (2.45) for GA (p 0.58)

There were no differences in new lesion or clinical relapses for 2 yearsConclusion: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity

There are no published MRI studies comparing interferon beta 1b (IFN-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). Recent MRI data have suggested that GA and IFN-beta have a similar impact on contrast-enhancing lesion activity after 1 year of therapy.[35]The Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) is the first head-to-head, randomized, prospective study comparing IFN-beta-1b and GA by MRI parameters in relapsing MS.

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Switching From IFN or GA to Natalizumab Therapy

942 patientsRandomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two yearsThe primary end points: Rate of clinical relapse at one year and the rate of sustained progression of disability (EDSS) at 2 yearsNatalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent CI, 0.43 to 0.77; P