Treatment Optimization in MS: When to Start, When to Shift, when to Stop

Treatment Optimization in MS: When to Start, When to Shift, when to Stop Mark S. Freedman MSc MD FAAN FANA FRCPC Director, Multiple Sclerosis Research Unit University of Ottawa Sr. Scientist, Ottawa Hospital Research Institute Ottawa, Ontario CANADA

Disclosures 1. Receipt of research or educational grants: BayerHealthcare; Genzyme 2. Receipt of honoraria or consultation fees: BayerHealthcare, BiogenIdec, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, Teva Canada Innovation 3. Member of a company advisory board, board of directors or other similar group: BayerHealthcare, BiogenIdec, Hoffman La- Roche, Merck Serono, Novartis, Opexa, Sanofi- Aventis, 4. Participation in a company sponsored speaker s bureau: Genzyme

Disease parameter RIS MS: Pathological vs. Clinical Course of Disease New Diagnostic Criteria Have Changed the Definition of CIS CIS Relapsing Remitting Transitional Secondary Progressive First Clinical Attack Treatment depends on Are you dealing with new WHERE Or disease old (silent) in the disease window you presenting early? think presenting the patient late? is when Axonal Loss Time Window for you are initiating treatment 12,000 11,236 Early Treatment Clinical Threshold 10,000 8,000 6,000 4,000 3,138 Demyelination 2,000 0 Active Chronic active edge 875 Chronic active core 17 0.7 NAWM Control white Inflammation Time (Years)

Disability Early Treatment & Optimization Maximizes Long-Term Benefit Optimal Window of Opportunity Later treatment Earlier treatment Symptom Onset Time Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.

Goals of Therapy in MS Have Evolved Along with Treatment Options Address Symptoms Slow Disease Progression Stop Disease Progression Repair Establishment of Disability Outcome Measures EDSS 1 1983 MSFC 2 1995 Disease Activity Free 3 2009 Sustained EDSS improvement 4 2011 1983 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 IFNβ-1b 1993 IM IFNβ-1a 1996 SC IFNβ-1a 1998 Mitoxantrone 2000 GA 1997 Introduction of RRMS Therapies Natalizumab 2004/2006 Fingolimod 2010 BG12 Teriflunomide 2012? Alemtuzumab 2013 1. Kurtzke J. Neurology. 1983;33:1444-1452; 2. Whitaker J et al. Mult Scler. 1995;1:37-47; 3. Havrdová E et al. Lancet Neurol. 2009;8:254-260; 4. Phillips J et al. Mult Scler. 2011;17:970-

Key Decision Points in the Treatment of MS Are Also Evolving as Goals Change Initiating therapy When to start Choice of 1 st - line therapy Induction vs. escalation Stopping therapy Deciding point of futility Disease progression Switching therapy Tolerability Safety Relapse/Progression/MRI

Initiating Treatment What are the factors that should be considered before starting treatment?

What is the Time Course for Disease Progression for the Patient? Escalation? Induction? DISEASE PROGRESSION

Prognostic Features in Early MS Better prognosis Caucasian Monofocal onset Onset with optic neuritis or isolated sensory symptoms Low relapse rate first 2 5 years Long interval to second relapse No or low disability at 5 years Abnormal MRI Low lesion load Poorer prognosis Afro-American or non-white Multifocal onset Onset with motor, cerebellar, or bladder/bowel symptoms High relapse rate first 2 5 years Short inter-attack latency Disability at 5 years Abnormal MRI 2 contrast lesions 9 T 2 lesions Miller DH, et al. J Manag Care Pharm 2004;10:S4 S11; Kantarci O, et al. Prognostic Factors in Multiple Sclerosis. In: Handbook of Multiple Sclerosis (3rd ed). Cook SD, editor. New York: Marcel Dekker. 2001. pp 449 463.

Induction vs. Escalation Choice Depends on Disease Perception The level of disease at any point in time will dictate the need for an aggressive approach Consider the window position LOW risk: Escalation Perception is that patient is at a level of disease where it is reasonable to start with agents considered 1 st line Safety first HIGH risk: Induction Perception is that patient is already at an advancing stage requiring rapid and definitive control Efficacy first

What is the Risk of a Patient for Imminent Disease Progression? What is the impression of the patient s disease to date? Mild, early, typical Moderate or severe accumulated deficits, later disease, more aggressive than normal How fast do we want a given treatment to work? What other factors (e.g. pregnancy, adherence, moving) should be considered?

Initiating Treatment : Early (Low Risk) Window All agents are highly effective in the early phase where all were tested IFNb, GA, teriflunomide, BG-12, fingolimod* are considerations Safety important if no obvious difference among agents Adherence important given that therapy will be maintained for many years Early detection of sub-optimal response is key as the early years are prognostic *not available 1 st line in many countries

Initiating Therapy: Late (High Risk) Window Natalizumab or Fingolimod currently considered for 2 nd line use due to greater toxicity yet perception of greater efficacy Induction with Alemtuzumab Toxicity risk early or late, possibly prolonged Immunosuppression Mitoxantrone, cyclophosphamide Dose limitation due to accumulated toxicities Cladribine BMT

De-Escalating Therapy: Late (High Risk) Window Can induction therapy establish a long lasting response that might be sustained using a safer 1 st line treatment? How much exposure time is needed for the induction treatment? Most trials are only 2 years long May be dictated by risk of toxicity from prolonged exposure (e.g. 2 years of Natalizumab) Will rebound be a problem? Natalizumab, fingolimod

Initiating Therapy: Sequence May Matter Will the choice of 1 st therapy affect choices down the road? Will safety be an issue depending on the choice of treatment? Can an immunosuppressant be followed safely by natalizumab? Will response be an issue? If one starts with cladribine, could one follow with GA and expect as good a response?

Treatment Initiation (High Risk) Induction Start with a 2 nd or higher line agent Obtain a treatment response for a given period of time Revert back to a 1 st line treatment to maintain efficacy and minimize toxicity or Maintain or escalate further as necessary Escalation VS. Start with a 1 st line agent Monitor treatment response If sub-optimal response, move to a 2 nd line agent Monitor treatment response Consider de-escalation If sub-optimal response, move to another 2 nd line or escalate to a 3 rd line or higher agent

Defining Response to Treatment In the absence of a cure, how do you define a suboptimal response to treatment?

Establish Monitoring Approach Approach needs to be reasonable & feasible Call-in instructions regarding tolerability or indication of new attacks Clinic visits 3-4x/year for 1 st year Baseline & 1 year MRI with Gadolinium Baseline study should be performed when patient is stable and enough time has elapsed to expect that treatment is effective Pre-conceived plan B for unacceptable breakthrough disease or a deemed suboptimal response to therapy

What to Follow? Adherence is the drug tolerated? Managing side effects Laboratory monitoring Disease activity Relapse: Quality, quantity, recovery Progression EDSS, MSFC, cognition MRI

Determining the level of concern to consider treatment modification based on relapse outcomes Low Medium High Rate 1 attack in 2 nd yr Tx 1 attack in 1 st yr Tx > 1 attack in 1 st year of Tx Severity Mild Moderate Severe No Steroids Steroids required Steroids/hospital Min effect on ADL Mod effect on ADL Severe effect on ADL 1 FS involved >1 FS involved >1 FS involved No motor/cerebellar involvement Moderate motor/cerebellar involvement Severe motor/cerebellar involvement Recovery Prompt Incomplete at 3 mths Incomplete at 6 mths Note: 1. It is best to examine patients with more severe attacks 2. Recovery requires a re-examination at specific timepoints 3. Cognitive only attacks are hard to objectively define FS, functional system; ADL, activities of daily living; mths, months Freedman MS, et al. Can J Neurol Sci 2013

Determining the level of concern to consider treatment modification based on progression outcomes Baseline EDSS Low Medium High 3.5 <2 points 2 points confirmed at 3 mths >2 points confirmed at 6 mths 2 points confirmed at 1 year 4 5 <1 point 1 point confirmed at 6 mths 5.5 0.5 points confirmed at 6 mths Clinically documented progression No motor Minor sensory T25FW* 20% confirmed 6 mths *T25FW tested at baseline with aid if required Some motor, cerebellar or cognitive Multiple domains affected > 20% and < 100% increase confirmed 6 mths >1 point confirmed at 6 mths 1 point confirmed at 1 year >0.5 points confirmed at 6 mths Pronounced motor, cerebellar, or cognitive Multiple domains affected 100% increase confirmed 6 mths Freedman MS, et al. Can J Neurol Sci 2013

Determining the level of concern to consider treatment modification based on MRI outcomes Change in MRI Categories Low Medium High Gd-enhancing lesions 1 lesion 2 lesions 3 lesions New T2 lesions (per year)* 1 lesion 2 lesions 3 lesions *There must be confidence that lesions are truly new compared to previous scans Note: 1. Routine follow-up MRI is recommended 6-12 months after initiating therapy (or in CIS if therapy is not initiated) 2. New T2 lesions that are also enhancing on the same scan are only counted once as unique active lesions Baseline study should be performed when patient is stable and enough time has elapsed to expect that treatment is effective Freedman MS, et al. Can J Neurol Sci 2013

The Canadian Treatment Optimization Model Assessing concern whether to modify a treatment regimen Relapse Progression Each gauge represents a continuum from 0 no concern Low concern Medium concern High concern MRI Freedman MS, et al. Can J Neurol Sci 2013

The Canadian Treatment Optimization Model Assessing concern whether to modify a treatment regimen Each gauge represents a continuum from 0 no concern Low concern Medium concern High concern Relapse Progression Sub-optimal response Consider treatment change if: 3 X low low low 2 X med med 1 X high MRI Freedman MS, et al. Can J Neurol Sci 2013

The Modified Rio Score Identifying Poor Response to Therapy Patients are categorized by risk of progression based on outcomes after 1 year of treatment Higher score predicts greater risk of progression in 2 nd or later years if same treatment is maintained Score Criteria 0 5 new T2 lesions and 0 relapses 1 5 new T2 lesions and 1 relapse, or >5 new T2 lesions and 0 relapses 2 5 new T2 lesions and 2 relapses, or >5 new T2 lesions and 1 relapse 3 >5 new T2 lesions and 2 relapses Sormani MP et al. Mult Scler 2013; 19: 605-12

Disease Breakthrough or Sub-Optimal Response to Treatment How to define it, but more importantly, how to deal with it

Therapeutic Choices Landscape is changing rapidly but class of agent is determined by the benefit : risk profile 1 st line agents (usually for low risk patients): proven efficacy - very low long-term risks IFNb, GA (long-term risks known) Teriflunomide, BG-12 (long-term risks unknown) 2 nd line agents: Proven efficacy & known but possibly manageable risks, however long-term risks known or unknown Natalizumab, Fingolimod Consider also the risk of discontinuation (i.e. rebound) Alemtuzumab, cladribine, mitoxantrone

Managing Breakthrough Disease: Lateral vs. Escalation Approach Lateral switch Perception is that patient is still at a low risk of disease progression Another trial of a 1 st line agent may be warranted Escalation to higher line agent Temporary switch: (risk of progression medium) Period of exposure (e.g. 1-2 years) followed by a return to a 1 st line agent in order to minimize toxicity Permanent switch: (risk of progression high) Disease level warrants a switch to 2 nd line agent that needs to be maintained

Patient Experiencing a Sub-optimal Treatment Response 1 st line treatment IFN, GA (teriflunomide, BG12) Perceived level of disease LOW HIGH Switch Therapy Another 1 st line 2 nd line agent Fingolimod, NZ Type of escalation Temporary Permanent Monitor Tx Response 1 year Switch Therapy Monitor Tx Response 1 year Switch Therapy Further Sub-Optimal Tx Response 3 rd line agent Mx or Alemtuzumab or Cladribine (sc, iv) both temporary with exposure dictated by dose Further Sub-Optimal Tx Response 4 th line agent

Stopping DMD Therapy No randomized trials to consider when it might be safe to permanently stop treating disease But many have shown resurgence of disease after a period of < 2 years Evolution to SPMS without ongoing relapses or MRI activity? EDSS milestone (e.g. EDSS 6.5)? Long periods of stability (?5 years+) with no perceived disease activity? Severe cognitive decline

Personalizing Treatment for MS Start early with the most effective treatment appropriate to the window of presentation Future biomarkers may allow for more precise personalized DMD selection Consider more aggressive starting therapy for patients with either silent advanced disease or early signs of poor prognosis Have a plan to determine sub-optimal responders after a reasonable time on first therapy and an approach to switching or escalating therapy

The Future of MS Therapy