Assessing Risk Tolerance to DMTs: Understanding and Educating About Safety

Benjamin Greenberg, M.D., M.H.S. UT Southwestern and Childrens Medical Center Dallas, Texas CMSC 2014

Objectives

In a world of increasing numbers of disease modifying therapies, each with unique mechanisms of actions, relative efficacy, relative risk and safety concerns, how should clinicians counsel patients? What are your obligations relative to safety education and monitoring of patients? Are you responsible when patients suffer from rare unexpected complications?

1 Example Package Insert

Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received XXX doses (Y-YY) higher than recommended for use in MS. Similar events have been reported with XXX in the post-marketing setting although a casual relationship has not been established.

Cases of lymphoma (cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) were reported in premarketing clinical trials in MS patients receiving XXX at, or above, the recommended dose of Y, based on the small number of cases and short duration of exposure, the relationship to XXX remains uncertain.

Agenda

9:00 to 9:45 Introduction to DMTs Benjamin Greenberg, MD, MHS 9:45 to 10:30 Quantifying Relative Risk of DMTs Donna Graves, MD 10:30 to 10:45 Break 10:45 to 11:30 Medico-Legal Obligations Neal Flagg, JD 11:30 to 12:00 Case Examples/Discussion

2 The Past, Present and Future of Disease Modifying Therapies in

Benjamin Greenberg, M.D., M.H.S. Director, Transverse Myelitis and Neuromyelitis Optica Program Director, Pediatric Program UT Southwestern Childrens Medical Center Dallas, Texas CMSC 2014

Multiple Sclerosis Throughout History

 1868 – Jean-Martin Charcot describes in detail, clinical multiple sclerosis and relates it to white matter lesions.

3 Suggested Causes of Multiple Sclerosis Throughout History

1900 1940 1960 2000

Lack of Sweat Poor Circulation Allergic Reaction Autoimmune reaction against Toxic Exposure myelin

Bedrest Vasodilators Vitamins/ Purgatives Anti-histamines Immunomodulators

Where it all began……

4 FDA Approval of Multiple Sclerosis Therapies

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Interferon Beta-1b (Betaseron)

Interferon Beta-1a (Avonex)

Glatiramer Acetate (Copaxone)

Mitoxantrone (Novantrone)

Interferon Beta-1a (Rebif)

Natalizumab (Tysabri)

Fingolimod (Gilenya)

Teriflunomide (Aubagio)

Tecfidera (BG0012)

5 Disease Modifying Therapy in MS

Present Future (Current Phase II/III)

 Interferon β 1a 

 Interferon β 1a 

 Interferon β 1b 

 Estradiol

 Abatacept

 Glatiramer Acetate

 Interferon β 1a

 BG-00012

The Complicated Current Therapeutic Climate of Multiple Sclerosis

 Changing diagnostic criteria

 Lack of consensus definition of what success in MS means

 Lack of consensus on appropriate ‘risk’ taking in MS therapeutics.

 Lack of reliable biomarkers that predict outcome, guide therapy selection or confirm response to therapy.

 A complete lack of agents for progressive disease

6 The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical

The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical Poser Criteria for Separation in Space and Time

7 The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical MRI Events TransitionTransition toto 20102005 McDonaldMcDonald CriteriaCriteria

The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical

25% of cases diagnosed with MS at Autopsy are undiagnosed in life Acta Neurol Scand. 1989 May 79(5):428-30

8 The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical

25% of cases diagnosed with MS at Autopsy are undiagnosed in life Acta Neurol Scand. 1989 May 79(5):428-30

The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical

25% of cases diagnosed with MS at Autopsy are undiagnosed in life Acta Neurol Scand. 1989 May 79(5):428-30

9 The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events Clinical

25% of cases diagnosed with MS at Autopsy are undiagnosed in life Acta Neurol Scand. 1989 May 79(5):428-30

The Impact of Increased Diagnostic Sensitivity Relative to Outcomes Clinical Events MRI Events MRI Inflammation Atrophy

10 HOW SHOULD WE JUDGE SUCCESS IN MS?

We All Have an Internal Barometer of Concern

Relapses MRI

“Disability”

Is the therapy working?

11 Success is not Defined in a Vacuum Maintain Change Therapy Therapy

Success is not Defined in a Vacuum Maintain Change Therapy Therapy

12 MEASURES OF SUCCESS: REVIEW OF THE DATA

How Do We Define Success in Treating Multiple Sclerosis

 Stable MRI

 Lack of Relapses

 Lack of new changes in walking, vision or sensation

 Lack of changes in cognition

 Improvement in symptoms

13 FDA Approved Injectable Therapies in RRMS

Betaseron™/Extavia™ Avonex™ Copaxone™ Rebif ™

FDA Approval 1993 1996 1996 2002

Route SC IM SC SC Frequency QOD Weekly Daily 3x week

Reduction in 31% 32% 29% 32% Relapses

Natalizumab Risk of Relapse Over 2 Years 0.7 HR = 0.41 (CI: Placebo 0.6 0.33–0.51) 56% 0.5 P < .0001 0.4 0.3 Natalizumab Relapse 0.2 28% Probability of Probability 0.1 0.0 02412 36 48 60 7284 96 104 Weeks

Number of Patients at Risk Placebo 315 257 229 204 182 164 154 141 133 129 Natalizumab 627 577 542 515 487 464 447 436 424 418 NEJM, March 2, 2006

14 Sustained Disability Progression with Natalizumab

0.4 Hazard ratio (HR) = 0.58 (95% P = CI: 0.43–0.77) Placebo 0.3 .0002 29%

0.2 Natalizumab

0.1 17%

Proportion With Sustained Progression 0.0

0 12 24 36 48 60 72 84 96 108 120 Weeks Number of Patients at Risk Placebo 315 296 283 264 248 240 229 216 208 200 199 Natalizumab 627 601 582 567 546 525 517 503 490 478 473 NEJM, March 2, 2006

Outcome Measures For Fingolimod

Outcome Placebo Fingolimod Fingolimod P Value 0.5 mg 1.25 mg Annualized Relapse Rate 0.40 0.18 0.16 <0.001 Patients without a 6 month 75.9% 87.5% 88.5% 0.01 sustained change in EDSS Mean Number of Gd 1.1 0.2 0.2 <0.001 Enhancing Lesions at 24 months Mean Number of new or 9.8 2.5 2.5 <0.001 enlarged T2 lesions Change in brain volume over -1.31 -0.84 -0.89 <0.001 24 months

NEJM, 2010, 362:387-401

15 Outcome Measures For Fingolimod

Outcome Interferon Fingolimod Fingolimod P Value beta 1a 0.5 mg 1.25 mg (IM) Annualized Relapse Rate 0.33 0.16 0.20 <0.001 Patients with Zero Relapses 70.1% 82.5% 80.5% 0.01

Mean Number of Gd 0.51 0.23 0.14 <0.001 Enhancing Lesions at 24 months Mean Number of new or 2.6 1.7 1.5 <0.001 enlarged T2 lesions Change in brain volume over -0.45 -0.31 -0.30 <0.001 24 months

NEJM, 2010, 362:402-415

Outcome Measures For Teriflunomide

Outcome Placebo Teriflunomide Teriflunomide P Value 7 mg daily 14 mg daily Mean Number of New Gd 2.25 0.17 0.17 <0.02 Enhancing Lesions Mean Number of new or 1.52 0.41 0.71 <0.03 enlarged T2 lesions

Neurology, 2006, 66:894-900

16 Teriflunomide: Phase III TOWER Study Primary Endpoint: ARR

RRR: 22.3% RRR: 36.3% P = 0.0183 P = 0.0001

Kappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]

TOWER: Secondary Efficacy Outcomes

Secondary Endpoint Placebo Teri 7 mg Teri 14 mg Patients free from relapse 37.7% 55.4* 51.5*

Time to 12-week confirmed disability progression 0.955 0.685* HR vs placebo

Mean change from baseline EDSS to week 48 0.089 0.042 -0.05*

Mean change from baseline FIS to week 48 4.7 2.5 1.9

Mean change from baseline SF-36 scores to week 48 -1.082 -0.396 -0.105 Physical -2.913 -2.031 -1.434 Mental

*Statistically significant vs placebo. FIS = Impact Scale; SF-36 = Short Form 36 questionnaire Kappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]

17 Outcome Measures For

Outcome Placebo BG00012 BG00012 BG00012 P Value 120 mg daily 120 mg tid 240 mg tid Mean Number of 4.5 3.3 3.1 1.4 <0.0001 New Gd Lesions weeks 12-24 Number of patients 26% 27% 27% 63% 0.0006 with no new T2 lesions at week 24 ARR 0.65 0.42 0.78 0.44 0.272 Weeks 0-24 ARR 0.26 0.24 0.47 0.16 Weeks 25-48

Lancet, 2008, 372:1463-72

Dimethyl Fumarate Pooled Efficacy Analysis of DEFINE and CONFIRM Endpoint (at 2 years) Placebo BG-12 BID ARR 0.371 0.191* Reduction vs placebo 49% Time to 12-week confirmed disability progression 0.68* HR vs placebo Time to 24-week confirmed disability progression 0.71* HR vs placebo Mean number of Gd-enhancing lesions 1.9 0.3* Reduction vs placebo 83% Mean number of new or enlarging T2 lesions 16.8 3.7* Reduction vs placebo 78% Mean number of new T1 hypointense lesions 6.3 2.2* Reduction vs placebo 65%

*Statistically significant vs placebo. Gold R, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 151]

18 Annualized Relapse Rates From Pivotal Clinical Trials

IFNB Multiple Sclerosis Study Group (1993) Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. Neurology: 655–661; Jacobs LD, Cookfair DL, Rudick R a, Herndon RM, Richert JR, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of neurology 39: 285–294 ; Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, et al. (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer Multiple Sclerosis Study Group. Neurology 45: 1268–1276 ; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352: 1498–1504 ; Polman CH, O Connor PW, Havrdova E, Hutchinson M, Kappos L, et al. (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 354: 899. ; O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, et al. (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England journal of medicine 365: 1293–1303 ; Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, et al. . (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine: 387–401. ; Gold R, Kappos L, Bar-Or A, Arnold D, Giovannoni G, et al. . (2011) Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial. In: ECTRIMS. Amsterdam ; Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, et al. (2012) Placebo-controlled trial of oral laquinimod for multiple sclerosis. The New England journal of medicine 366: 1000–1009

The Ins and Outs of Annualized Relapse Rate

19 The Ins and Outs of Annualized Relapse Rate

Treated Placebo

The Ins and Outs of Annualized Relapse Rate

Treated Placebo

20 Alemtuzumab

 “Campath”, developed in the Cambridge Pathology Department

 Humanized monoclonal antibody targeting CD52

 FDA approved for treatment of B-cell CLL

 CD52 is expressed on lymphocytes, natural killer cells, dendritic cells and macrophages.

Biologic Effect of Alemtuzemab

 Induces apoptosis of lymphocytes and NK cells.

 Subsequent reconstitution of the immune system with relative overexpression of Treg cells and naïve B cells.

21 Alemtuzumab Phase II Trial

111 Interferon beta1a (SC 3x/wk)

113 108 Received first 102 Received 24 Received 334 Randomized 12 mg cycle second cycle third cycle Alemtuzumab

110 108 Received first 105 Received 22 Received 24 mg cycle second cycle third cycle Alemtuzumab

December 2002 July 2004 September 2004 September 2005

Enrollment Begins Last Patient Last Patient Alemtuzumab Randomizes Dosed Dosing Suspended

NEJM, 2008, 359(17):1786-801)

Outcome Measures For Alemtuzumab

Outcome Interferon Alemtuzumab P Value (Combined Doses) Annualized Relapse Rate 0.36 0.10 <0.001 Change in Mean EDSS from Baseline 0.38 -0.39 <0.001

EDSS Score Improvement 33.7% 57.2% <0.001

Sustained Disability for 6 months 26.2% 9.0% <0.001

Patients with No Relapse 51.6% 80.2% <0.001

NEJM, 2008, 359(17):1786-801)

22 Adverse Events and Safety for Alemtuzumab

Event Interferon Alemtuzumab Alemtuzumab 12 mg Dose 24 mg dose Serious SAE 22.4 22.2 25.0 Liver Toxicity 15% 1.9% 2.8% Serious Infection 1.9% 2.8% 5.6% URI 27.1% 44.4% 50.9% HSV 2.8% 8.3% 8.3% Thyroid Changes 2.8% 25.9% 19.4% Serious 0 0.9% 1.9% Hyperthyroidism ITP 0.9% 1.9% 3.7% Cancer 0.9% 0 2.8% Death 0 0.9% 0.9%

NEJM, 2008, 359(17):1786-801)

Figure 2 Efficacy outcomes through month 60 and complete follow-up (A) Kaplan-Meier estimates of time to sustained accumulation of disability through complete follow-up with the number of at-risk patients listed below.

Coles A et al. Neurology 2012;78:1069-1078

© 2013 American Academy of Neurology

23 Figure 3: Proportion of patients with infections and first autoimmune event (A) Proportion of patients with infections.

Coles A et al. Neurology 2012;78:1069-1078

© 2013 American Academy of Neurology

Phase III Alemtuzumab Trials CARE-MS II Patients Who Failed Prior Therapy

 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses.

 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab.

 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001).

 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group.

24 Choosing A Therapy

MS Therapeutics: A Brave New World Efficacy

Safety

25 MS Therapeutics: A Brave New World Efficacy

Safety

MS Therapeutics: A Brave New World Efficacy

Safety

26 MS Therapeutics: A Brave New World Efficacy

Safety

MS Therapeutics: A Brave New World Efficacy

Safety

27 What is an Acceptable Risk Benefit Ratio?

 How do we handle therapies with a risk of death?

 How do we handle risk of malignancy?

 How do we handle risk of infection?

 Defining benefits is based on development of accurate measures/markers.

Improving Therapeutic Choices

Responder Status

Disease Risk of Severity Therapy

28 Conclusions

 The therapeutic landscape is complicated and getting more complicated

 Therapies have to be individualized based on disease severity, risk of disease progression and risk of therapeutic options

 Side effect profiles and adherence

 A detailed conversation with patients is needed

29