13 September 2016 - London, UK

MS Academia: advanced course

IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION www.excemed.org Mark S. Freedman, HBSc, MSc, MD, CSPQ, FANA, FAAN, FRCPC Multiple Sclerosis Research Unit The Ottawa Hospital Ottawa, Canada Disclosure Declared the receipt of honoraria or consultation fees from: Actelion, BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi- Aventis, Teva Canada Innovation. He declared to be member of a company advisory board, board of directors or other similar group: Actelion, BayerHealthcare, BiogenIdec, Hoffman La-Roche, Merck Serono, Novartis, Opexa, Sanofi-Aventis and the participation in a company sponsored speaker’s bureau:Genzyme. Mark S. Freedman

Efficacy and safety of immunomodulators in RR MS

IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION www.excemed.org Existing & Emerging MS therapies

Other Phase I Lymphocyte CS-0777 BIIB033 trafficking Phase II Idebenone Phase III Firategrast Interferons ONO-4641 ELND-002 Marketed Siponimod Ponesimod AZD5904 Peg IFNb 1a IFNb-1b Fingolimod GRC4039 IFNb-1a im Natlizumab IFNb-1a sc CCX-140 Laquinimod Azathioprine Immune Novantrone BG12 AIN457 Teriflunomide GA regulation Antiproliferative agents THC:CBD NI-0801 Cladribine GA generics x2 4-AP Pixantrone GA 40 tiw IPX-056 Alemtuzumab RPI-78M ATX-MS-1467 Ofatumumab Nerispirdine PI2301 LY-2127399 Vaccine, RTL1000 Symptomatic Tx tolerization = Oral administration Cytolytic mAbs = Injectable mAb, ; Tx, treatment Evolving Treatment Landscape in MS

RRMS Progressive MS (SPMS/PPMS) Generic/Biosimilar RRMS mAb

Firategrast Fingolimod MD1003 Orals Teriflunomide Next Gen Fingolimod Laquinimod S1pRA Dimethyl Next Gen Fumarate Masitinib Siponimod Fumarates

Approved 2013 2014 2015 2016 2017 2018+ 1st Line GA GA 3TW Tcelna Injectables Is there still aPeg IFNroleb1a for the IFNb1a Biosimilar IFNb1b Interferon-b injectablesGeneric GA? ? Mitoxantrone

Natalizumab Alemtuzumab Daclizumab Ocrelizumab Ofatumumab mAbs Secukinumab

Anti-LINGO1 Remyelination rHIgM22 GSK239512 Tiers of Treatment

First line IFNβ-1a, IFNβ-1b, GA, teriflunomide, DMF Second line Fingolimod, natalizumab, alemtuzumab, daclizumab Third line Alemtuzumab, mitoxantrone, cladribine (IV), cyclophosphamide Experimental/ Ocrelizumab, (rituximab), ofatumumab, unproven bone marrow transplant therapies The “Lure” of Oral Therapies

 Convenience  Ease of use  Adherence

But…..

 New concerns re: side effects – First pass effects  Long term safety unknown  Compatibility with other meds for other conditions

Comparing New to Old

 How do the new agents compare to the older ones in terms of efficacy? – In the absence of “head to head” studies is there any way to assess benefit? – As placebo groups today do better than treated groups from previous years, how do we compare “relative” efficacies? • NNT increases with lowered event risk – Is a 50% reduction in annualized relapse rate from 1 to 0.5 mean the same as from .3 to .15? – NNT would suggest not as NNT goes from 2 to 7.  How do we factor in novel and different risks? Treatment Outcomes for RRMS Trials

 All agents licensed based on primary outcome of reducing relapses  Secondary outcomes almost always included effect on EDSS progression and reducing MRI activity  It is NOT possible to compare the outcomes across clinical trials owing to many differing factors: – Trial design (frequency of imaging, definitions) – Analysis of outcomes (3 vs. 6 month confirmed EDSS progression; MRI activity) – Behaviour of placebo group comparator

Differences in Randomized Placebo Controlled Pivotal Trials over the Years

IFN ß-1a Glatiramer IFN ß-1a Study (IFN ß-1b1 Natalizumab5 Fingolimod6 Cladribine7 30mcg im qw2 Acetate3 44mcg sc tiw4

Date 1988-1993 1990-1993 1991-1994 1994-1997 2001-2004 2006-2009 2005-2007

372 301 251 560 942 1272 1326 N 3 arms 2 arms 2 arms 2 arms 2 arms 3 arms 3 arms

Relapse (yr1) PEP Relapse Disability Relapse Relapse Relapse Relapse Disability (yr2)

Placebo ARR 1.27 0.82 0.91 1.28 0.73 0.4 0.33

Relapse 24h 48h? 48h 24h 24h 24h 24h definition

EDSS range 0 – 5.5 1 – 3.5 0 – 5 0 - 5 0 - 5 0 – 5.5 0 – 5.5

EDSS 2.9 2.3 2.6 2.5 2.3 2.6 2.9

Revised 2005 Diagnosis Poser Poser Poser Poser McDonald McDonald McDonald

1) IFNb MSSG. Neurology. 1993;43(4):655-61. 2) Jacobs LD, et a. Ann Neurol. 1996;39(3):285-94. 3) Johnson KP, et al. Neurology. 1995;45(7):1268- 76. 4) PRISMS Study Group. Lancet. 1998;352(9139):1498-504. 5) Polman CH, et al. N Engl J Med. 2006;354(9):899-910. 6) Kappos L, et al. N Engl J Med. 2010;362(5):387-401. 7) Giovanonni G, et al. N Engl J Med. 2010;362(5):416-26. ARR – Placebo Rates Reduce Over Time

1992-2002 2003-2011

1.5

1 ARR

0.5

0

Slide courtesy of Dr. Ron Milo, M.D. Comparison of Main Outcome Measures in Established Treatments

IFNb-1b 250mg IFNb-1a 30mg im IFNb1a 44mg sc Glatiramer Acetate Study Agent sc eod1 qw2 tiw3 20mg sc od4

ARRR 34% 18% 32% 29%

Absolute RRR 0.43 0.15 0.41 0.4

Relative Reduction in new T2 & Gd+ MRI 83% 52% 78% 30% Activity

Relative Reduction in EDSS 29%* 37% 30% 12%* Progression

Absolute Reduction in Proportion 8%* 13% 11% 3%* Progressing

*p= ns 1IFNB Study Group Neurol 1993; 43(4):655–61; 2Jacobs et al Ann Neurol 1996;39(3):285–9; 3PRISMS Study Group Lancet 1998;352(9139):1498–504; 4Johnson et al Neurology 1995;45(7):1268–76 Comparison of Main Outcome Measures in More Recent Treatments

Dimethyl Study Agent Natalizumab Fingolimod Teriflunomide Fumarate

ARRR 68% 54% 31% 53%

Absolute RRR 0.5 0.22 0.17 0.19

Relative Reduction in 83% 74% 85%* 67% new T2 & Gd+ 92% 82% 90%* MRI Activity Relative Reduction in 42% 30% 30% 38% EDSS Progression Absolute Reduction in 12% 6.4% 7.1% 11% Proportion Progressing *MRI studies performed on 43% of patients Interferon-b IFNb-1b sc IFNb-1a sc, IM Potential IFN-b action sites in MS BDNF NGF

FcR CD8 gdT Ab+C9neo CTL Oligo NO Pl CD8 Oi TNFa CTL CD8 MMP Reg Oi EBV Glutamate IFNg B TNF Tr1 IL-10 Th2 Neut TGFb Th3 B7 CD28 MCP-1 IL-17 Th1 MIP-1a IP-10 RANTES Th17 Treg CD40 CD40L Foxp3 Astrocyte BBB

IL-17 ICAM-1 VCAM-1 IL-23 Treg MMP-2/9 Foxp3 IFN IL-4 Tr1 Th17 g IL-5 Th2 LFA-1 IL-10 Th17 IL-6 VLA-4 TNF B Th3 CD8p Th1 IL-13 TGFb IL-6 & TGFß Treg BAFF APRIL IL-4 & IL-10 Foxp3 B7 CD28 TGFß TACI IL-12 B7 CD28 APC CD4 CD4+CD25+ CD4 HLA APC APC CD4 Thp TCR Myelin Ag Thp CD40 CD40L Thp Courtesy of S. Dhib-Jalbut Microbial Ag CD40 CD40L Change in Efficacy Responses over time in IFN-b 1a im MS trials

0,8 0,67 0,64 0,6

0,4 0,33 0.30 0,26 0,2

Annualized Annualized relapse rate 0,0 MSCRG EVIDENCE TRANSFORMS BRAVO COMBI-Rx

IFN b-1a im 1993 2011

MSCRG Jacobs LD et al. Ann Neurol 1996;39:285–94; EVIDENCE Panitch H et al. Neurology 2002;59:1496-506; TRANSFORMS Cohen JA et al. N Engl J Med 2010;362:402-15; BRAVO Vollmer TL et al. J Neurol. 2014 261(4):773-83 ; COMBI Rx Lublin FD et al. Ann Neurol. 2013 73(3):327-40 Change in Efficacy Responses over time in IFN-b 1a sc MS trials

1,0 0,87 0,8 0,77

0,6 0,54 0,39 0,4 0,34 0.30 0,292 0,29 0,2

Annualized Annualized relapse rate 0,0

IFN b-1a sc 1994 2015

PRISMS Lancet 1998;352:1498–504; OWIMS Neurology 1999;53:679–86; EVIDENCE Panitch H et al. Neurology 2002;59:1496-506; EVIDENCE; The CAMMS223 N Engl J Med 2008;359:1786-801; Mikol DD et al. Lancet Neurol 2008;7:903– 14; CARE MS 1 Cohen JA et al. Lancet. 2012 380(9856):1819-28; Opera I,II (reviewed in Menge T et al. Expert Rev Neurother. 2016 Sep 1:1-9) Change in Efficacy Responses over time in IFN-b 1b MS trials

1,0 0,84 0,8

0,6

0,4 0,36 0,37

0,2

Annualized Annualized relapse rate 0,0 IFN β-1b BEYOND BECOME

IFN b-1b 1988 2007

The IFNβ Multiple Sclerosis Study Group. Neurology 1993;43:655–61; O’Connor PW et al. Neurology 2006;66:894–900; BECOME Cadavid D et al. Neurology. 2009 72(23):1976-83 Glatiramer Acetate (GA) Glu – Ala – Tyr - Lys GA-Mechanism of Action

GA-T cells CD8 (Th1 & Th2) GA-Th2 cells

1-3M Th2 Th2 Cross reactive T Myelin T Ag TcR T reg reg Bystander GA FOXP3 BDNF Myelin DR Suppression NTs Ag X Th2/Th3 X cytokines My X My (IL-10, Neuron APC TGFß) GA Th1 IL-27 type-2 Autoreactive Bystander Th1 cell My IL-10 Suppression Anergy Periphery Apoptosis BBB CNS

Dhib-Jalbut, S. Pharmacol Ther. 2009 121(2):147-59 Change in Efficacy Responses over time in GA MS trials

0.8

0.59 0.6

0.4 0.34 0.29 0.29 0.23

0.2 Annualized rate relapse Annualized 0.0 Johnson REGARD BEYOND CONFIRM COMBI Rx

1991 2013

Johnson KP et al. Neurology 1995;45:1268–76; Mikol DD et al. Lancet Neurol 2008;7:903–14; O’Connor PW et al. Neurology 2006;66:894–900; Fox RJ N Engl J Med. 2012;367:1087–97; COMBI Rx Lublin FD et al. Ann Neurol. 2013 73(3):327-40 Results For EDSS Progression In Pivotal Trials Assessing MS Therapies

Statistically Agent Study Control Significant p values Benefit? GA COP-1 Placebo NO p=0.11 sc IFNb-1a PRISMS Placebo YES p<0.05 im IFNb-1a MSCRG Placebo YES p=0.02 IFNb-1b IFNB-1a Placebo NO p=0.161 CARE MS-I s.c. IFN-β1a NO p=0.22 Alemtuzumab CARE MS-II s.c. IFN-β1a YES p=0.008 DEFINE Placebo YES p=0.005 DMF CONFIRM Placebo NO p=0.25 FREEDOMS I Placebo YES p=0.02 Fingolimod FREEDOMS II Placebo NO p=0.25 Natalizumab AFFIRM Placebo YES p<0.001 TEMSO Placebo YES p=0.03 (14 mg) Teriflunomide TOWER Placebo YES P=0.04 New vs. Old: Disadvantages

 Though statistically “significant”, efficacy outcomes become more questionably “meaningful”  Newer medications bring different side effects in realms not previously seen with older agents – Different preparatory tests and evaluations are now necessary to avoid some new toxicity  Monitoring for side effects is more complex  Long term safety is unproven  Full spectrum of toxicity may not yet be realized  Safety following or preceding agents such as Natalizumab is unknown

Comparing Harm Among DMDs

 Toxicities differ greatly among agents – IFNb - skin reactions, liver function abnormalities, nephrotoxicity – GA - skin reaction, anaphylaxis – Natalizumab - liver toxicity, PML, lymphoma, Herpes, rebound hyperactivity, neuronopathy – Fingolimod – cardiac, macular edema, Herpes, haemophagocytic syndrome, PML – DMF – flushing, GI discomfort, PML, kidney failure – Teriflunomide – liver toxicity, hair thinning – Mitoxantrone - cardiotoxicity, leukemia Risk of Major Infections with Injectable Immunomodulators

From A Winkelmann et al. Nat Rev Neurol. 2016 12(4):217-33 Current Perception Myths of the Injectable Immunomodulators

Gone the way of the buffalo No role for injectables given the superior efficacy of the newer agents Intolerance leads to poor adherence Effectiveness decreases with time on the drug Patient populations have changed and are no longer responsive to the immunomodulators Countering the Myths of the Injectable Immunomodulators

 Like the diuretics, they will always play a role in initiating antihypertensive therapy  Superior efficacy has been convincingly shown in a scant number of trials with other 1st line therapies  Newer devices and formulations have led to improved adherence and better tolerability  Effectiveness is maintained in long term trials  Patient populations have changed, they are even milder than those in the pivotal studies and therefore are even more amenable to treatment with immunomodulators  Long term safety is unrivaled by any other agents Diuretics Are Not Dead! New vs. Old: Advantages

 Some “head to head” or at least “active comparator” trials suggest valid comparisons of new to old therapies – Fingolimod > IFNb-1a im qw (TRANSFORMS) – BG-12  GA (CONFIRM) – Teriflunomide 14 mg  IFNb-1a 44 mg sc tiw (TENERE)  Some newer agents offer potentially important new mechanisms that might prove superiority but not without new safety issues

Long Term Follow-up Studies with Immunodulators

Therapy Study, Pts Ascertainment Length of F/U

16-year LTF; RRMS 328/372 (88%) 16 yrs IFNβ–1b 21-year LTF; RRMS 366/372 (98%) 21 yrs GA LTF; RRMS 100/231 (43%) 15 yrs IFNβ–1a im MSCRG LTFU; RRMS 136/301 (45%) 15 yrs IFNβ–1b EUSPMS LTFU; SPMS 233/340 (69%) 8 yrs PRISMS LTFU; RRMS 382/560 (68%) 8 yrs IFNβ–1a sc PRISMS 15; RRMS 291/560 (52%) 15 yrs IFNβ–1a im CHAMPIONS; CIS 203/383 (53%) 5 yrs BENEFIT; CIS 358/468 (76%) 5 Yrs IFNβ–1b 284/468 (61%) 8 Yrs

Ebers et al. Clin Ther 2009; Ford et al Mult Scler 2010, Bermel et al, Mult Scler 2010; Kuhle et al. ECTRIMS 2004, Kappos et al., Neurology 2006, Kappos et al Lancet Neurol 2009, CHAMPIONS Study Group Neurology 2006,

30 Synergy Shown When Injectable Immunomodulators are Combined with Teriflunomide T1-Gd lesions per scan*: 6-month follow-up GA study (adjusted data)** IFN-b study (adjusted data)** RR: 84.4% 0.8 0.8 (p<0.0001)

0.7 0.7 RR: 82.6%

RR: 53.6% (p=0.0009) 0.6 (p=0.1157) 0.6 0.570 0.5 RR: 70.2% 0.5 (p=0.0110) 0.4 0.4 0.367

0.3 0.3

Number per scanper Number Number per scanperNumber

0.2 0.2 0.171 0.1 0.1 0.109 0.099 0.089 0 0 7 mg 14 mg 7 mg 14 mg Placebo Placebo Teriflunomide Teriflunomide

*The total number of Gd-enhancing T1-lesions that occurred during the study divided by the total number of scans during the study **Adjusted for baseline number of Gd-enhancing T1-lesions, region, and IFN-beta dose strata (for IFN-beta study only) using a Poisson model No Evidence of Disease Activity (NEDA): A New Metric

 Given our inability to distinguish meaning among the current MS metrics the simplest way to equalize them is to acknowledge that: “they’re all bad” - but they may not be or more accurately: “they can’t be good” so being “free” of them is probably a good thing  But…being free of one but not the others would make no sense (i.e. someone who is free of relapses but had significant EDSS change is counter-intuitive) NEDA: PROs

 Concept used in other conditions to imply “remission” – Meaning driven by risk of continued activity in comparator • Migraine, epilepsy, IPD  There is no question as to the “meaning” of the outcome if no activity is detectable  May be more useful now that MS trials are experiencing such low event rates, especially relapses – Is it more sensitive to change/time? – Will we require fewer patients to see differences? – Will we need less time to see those differences NEDA: CONs

 Overall metric driven by the event with the greatest level of activity (i.e. MRI)  There is an increasing rate of NEDA in placebo populations – in the absence of a placebo group it may not be possible to know who is truly benefitting a therapy  There is more to having disease than experiencing relapses, MRI or EDSS change – What about cognition? – Fatigue? – QoL? NEDA: A Potentially Better Outcome Measure?

 What sort of relative or absolute difference in NEDA would be meaningful in a clinical trial?  How do we insure “meaningfulness” of change? – How do we insure that all disease “activity” is not dominated by MRI?  If events in populations are becoming less meaningful (due in part to earlier identification and change in diagnostic criteria), is being free of these less meaningful events more meaningful? Clinical trials that have reported NEDA: 1 year data

80 All clinical trials that have reported NEDA – 1 year data (Note requires MRI assessment)

60

EVIDENCE (1999)

CARE-MS I (2007) 40 CARE-MS II (2007)

ADVANCE (2009) NEDA patients (%) patients NEDA 20

0 placebo Peg-IFNβ-1a im IFN β-1a sc IFN β-1a alemtuzumab Q2W 30 µg qw 44 µg tiw

Note: ADVANCE and EVIDENCE present 48 week data, while CARE MS I and II present 1 year data

Data cannot be directly compared between trials because of different populations and lengths of treatment Clinical trials that have reported NEDA: 2 year data

80 All clinical trials that have reported NEDA – 2 year data (Note requires MRI assessment)

AFFIRM (2001)

60 TEMSO (2004)

FREEDOMS (2006)

CARE-MS I (2007)*

40 CARE-MS II (2007)*

DEFINE (2007)

ADVANCE (2009) NEDA patients (%) patients NEDA 20

0 Placebo teriflunomide DMF fingolimod sc IFN β-1a alemtuzumab Peg-IFNβ-1a natalizumab 14 mg 240 mg bid 0.5 mg 44 µg tiw Q2W

*Data from CARE MS I and II trials present the percentage of patients who achieved NEDA between Year 1 and Year 2, all other trials present the cumulative percentage of NEDA patients over 2 years

Data cannot be directly compared between trials because of different populations and lengths of treatment NEDA: Endpoints are all Interlinked

 Relapse rates, disability progression and MRI lesions are not independent – Short-term treatment effects on T2 MRI lesions in patients treated with IFN β-1a can predict longer-term effects on relapses1 – A combined measure of 1-year changes in MRI lesions and relapses after IFN β-1a therapy fully estimated the corresponding effect on 2-year EDSS worsening2,3 Study PTE (95% CI)

Figure shows the proportion of the PRISMS 0.53 (0.28, 1.01) treatment effect (PTE) on relapses explained by MRI markers in each SPECTRIMS 0.67 (0.25, 1.59) trial and as pooled data Filled diamonds: PTE on relapses explained by MRI markers in EUSPSM 0.76 (0.36, 1.60) individual trials Open diamond: pooled estimate of GA9003 0.44 (0.07, 2.55) the PTE on relapses explained by MRI markers Overall 0.62 (0.41, 0.95)

Horizontal bars: 95% confidence 0.01 0.10 1.00 10.00 intervals 1. Sormani MP et al. Mult Scler 2011;17:541-9; 2. Sormani MP et al. Neurology 2011;77:1684-90; 3. Sormani MP et al. J Neurol 2011;258(Suppl. 1):S154 (P594) Conclusions

 Injectable immunomodulators are effective 1st line agents for the treatment of RRMS  They offer the greatest long term benefit:risk of all agents for initiating therapy in the majority of patients  In the future, when costs are reduced, they are most likely to be combined with other agents for greater efficacy