1 Assessing Risk Tolerance to DMTs: Understanding and Educating About Safety 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 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? 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?
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Assessing Risk Tolerance to DMTs:Understanding and Educating About Safety
Assessing Risk Tolerance to DMTs:Understanding and Educating About Safety
Benjamin Greenberg, M.D., M.H.S.UT Southwestern and Childrens Medical Center
Dallas, TexasCMSC 2014
ObjectivesObjectives
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?
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?
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Example Package InsertExample 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.
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.
AgendaAgenda
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
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
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The Past, Present and Future of Disease Modifying Therapies in Multiple SclerosisThe Past, Present and Future of Disease Modifying Therapies in Multiple Sclerosis
Benjamin Greenberg, M.D., M.H.S.Director, Transverse Myelitis and Neuromyelitis Optica Program
Time to 12-week confirmed disability progressionHR vs placebo
0.955 0.685*
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
PhysicalMental
-1.082-2.913
-0.396-2.031
-0.105-1.434
*Statistically significant vs placebo.FIS = Fatigue Impact Scale; SF-36 = Short Form 36 questionnaireKappos L, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 153]
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Outcome Measures For Dimethyl Fumarate
Outcome Measures For Dimethyl Fumarate
Outcome Placebo BG00012120 mg daily
BG00012120 mg tid
BG00012240 mg
tid
P Value
Mean Number of New Gd Lesions
weeks 12-24
4.5 3.3 3.1 1.4 <0.0001
Number of patients with no new T2
lesions at week 24
26% 27% 27% 63% 0.0006
ARR Weeks 0-24
0.65 0.42 0.78 0.44 0.272
ARRWeeks 25-48
0.26 0.24 0.47 0.16
Lancet, 2008, 372:1463-72
Dimethyl Fumarate Pooled Efficacy Analysis of
DEFINE and CONFIRM
Dimethyl Fumarate Pooled Efficacy Analysis of
DEFINE and CONFIRMEndpoint (at 2 years) Placebo BG-12 BID
ARRReduction vs placebo
0.371 0.191*49%
Time to 12-week confirmed disability progressionHR vs placebo
0.68*
Time to 24-week confirmed disability progressionHR vs placebo
0.71*
Mean number of Gd-enhancing lesionsReduction vs placebo
1.9 0.3*83%
Mean number of new or enlarging T2 lesionsReduction vs placebo
16.8 3.7*78%
Mean number of new T1 hypointense lesionsReduction vs placebo
6.3 2.2*65%
*Statistically significant vs placebo.Gold R, et al. Presented at ECTRIMS 2012; October 9–13, 2012; Lyon, France. [Abstract 151]
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Annualized Relapse Rates From Pivotal Clinical Trials
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
The Ins and Outs of Annualized Relapse Rate
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The Ins and Outs of Annualized Relapse Rate
The Ins and Outs of Annualized Relapse Rate
PlaceboTreated
The Ins and Outs of Annualized Relapse Rate
The Ins and Outs of Annualized Relapse Rate
Treated Placebo
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AlemtuzumabAlemtuzumab
“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.
“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 AlemtuzemabBiologic 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.
Induces apoptosis of lymphocytes and NK cells.
Subsequent reconstitution of the immune system with relative overexpression of Treg cells and naïve B cells.
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Alemtuzumab Phase II TrialAlemtuzumab Phase II Trial
334 Randomized
111
Interferon beta1a
(SC 3x/wk)
113
12 mg Alemtuzumab
108 Received first cycle
102 Received second cycle
24 Received
third cycle
110
24 mg Alemtuzumab
108 Received first cycle
105 Received second cycle
22 Received
third cycle
December 2002 July 2004 September 2004 September 2005
Enrollment Begins Last PatientRandomizes
Last PatientDosed
AlemtuzumabDosing
Suspended
NEJM, 2008, 359(17):1786-801)
Outcome Measures For AlemtuzumabOutcome Measures For Alemtuzumab
Outcome Interferon Alemtuzumab(Combined Doses)
P Value
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)
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Adverse Events and Safety for Alemtuzumab
Adverse Events and Safety for Alemtuzumab
Event Interferon Alemtuzumab12 mg Dose
Alemtuzumab24 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 Hyperthyroidism
0 0.9% 1.9%
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
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.
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.
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Choosing A TherapyChoosing A Therapy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
MS Therapeutics: A Brave New WorldMS Therapeutics: A Brave New World
Safety
Effi
cacy
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What is an Acceptable Risk Benefit Ratio?
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.
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.