Download Update on MS Internal Medicine Comprehensive Review and Update 2012

Update on MS
Internal Medicine
Comprehensive Review and Update 2012
June 7, 2012
Guy Buckle, MD, MPH
Director of Clinical Care
Partners MS Center
Brigham & Women’s Hospital
Assistant Professor
Department of Neurology
Harvard Medical School
Boston, MA, USA
Guy Buckle, M.D. Disclosures
•
•
•
•
•
•
•
•
Acorda: Consultant/Advisor
Bayer: Consultant/Advisor
Biogen-Idec: Consultant/Advisor
EMD-Serono: Consultant/Advisor
Genzyme: Consultant/Advisor
Novartis: Consultant/Advisor
Questcor: Consultant/Advisor
Teva Neuroscience: Consultant/Advisor
Learning Objectives
• The participant will be able to:
– Discuss the epidemiology, possible etiology and risk
factors for developing MS
– Recognize common presenting signs and symptoms
of MS
– Discuss the development of diagnostic criteria for MS
based on clinical presentation and MRI
– Discuss the FDA-approved and newly emerging
therapies for MS and their risks/benefits
Overview
• Epidemiology: Genetics and Risk Factors
• MS Presentation: CIS, RIS, RRMS, SPMS, PPMS
• Diagnostic Criteria: Old and new
• FDA-Approved Therapies: Old drugs, new trials
• Emerging Disease Modifying Therapies in Phase III:
New drugs, new problems
Epidemiology of MS
•
The most common chronic disabling disease affecting the CNS in young adults
•
Approximately 400,000 cases in the United States (1997).
– Estimates range from 250,000 to 500,000 (probably higher).
•
The chances of developing MS are approx. 1:1000 in the general population
•
Incidence increases with distance from the equator
•
Estimated 2.5 million cases worldwide (probably more).
•
Highest incidence in Caucasians
•
Higher incidence in women (approximately 2.5:1)
•
MS strikes individuals between the ages 20-50, normally a time of peak
productivity
CNS = central nervous system.
Compston A, et al. Lancet. 2002;359(9313):1221-1231. Frohman EM. Med Clin N Am. 2003;87(4):
867-897. Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9):871-878. National Multiple Sclerosis Society.
Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed
January 8, 2009. Lage MJ, et al. Work. 2006;27(2):143-151.
Economic Implications
•
Annual cost of MS in the United States is estimated at approximately $13.6 billion
(in 1994 dollars)
•
Total lifetime direct and indirect costs per patient are estimated at approximately
$2.4 million (in 1994 dollars)
•
Mean annual direct and indirect costs per patient total an estimated $47,215 (in
2004 dollars)
•
Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times
higher than those without MS
•
Direct correlation between cost (direct and indirect) and severity of disease has
been well-established
•
Therapeutics that modify MS activity and severity can result in both clinical and
economic benefits
Whetton-Goldstein K, et al. Mult Scler. 1998;4(5):419-425. Pope GC, et al. Neurology. 2002;58(1):37-43.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702. Patwardhan MB, et al. Mult Scler. 2005;11(2):232-239.
O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:918-926.
Age of Onset of MS
Distribution of Patients According to
the Decade of Life of MS Symptoms Onset
35
Patients (%)
30
25
20
15
10
5
0
0-10
11-20
21-30
31-40
Years
Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.
41-50
51-60
MS: Prevalence
Pathogenesis of MS
Infectious
Agent
Genetic
Predisposition
Abnormal Immunologic Response
Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):727-730.
Environmental
Factors
MS
Figure 1 The immunopathogenesis of the MS lesion. Overview of the components of the
immune system that are involved in pathogenesis in MS, as discussed in the text.
Dhib-Jalbut S , Marks S Neurology 2010;74:S17-S24
©2010 by Lippincott Williams & Wilkins
MS Genetics: Approximate Probability of Developing MS
1)Hauser SL, Goodin DS. Chapter 375. Multiple sclerosis and other demyelinating diseases. In: Harrison's
Principles of Internal Medicine. Fauci AS, Braunwald E, Kasper DL, et al, eds. Available at:
http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: September 11, 2009.
2)Willer CJ, Dyment DA, Risch NJ, et al, and the Canadian Collaborative Study Group. Twin concordance and
sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A. 2003;100:12877-12882.
Higher Vitamin D is Associated With
Fewer T2 and Gd-Enhancing Lesions
•
•
•
•
469 subjects with clinically isolated syndrome or RRMS evaluated
annually for 5 years by clinical evaluations, brain MRI, and blood
draws
Annual vitamin D (25-hydroxyvitamin D3) levels evaluated for
association with subsequent development of:
– New T2-weighted lesions
– New Gd enhancing T1-weighted lesions
– Clinical relapse of MS
Each 10 ng/mL higher vitamin D level was associated with:
– 15% lower risk of developing a new T2 lesion (P = 0.004)
– 32% lower risk of developing a new Gd-enhancing lesion (P =
0.002)
Higher vitamin D levels were associated with lower relapse rate (P
not significant)
Mowry E, et al. ECTRIMS/ACTRIMS 2011; Amsterdam, The Netherlands. Oral Presentation 129.
Overview
• Epidemiology: Genetics and Risk Factors
• MS Presentation: CIS, RIS, RRMS, SPMS, PPMS
• Diagnostic Criteria: Old and new
• FDA-Approved Therapies: Old drugs, new problems
• Emerging Disease Modifying Therapies in Phase III:
New drugs, new problems
Types of Multiple Sclerosis (MS)
Relapsing-remitting
Disability
– Relapsing-remitting (RRMS)
– Secondary Progressive
(SPMS)
– Primary Progressive (PPMS)
– Progressive-relapsing (PRMS)
Secondary Progressive
Primary Progressive
Progressive-relapsing
Time
Lublin FD, Reingold SC. Neurology. 1996;46(4):907-911
Clinical Manifestations
•
Fatigue
•
Bladder dysfunction
•
Pain
•
Bowel dysfunction
•
Depression
•
Cerebellar dysfunction
•
Numbness/paresthesias
•
Sexual dysfunction
•
Cognitive dysfunction
•
Gait abnormalities
•
Weakness/ Spasticity
•
Partial/complete paralysis
•
Visual loss/Optic neuritis
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiplesclerosis/what-we-know-about-ms/symptoms/index.aspx. Accessed February 21, 2010.
Natural History of MS
Measures of brain volume
Relapses and impairment
MRI burden of disease
MRI activity
Preclinical
RIS
Secondary-Progressive
Relapsing-Remitting
CIS
Time
Comi. Opin Neurol. 2000;13:235; Munschauer. Clin Ther. 1997;19:868; Weinshenker. Brain. 1989;112:1422.
Clinically Isolated Syndrome: Optic Neuritis
•
•
26 year-old woman with acute
onset of monocular visual loss O.S.
with pain on eye movement.
Examination: Mild papilledema;
Acuity of 20/200 w/ red desat.
central scotoma and RAPD.
Remainder of exam is normal.
Clinically Isolated Syndrome: Optic Neuritis
• Symptoms
– Periocular pain (unilateral) on
EOM
– Monocular visual loss
– Fading or blurring of vision
– Uhthoff’s effect
• Signs
– Decreased visual acuity
– Decreased color vision (red
desaturation).
– Decreased contrast sensitivity
– Central scotoma
– Relative afferent pupillary defect
– +/-Disc swelling or pallor (chronic)
Clinically Isolated Syndrome 1: Optic Neuritis
Initial Findings on FLAIR MRI
FLAIR = fluid-attenuated inversion recovery
Clinically Isolated Syndrome 1: Discussion Points
•
•
•
•
•
Does this patient have MS?
If not, what is her risk of developing CDMS?
Would you perform a lumbar puncture?
Would you treat with steroids?
Would you recommend immunomodulatory treatment?
– If yes, what type of treatment should be offered?
– If no, how should this patient be followed?
Clinically Isolated Syndrome 2: Transverse Myelitis
• 23-year-old woman with
gradual onset of tingling and
numbness in her feet that
ascends to the umbilicus over
the next 4 days.
• Exam shows a T8 sensory
level to LT and temp. and
reduced vibratory sensation
with hyper-reflexia in the LE’s.
The remainder of the
neurological examination is
normal.
T2
T1 + Gd
Clinically Isolated Syndrome 2: Transverse Myelitis
• Patient is active and appears to be in good health.
• No personal history of previous neurological disease.
• There is no family history of neurological or autoimmune disease.
• Patient c/o urinary frequency/urgency.
• Unexplained fatigue since college.
Basic Differential Diagnosis TM
• Metabolic — Vit. B12, Copper deficiency
• Infectious — Lyme, syphilis, HIV, HTLV-1
• Vascular — arteriovenous malformation (AVM)
• Malignancy — intramedullary or extrinsic tumor
• Inflammatory/autoimmune — SLE, Sjögren's,
sarcoidosis, APLS, NMO
• Structural — cervical spondylosis
Clinically Isolated Syndrome 2:
Initial Findings on Proton Density MRI
Proton Density
T1 w/Gd
Sagittal FLAIR – Dawson’s Fingers
Unlikely MS
Perivenular
Random
Pathology of MS: Demyelination
•
Areas of demyelination
•
Followed by partial
remyelination and gliotic
scarring
Used with permission from Florida State University College of Medicine.
Axons Are Transected in MS Plaques and in NAWM
SMI-32 (non-phosphorylated neurofilament)
Trapp. N Engl J Med. 1998;338:278.
Number of Transected Axons Increases With Level of Activity in
MS Lesions
12,000
11,236
10,000
8,000
6,000
3,138
4,000
875
2,000
17
0.7
NAWM
Control
white
0
Active
Chronic
active
edge
Chronic
active core
(NAWM: normal-appearing white matter)
Trapp BD, et al. N Engl J Med. 1998;338:278-285.
Clinically Isolated Syndrome (CIS)
Patients who present with clinically isolated
syndrome (CIS) should be managed based on their
risk of progression to MS:
• In the Optic Neuritis Trial, risk at 10 years was:
– 56% for patients with ≥1 lesion
– 22% for patients with no lesions
• In patients with CIS and no lesions, risk of MS at
14 years was:
– 19% for clinically definite (CD) MS
Brex et al. N Engl J Med. 2002;346:158-164.
Optic Neuritis Study Group. Arch Ophthalmol. 2003;121:944-949.
12
EDSS Has Long Been a Standard
Disability Measure accepted by FDA
Expanded Disability Status Scale
Death
Normal
neurological
exam
0
0.5
1.0
Increased
limitation in
walking
ability
Minimal
disability
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Need for Restriction to
walking
wheelchair
assistance
5.5
6.0
6.5
7.0
7.5
8.0
8.5
Helpless
bed
patient
10.0
9.0 9.5
Patient Disability Classification
Expanded Disability Status Scale (EDSS): Rating system used by neurologists and
clinical trial investigators to follow the progression of disability in MS.
Kurtzke JF. Neurology. 1983;33(11):1444-1452.
Median EDSS Score at Year 14
Number and Volume of T2 Lesions at Presentation Predict Disability
7
6
6
5
4
4
3
2
1.75
2
0
(0 cm3)
1 to 3
(0.6 cm3)
1
0
4 to 10
(0.9 cm3)
>10
(5.6 cm3)
Number (Median Volume) of T2 Weighted Lesions at Presentation
Brex. N Engl J Med. 2002;346:158.
Overview
• Epidemiology: Genetics and Risk Factors
• MS Presentation: CIS, RIS, RRMS, SPMS, PPMS
• Diagnostic Criteria: Old and new
• FDA-Approved Therapies: Old drugs, new problems
• Emerging Disease Modifying Therapies in Phase III:
New drugs, new problems
Poser Criteria (1983) Define MS as
“Clinically Definite” or “Probable”
8
• Clinically definite MS
– A1: 2 attacks + 2 lesions
– A2: 2 attacks + 1 lesion + 1 paraclinical lesion
• Laboratory-supported definite MS
– B1: 2 attacks + 1 lesion or 1 paraclinical lesion + abnormal CSF
– B2: 1 attack + 2 lesions + abnormal CSF
– B3: 1 attack + 1 lesion + 1 paraclinical lesion + abnormal CSF
• Poser criteria also includes 2 additional categories
– Clinically probable MS
– Laboratory-supported probable MS
Poser CM et al. Ann Neurol. 1983;13(3):227-231.
McDonald Criteria (2001, rev. 2005)
Incorporated MRI Measures
Clinical
(attacks)
Objective
lesions
Additional requirements to make diagnosis
2 or more
2 or more
• None; clinical evidence will suffice (additional evidence desirable but must be
consistent with MS)
2 or more
1
1
2 or more
1 monosymptomatic
0 (progression
from onset)
9
• Dissemination in space by MRI or positive CSF and 2 or more MRI lesions
consistent with MS or further clinical attack involving different site
• Dissemination in time by MRI or second clinical attack
1
• Dissemination in space by MRI or positive CSF and 2 or more MRI lesions
consistent with MS
AND
• Dissemination in time by MRI or second clinical attack
1
• Positive CSF
AND
• Dissemination in space by MRI evidence of 9 or more T2 brain lesions
or 2 or more cord lesions or 4–8 brain and 1 cord lesion
or positive VEP with 4–8 brain lesions
or positive VEP with less than 4 brain lesions plus 1 cord lesion
AND
• Dissemination in time by MRI
or continued progression for 1 year
McDonald WI et al. Ann Neurol. 2001;50(1):121-127.
Diagnostic Criteria Vary Across DMD Pivotal
Trials for Relapsing Forms of MS
DMD
Study group
n
IFN β-1b
SC
IFNB MS
Study Group
372
Poser (“clinically definite” or “laboratory-supported definite”
MS)
IFN β-1a
IM
MSCRG
301
Poser (“clinically definite” MS)
Glatiramer
acetate
Copolymer 1
MS Study
Group
251
Poser (“clinically definite” or “laboratory-supported definite”
MS)
IFN β-1a
SC
PRISMS
Study Group
560
Poser (“clinically definite” or “laboratory-supported definite”
MS)
Natalizumab
AFFIRM
Investigators
627
McDonald (17% in placebo arm met McDonald but not
Poser definition of “clinically definite” MS)
Only comparative, head-to-head studies allow evidence-based
comparisons of efficacy and safety between drug products.
11
Diagnostic criteria used
IFNB MS Study Group. Neurology. 1993;43(4):655-661.
Jacobs LD et al. Ann Neurol. 1996;39(3):285-294.
Johnson KP et al. Neurology. 1995;45(7):1268-1276.
PRISMS Study Group. Lancet. 1998;352(9139):1498-1504.
Polman CH et al. N Engl J Med. 2006;354(9):899-910.
On-Treatment Annualized Relapse Rates Have
Decreased Over Time
Mean Event Rates in Major MS Clinical Trials
1.0
Mean Annualized Relapse Rate
0.91
0.9
0.87
0.84
McDonald criteria introduced
0.8
0.7
0.70
0.67
0.64
0.59
0.6
0.54
0.50
0.5
0.4
0.35
0.35
0.30
0.3
0.34
0.34
0.29
0.22
0.2
0.10
0.1
0.0
1992–2001
2002–2007
Only comparative, head-to-head studies allow evidence-based comparisons of efficacy and safety between drug products.
A 32-year-old woman with left heminumbness and left leg weakness. No prior
Patient Meets Criteria for MS Using the MAGNIMS
medical history. Examination demonstrates diminished sensation in the left
upper and lower extremities; 2010
mild weakness
of the left leg with extensor
Criteria
plantar response and asymmetrically hyperreflexic. Brain MRI shows:
Posterior fossa lesion
Juxtacortical lesion
Asymptomatic
gadolinium-enhancing
lesion
Periventricular lesion
Asymptomatic T2 lesion
Images courtesy of Omar Khan, MD.
Why Treat Early?
• Relapses and impairment parallel the MRI burden of
disease.1-3
• Axonal damage occurs early and may cause permanent
neurological dysfunction.4
• Number of MRI lesions are predictive of future
disability.5
• Preventing development of lesions may prevent
progression of disability in patients.6
• Early treatment may delay mortality.
1. Comi. Curr Opin Neurol. 2000;13:235; 2. Munschauer. Clin Ther. 1997;19:868; 3. Weinshenker. Brain.
1989;112:1422; 4. Trapp. N Engl J Med. 1998;338:278; 5. Brex. N Engl J Med. 2002;346:158; 6. O’Riordan.
Brain. 1998;121:495.
Early Relapses Affect Long-Term Disability
100
Low (0―1 attacks in 2 years)
Intermediate (2―4 attacks in 2
years)
High (>5 in 2 years)
Patients (%)
80
60
40
20
0
0
10
20
30
40
50
Time From Onset of MS
(years)
Actuarial analysis of disability: percentage of patients not having reached
EDSS 6: difference between the groups significant (P<0.0001).
Weinshenker. Brain. 1989;112:1422.
Mortality for IFNβ-1b vs Placebo 21 Years After
Randomization In Pivotal Trial
100
IFNβ-1b 250 µg
Placebo
Proportion of Patients
Still Alive
95
90
85
80
78.3% of
deaths MSrelated
HR = 0.532
46.8% reduction in mortality risk
P = 0.0173
75
70
65
0
At risk:
INFβ-1b 250 µg 124
Placebo
123
5
10
124
120
121
117
15
Time (yrs)
118
109
Reder AT, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract P04.129.
20
104
88
25
Overview
• Epidemiology: Genetics and Risk Factors
• MS Presentation: CIS, RIS, RRMS, SPMS, PPMS
• Diagnostic Criteria: Old and new
• FDA-Approved Therapies: Old drugs, new trials
• Emerging Disease Modifying Therapies in Phase III:
New drugs, new problems
FDA-Approved Therapies for MS:
Immunomodulators
Agents*
Indications
Doses and Administration
1996 Glatiramer acetate
(Copaxone®)
 Relapsing-remitting MS
 1st clinical episode and MRI
consistent with MS
20 mg/d SC
1996 Low-dose IFNβ-1a
(Avonex®)
 Relapsing forms of MS
 1st clinical episode and MRI
consistent with MS
30 mcg/wk IM
2002 High-dose IFNβ-1a
(Rebif®)
 Relapsing forms of MS
1993 High-dose IFNβ-1b
(Betaseron®, Extavia®)
 Relapsing forms of MS
 1st clinical episode and MRI
consistent with MS
22 mcg or 44 mcg tiw SC
250 mcg qod SC
INFβ = interferon beta; SC = subcutaneous; IM = intramuscular; tiw = 3 times per week; qod = every other day
*Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way
endorses the use of the product with the trade name.
Copaxone. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf
Avonex. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103628s5115lbl.pdf
Rebif. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/103780s5062lbl.pdf
Betaseron. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/103471s5032lbl.pdf
Extavia. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125290s0000lbl.pdf
REGARD: Primary endpoint10
Survival distribution function
1.00
Rebif® (IFNβ-1a)
672 days
(96 weeks)
(n=386)
0.75
Hazard ratio: 0.94
95% CI: 0.74-1.21
P=0.643
0.50
0
100
200
COPAXONE®
(glatiramer acetate injection)
(n=378)
300
400
500
600
Time to first relapse (days)
CI=confidence interval.
A hazard ratio of 1 would indicate that the curves were exactly identical.
10. Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
No significant difference
in:
– Hazard rates for time
to first relapse
between the Rebif®
and COPAXONE®
groups
– The proportion of
patients who were
relapse free over 96
weeks
0.25
0
•
700
REGARD: Safety and
immunogenicity10
35
COPAXONE® (n=378)
(glatiramer acetate injection)
30
Rebif® (IFNβ-1a) (n=386)
Patients (%)
25
20
15
10
5
0
Injection
site pruritis
Injection
site
swelling
Injection site Immediate
induration post-injection
drug reaction
Flu-like
illness
Headache
Adverse events
10. Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
Myalgia
AAT
elevation
Dyspnea
Depression
BEYOND: Primary efficacy endpoint8,15
Relapse rate reduction vs
pretreatment
– There was no significant difference among the 3 treatment arms
on the primary endpoint of risk for relapses
– Relapse rate reductions during the study period of up to 3.5
years were similar
in all 3 treatment groups
®
0
-20
-40
Betaseron 250 mcg
(IFNβ-1b)
COPAXONE®
Betaseron® 500 mcg
(glatiramer acetate injection)
79%
79%
n=899
n=448
78%
n=897
-60
-80
-100
During a double-blind, placebo-controlled pivotal trial, COPAXONE® reduced relapses by 29% vs
placebo over 2 years (1.19 vs 1.68; P=0.055).4
4. Johnson KP, Brooks BR, Cohen JA, et al. Neurology. 1995;45:1268-1276.
8. Data on file, Teva Neuroscience, Inc.
15. BEYOND press release. Bayer HealthCare AG. Oct 29, 2007.
FDA-Approved Therapies for MS:
Immunosuppressive
Agents*
Indications
Doses and Administration
2005 Natalizumab
(Tysabri®)a
Relapsing forms
of MS
300 mg q4wk IV
2000 Mitoxantrone
(Novantrone®)b
SPMS, PRMS,
worsening RRMS
12 mg/m2 over 5–15 min;
q3mo IV infusion
q4wk = every 4 weeks; q3mo = every 3 months
*Trade names are included in this presentation to reduce confusion regarding medication
formulations and in no way endorses the use of the product with the trade name.
aCurrently used as 2nd-line therapy
bOnly indicated for progressive and/or worsening disease; cumulative dose should not exceed
140 mg/m2
Natalizumab. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s106lbl.pdf
Mitoxantrone. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019297s030s031lbl.pdf
Natalizumab-Associated PML: Updated Incidence
and Risk Stratification
3
2.77
Incidence per 1,000 patients
2.61
2.5
2.38
2.30
2
2.17
2.10
1.94
2.01
1.56
1.5
1.68
1.37
1
0.79
0.85
0.58
0.5
0.41
0.04
0
Post
Marketing
1–12
13–24
25–36
37–48
49–60
Number of infusions
 PML risk lowest in anti-JCV Ab(-) pts: ≤ 0.10 cases/1,000 pts treated
 PML risk highest in pts with all 3 known risk factors (anti-JCV Ab(+), prior
immunosuppressant use, and 25-48 months of tx): 10.6 cases/1,000 pts
232 cases of PML have been documented in patients treated with natalizumab as of May 3, 2012. Available at:
http://chefarztfrau.de/?page_id=716
Bloomgren G, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S41.001.
Fingolimod (FTY720): Overview
• Therapeutic class
– Sphingosine-1-phosphate (S1P) receptor modulator
• Molecular mechanism of action (MOA)
– FTY720 binds to S1P receptors on lymphocytes
– Circulating lymphocytes are sequestered in lymph nodes
– Thought to reduce the infiltration of reactive effector T cells
and macrophages into the CNS
• Neurodegeneration/neuroprotection
– Modulation of S1P receptors located within the CNS may
lead to neuroprotective effects
Mandala S, et al. Science. 2002;296:346-349.
Kappos L, et al. N Engl J Med. 2006;355:1124-1140.
Jaillard C, et al. J Neurosci. 2005;25:1459-1469.
FREEDOMS: Key Efficacy Results
Annualized Relapse Rate
Disability Progression
0.4
30
- 60% versus
placebo
p < 0.001
FTY720 1.25 mg vs placebo
HR = 0.68, p = 0.017
0.3
0.2
0.18
0.16
0.1
Placebo
FTY720 0.5 mg vs placebo
HR = 0.70, p = 0.024
25
% with 3-mo confirmed
EDSS progression
Annualized Relapse Rate
0.4
- 54% versus
placebo
p < 0.001
20
FTY 0.5 mg
15
FTY 1.25 mg
10
5
0
0
Placebo
(n = 418)
Fingolimod 0.5
mg (n = 425)
Fingolimod 1.25
mg (n = 429)
0
90
180 270 360 450
Days on Study
540 630
http://www.novartis.com/downloads/investors/presentations-events/other-events/2009/20090930_fty720.pdf (accessed 2009-10-06)
Adapted from Kappos L, et al. N Engl J Med. 2010;362(5):387-401.
720
TRANSFORMS: Primary Efficacy Endpoint
Annualized Relapse Rate
Annualized Relapse Rate at 12 months
0.4
0.33
-52% vs IFNβ-1a,
P < 0.001
-38% vs IFNβ-1a,
P < 0.001
0.3
0.20
0.2
0.16
0.1
0
IFNβ-1a 30 µg IM
once weekly
(n = 431)
Oral fingolimod
0.5 mg
(n = 429)
Adapted from Cohen J, et al. N Engl J Med. 2010;362(5):402-415.
Oral fingolimod
1.25 mg
(n = 420)
TRANSFORMS: Key Safety Data
•Event, n (%)
•Flu-like illness
•IFNβ-1a 30 µg IM
once weekly
•(n = 431)
•159 (36.9)
•Oral fingolimod
0.5 mg
(n = 429)
•15 (3.5)
•Oral fingolimod
•1.25 mg
(n = 420)
•15 (3.6)
•Pyrexia
•77 (17.9)
•18 (4.2)
•15 (3.6)
•Myalgia
•44 (10.2)
•14 (3.3)
•14 (3.3)
•Hepatic ALT elevation
•8 (1.9)
•28 (6.5)
•24 (5.7)
•Hypertension
•8 (1.9)
•16 (3.7)
•21 (5.0)
•Dyspnea
•7 (1.6)
•8 (1.9)
•22 (5.2)
•Malignancies
•2 (0.5)
•8 (1.9)
•4 (1.0)
•Bradycardia
•0 (0.0)
•2 (0.5)
•10 (2.4)
•Atrioventricular block
•0 (0.0)
•2 (0.5)
•5 (1.2)
•Herpes viral infections
•1 (0.2)
•1 (0.2)
•3 (0.7)†
ALT = alanine transaminase
†Includes 2 fatal viral infections: primary disseminated varicella zoster and herpes simplex encephalitis
Adapted from Cohen J, et al. N Engl J Med. 2010;362(5):402-415.
Recent Additions to Fingolimod
Prescribing Information
• First Dose Monitoring:
– Observe all pts for signs and symptoms of bradycardia for at
least 6 hrs after first dose with hourly pulse and blood pressure
measurement
– Obtain ECG prior to dosing and at the end of the observation
period
– Pts who develop a heart rate < 45 bpm, or a new onset 2nddegree or higher AV block should be monitored until resolution
– Pts at lowest post-dose heart rate at the end of observation
period should be monitored until heart rate increases
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
Recent Additions to Fingolimod
Prescribing Information
• First Dose Monitoring (cont’d)
– In pts experiencing symptomatic bradycardia, begin continuous ECG
monitoring until symptoms have resolved; if pharmacological
intervention is required for bradycardia, continuous ECG monitoring
should continue overnight in a medical facility, and 1st-dose monitoring
procedures should be repeated for the 2nd dose
– Patients who may be less tolerant of fingolimod-induced bradycardia,
are at higher risk of serious rhythm disturbance, or with prolonged QTc
interval at baseline or at any time during the observation period should
be observed overnight with continuous ECG monitoring
• Patients who have stopped taking fingolimod and re-initialize
treatment are advised to again follow these updated
recommendations
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
Recent Additions to Fingolimod PI:
Improving Patient Selection
• Contraindications
– Recent (within the last 6 months) occurrence of: myocardial infarction,
unstable angina, stroke, transient ischemic attack, decompensated heart
failure requiring hospitalization, or Class III/IV heart failure
– History or presence of Mobitz Type II 2nd degree or 3rd degree AV block
or sick sinus syndrome, unless patient has a pacemaker
– Baseline QTc interval ≥ 500 ms
– Treatment with Class Ia or Class III anti-arrhythmic drugs
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
Fingolimod Cardiac Effects and Safety in
Clinical Practice
– First dose observation (FDO) uneventful in 307/317 pts
– 3 pts (0.9%) developed symptomatic sinus bradycardia
• Seen only in pts with abnormal screening EKG
• Those with low resting heart rate (HR) appear most at risk
– 2 pts (0.6%) patients developed transient chest tightness
– Significant decreases in HR, sBP, dBP, MAP observed 3 and 6
hrs after 1st dose
• Average ∆ HR: -14.9%; maximal within first 3 hrs
• 12 pts (3.8%) had HR drops of ≥ 30 bpm (all had baseline
HR > 90 bpm)
– Discontinuation rate at 3 months (9.5%) was higher than in
clinical trials and mostly related to adverse events
sBP = systolic blood pressure; dBP = diastolic blood pressure; MAP = mean arterial pressure
Ontaneda D, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract P04.138.
Ontaneda D, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract P04.130.
New Therapies for MS
• Oral Medications
• Monoclonal Antibodies
Teriflunomide*: TEMSO Efficacy
Year Clinical Outcomes
• Teriflunomide*1
– Parent compound used in treatment of RA
(leflunomide)
– Inhibits pyrimidine synthesis
• Reversibly inhibits dihydro-orotate dehydrogenase, key
enzyme in de novo pyrimidine synthesis
– Inhibits T cell division
• Alters tyrosine kinase activation of calcium mobilization
•
TEMSO (108-week,
randomized, double-blind,
placebo-controlled, parallelgroup, multicenter study)1,2
12-Week Confirmed
Progression in Disability
23.7%
– Inhibits EAE
P = 0.084
27.3
0.54
2-
31.2%
P = 0.0002
0.37
21.7
31.5%
29.8%
P = 0.028
20.2
P = 0.0005
0.37
Placebo Teriflunomide Teriflunomide
14 mg
7 mg
Placebo Teriflunomide Teriflunomide
14 mg
7 mg
ARR
TEMSO: Study of Teriflunomide in Reducing the Frequency of
Relapses and Accumulation of Disability in Patients With MS
*Investigational agent
1Tallantyre
2O’Connor
E, et al. Int MS J. 2008;15:62-68.
P, et al. ECTRIMS 2010; Gothenburg,
Sweden. Abstract 79.
Teriflunomide*: TEMSO
Safety and Discontinuations
AEs
Placebo
Teriflunomide 7 mg
Teriflunomide 14 mg
Any AE
87.5%
89.1%
90.8%
Serious AE
12.8%
14.1%
15.9%
Discontinuation AE
8.1%
9.8%
10.9%
Serious Hepatic
Disorders
2.5%
1.9%
2.5%
ALT > 3 Times Upper
Limit Normal
6.7%
6.3%
6.7%
Serious Infections
2.2%
1.6%
2.5%
n = 1088 patients randomized to teriflunomide (7 mg or 14 mg daily) or placebo
73.2% of patients completed treatment1
Leflunomide is pregnancy category X2
1O’Connor
*Investigational
agent
P, et al. ECTRIMS 2010; Gothenburg, Sweden. Abstract 79.
2http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020905s022lbl.pdf.
Accessed August 10, 2011.
BG-12
CONFIRM: ARR (1o Endpoint)
44%***
51%***
29%*
0.401
0.224
0.198
0.286
Placebo
(n = 363)
BG-12 BID
(n = 359)
BG-12 TID
(n = 345)
GA
(n = 350)
0.6
0.5
ARR
0.4
0.3
0.2
0.1
0
*P < 0.05; ***P < 0.0001
Fox R, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.003.
CONFIRM: MRI Outcomes (2° Endpoint)
New or Enlarging T2
Hyperintense Lesions
***
71%
***
73%
***
54%
20
15
10
5
10
Adjusted Mean No. of Lesions
Adjusted Mean No. of Lesions
25
New T1
Hypointense Lesions
5.1
4.7
8.0
***
65%
**
41%
3.0
2.4
4.1
5
7.0
17.4
***
57%
0
0
Placebo BG-12 BID BG-12 TID
GA
(n = 139) (n = 140) (n = 140) (n = 153)
Placebo BG-12 BID BG-12 TID
GA
(n = 139) (n = 140) (n = 140) (n = 154)
**P < 0.01; ***P < 0.0001
Miller D, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S11.001.
CONFIRM: Time to
Disability Progression
12-wk Confirmed Progression of Disability
Probability of Confirmed Disability
Progression
0.2
24-wk Confirmed Progression of Disability
0.2
HR vs placebo
BG-12 BID: 0.79, 21% reduction; P = 0.2536
BG-12 TID: 0.76, 24% reduction; P = 0.2041
Proportion
progressed at 2 yrs
0.169 (Placebo)
HR vs placebo
BG-12 BID: 0.62, 38% reduction; P = 0.0630
BG-12 TID: 0.67,33% reduction; P = 0.1172
GA: 0.87, 13% reduction; P = 0.5528
Proportion
progressed at 2 yrs
0.130 (BG-12 TID)
0.128 (BG-12 BID)
0.125 (placebo)
0.108 (GA)
0.1
0.1
0.086 (BG-12 TID)
0.078 (BG-12 BID)
0
0
BL 12
24
36
48
60
72
84
96
BL 12 24 36 48 60 72 84 96
Weeks
Fox R, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.003.
Weeks
CONFIRM: Safety
– Flushing and gastrointestinal symptoms were common AEs reported
more frequently in BG-12 groups vs placebo
• Incidence of flushing and gastrointestinal symptoms decreased
substantially after the first month of BG-12
– AEs reported more frequently with GA were
injection-related
– The incidence of serious infections was low and similar across
groups (1–2%)
• No opportunistic infections reported in any treatment arm
– No malignancies reported in patients receiving BG-12
Philips JT, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S41.005.
Monoclonal Antibodies for MS in Late Stage
Clinical Development
Agent
Mechanism of Action
Alemtuzumab
• Anti-CD52
• Depletes T and B lymphocytes
Daclizumab
• Anti-CD25 (IL-2 receptor
α-chain)
• Inhibits T lymphocyte activation and
expansion
Rituximab/
ocrelizumab
• Anti-CD20
• Deplete B lymphocytes
Rituximab Phase II data in MS
Hauser et al. NEJM: 358 (7): 676, Figure 2
Reductions in MRI Lesions with Daclizumab Depend on Magnitude
of Natural Killer (NK) Cell Expansion
Mean No.New/Enlarged Gd + Lesions
87% reduction (P = 0.024)
4
3.8
75% reduction
(P = 0.037)
3
2.0
2
1
0.5
0
IFN + Placebo (n = 17)
IFN + DAC (n = 11)
Lowest Quartile
CD56tright NK
IFN + DAC (n = 12)
Highest Quartile
CD56tright NK
Sheridan JP, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 430.
Alemtuzumab
Alemtuzumab CAMMS223 Study: Key
Efficacy Results
Sustained Accumulation of Disability
Time to First Relapse
SC IFNβ-1a
Alemtuzumab 12 mg/day
Alemtuzumab 24 mg/day
Alemtuzumab Pooled
40
SC IFNβ-1a
Alemtuzumab 12 mg/day
Alemtuzumab 24 mg/day
Alemtuzumab Pooled
60
30
73%
p < 0.0001
20
% Patients Relapsing
% of Pts with Sustained
Accumulation of Disability
50
40
72%
p < 0.0001
30
20
10
10
0
0
0
6
12
18
24
Months
30
36
42
48
0
6
12
18
24
Months
Coles A. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 890.
30
36
42
48
Alemtuzumab CAMMS223 Study: Key Efficacy
Results
Annualized Relapse Rate
0.5
Years 0-3
(p < 0.0001)
Years 0-4
(p < 0.0001)
EDSS Change from
Baseline to Year 4
Year 4
(p < 0.0001)
0.4
0.3
EDSS - Year 4 Change from Baseline
Annualized Relapse Rate
0.4
0.3
0.2
0.1
0.2
0.1
-0
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
0
IFNβ-1a
Alem
Pooled
IFNß-1a
Alem
Pooled
IFNß-1a
Alem
Pooled
IFNβ-1a
Alem Pooled
N = 30
N = 122
Coles A. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 890.
Alemtuzumab CAMMS223 Study: Safety
• Principal AEs associated with alemtuzumab
included:
– Infusion reactions
– Mild-to-moderate infections
– Autoimmunity
• Immune thrombocytopenia (ITP)
• Thyroid disorders (28% vs 3% for IFNβ-1a)
Coles A. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, 2009. Poster # 890.
CARE-MS II:
Phase III Study Design
IFNβ-1a
44 mcg SC
Randomized 2:1
Alemtuzumab
12 mg IV
Alemtuzumab
24 mg IV
0
12
3 ×/week
Daily
×5
Daily
×3
Daily
×5
Daily
×3
– 1 g methylprednisolone QD × 3 days at months 0 and 12 in all
treatment arms
– Blinded raters scored relapse, EDSS every 3 months, MSFC every
6 months, and MRI annually
– Relapse Adjudication Panel
– Randomization into 3rd treatment arm (24 mg/day alemtuzumab) was
discontinued early and it was thereafter deemed “exploratory” for statistical
purposes
Cohen J, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.004.
24
CARE-MS II: Relapses
ARR (Co-Primary Endpoint)
Proportion of Patients Relapse Free
0.9
SC IFNβ-1a
0.6
Alem 12 mg/day
0.5
0.4
0.3
0.2
0.1
0.26
0.52
0
Years 0–2
Percentage of Patients
Without Relapse
Adjusted ARR (95% CI)
Reduction 49.4%
0.8 P < 0.0001
0.7
SC IFNβ-1a
100
Alem 12 mg/day
90
80
70
65%
60
50
47%
47% Risk Reduction
40
P < 0.0001
0 3 6 9 12 15 18 21 24
Follow-Up Month
Cohen J, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.004.
CARE-MS II: 6-Month Sustained Accumulation of Disability (Coprimary Endpoint)
Patinets with SAD (%)
30
SC IFNβ-1a
Alem 12 mg/day
HR = 0.58
Treatment Effect 42%
P = 0.0084
25
20
21.1%
15
10
12.7%
5
0
0
3
6
9
12
15
18
Follow-Up Month
Cohen J, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.004.
21
24
CARE-MS II:
EDSS Change from Baseline
3.25
SC IFNβ-1a
Alem 12 mg/day
Mean EDSS Score
3.00
0.24
P = 0.0064
2.75
-0.17
P = 0.0044
2.50
2.25
0
3
6
9
12
15
18
Follow-Up Month
Cohen J, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.004.
21
24
CARE-MS II: Safety
SC IFNβ-1a
n = 202
Alemtuzumab
12 mg/day
n = 435
Alemtuzumab
24 mg/day
n = 161
Infusion Reactions
NA
393 (90.3)
156 (96.9)
Serious Infusion
Reactions
0
12 (2.8)
5 (3.1)
134 (66.3)
334 (76.8)
134 (83.2)
3 (1.5)
16 (3.7)
6 (3.7)
2 (1.0)
2 (0.46)
3 (1.9)
10 (5.0)
69 (15.9)
31 (19.3)
0
2 (0.5)
2 (1.2)
0
4 (0.9)
3 (1.9)
0
3 (0.7)
2 (1.2)
Adverse Events
N (%)
Infections
Serious Infections
Malignancies
Autoimmune Events
N (%)
Thyroid AEs
Serious Thyroid AEs
ITP AEs
Serious ITP AEs
Cohen J, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract S01.004.
Alemtuzumab Effects on
Immune Cells
• Alemtuzumab induces a significant Treg and Th2 cell
expansion and inhibits Th1 and Th17 cells
– At day 7 post-therapy, depletion of CD4+ and CD8+
T-cells by 99.9% and 99.2%, respectively
• CD4+ cells remained significantly decreased for 12 months
– Predominant expansion of CD45RO+ memory cells at month 1
and decreased percentage of CD45RA+ naïve cells in both
CD4+ and CD8+ T-cell populations
– Significantly increased (4.1-fold) the percentage of
CD4+CD25+CD127lowFOXP3 Treg cells at month 1
Zhang X, et al. Presented at AAN; April 21-28, 2012; New Orleans, LA. Abstract P02.119.
Defining Immunomodulation
and Immunosuppression
• Immunomodulation*
– Ability to alter immune function from its current state of
activity without any cytotoxic activity or bone marrow
suppression
– Therapeutic manipulation of the immune system
• Immunosuppression*
– Ability to alter the immune system through a direct
cytotoxic activity or bone marrow suppression
– Immunosuppression can lead to immuno-modulation
secondarily
*Defined by Adil Javed, MD, PhD, University of Chicago.
*Defined by Adil Javed, MD, PhD. University of Chicago.
Risk-Benefit Assessment
• Risk-Benefit assessments should include:
– The benefits of therapies
– The risks of those therapies
– The risks of not treating or
under-treating the disease itself
• Quality of life
• Long-term outcomes
• Patient’s history of disease and
disease activity
• Costs
Risk-Benefit information should be communicated to patients!
Highest Priority Therapy Categories
On a scale from 1 to 5, where 1=lowest priority and 5=highest priority, rate the priority to manage
each drug category.
EMD Serono Specialty Digest, 6th edition
MS Cost Drivers
Informal Care (12%)
Sick Leave/Reduced Working Time (10%)
Adaptations (5%)
Services (2%)
Other Drugs (6%)
Early Retirement (34%)
DMTs (22%)
Tests (2%)
Ambulatory Care (4%)
DMT = disease-modifying therapy.
Kobelt G, et al. Neurology. 2006;66(11):1696-1702.
Hospital Inpatient Care (3%)
Dramatic Price Increases for MS Agents
$4,700
$4,500
Gilenya
$4,300
$4,100
$3,900
$3,700
$3,500
$3,300
Copaxone
Betaseron
Avonex
$3,100
Tysabri
$2,900
Rebif
Extavia
$2,700
Sep-09 Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Mar-10 Apr-10
May- Jun-10 Jul-10 Aug-10 Sep-10 Oct-10 Nov-10 Dec-10 Jan-11 Feb-11 Mar-11
10
Per First DataBank , pricing information represents a 28 day supply of each medication
MS Non-adherence Ranks High Compared to
Other Diseases
Patients not adhering, %
80
Non-adherence across chronic disease states
60
40
20
0
Cancer2
Asthma1
Renal
Transplant4
Epilepsy1
HIV5
Hypertension1
MS3
Depression5
Diabetes1
Arthritis1
Note: If range is available, mean number is presented.
1. Berg JS, et al. Ann Pharmacother. 1993;27(Suppl 9):S1-S24.
2. Cuzick J, et al. Lancet. 1999;353:930.
3. Hadijmichael O, et al. Neurology. 1999;52(Suppl 2):A549.
4. Wells H. Hosp Pharmacist. 2004;11:69-71.
5. World Health Organization. Adherence to Long-term Therapies—Evidence for Action. 2003.
82
Compounds in
development for
Multiple Sclerosis
MHC class II
modulator
Recombinant
human alphafetoprotein
T cell receptor
vaccine
CCR2 agonist
Phase I
MM-093
Integrin
antagonist
CCX140
Phase II
TV 3606
Tovaxin
NeuroVax
MLN-1202
PI-2301
Unidentified
Mechanism
AMPA
receptor
antagonist
TV-5010
Phase III
R 1295
Immunomodulator
INCB8696
Nrf2 activator
BGC20-0134 IR 208
Reg.
MCT125
anti CD52
Revimmune
Laquinimod
Heat
shock
protein
BG-12
Launched
E-2007
IL-27
agonist
Alemtuzumab
XToll
Novantrone
RPI-78M
CDP323
Copaxone
VLA-4
antagonist
Elnd002/Elnd
004
Firategrast
Estrogen
agonist
Estriol
Tysabri
DNA
ntercalating Pixantrone
agent
T cell
regulator
ATXMS1467
Avonex
LAS 186323
Teriflunomide
ATL-1102 / TV-1102
Rebif
Betaseron
dihydro-orotate
dehydrogenase
Atacicept
Extavia
Ocrelizumab
Biferonex
BAF312
Asonep
ONO-4641
CS-0777 S1P
Pegylated Avonex
ofatumumab
Anti CD 20
Fingolimod
Fampridine-sr
MBP8298
BHT-3009
Cladribine
AZD5904
Masitinib
RTL1000
Baroferon
LY2127399
T cell
activation
inhibitor
Tyrosine
kinase
inhibitor
Key
Biological
Antisense
inhibitor of
CD49d
NCE
Nerispirdine Daclizumab
Pegylated IFN-β
IFN-ß
IL-23 antibody
& anti-BAFF
human
antibody
K Channel
Blocker
IL-2 Blocker
6
ribonucleotide
reductase
inhibitors
B-lymphocyte
stimulator
modulators
myeloperoxidas
e inhibitor
Thank you for your attention
Questions
?