New and Emerging Therapies in
MS: Is It Time to Change the
Status Quo?
Anne H. Cross, MD
Professor of Neurology
Washington University School of Medicine
St. Louis, Missouri
1
Outline

How have our goals been altered by the new MS
therapies?
–
–

3 newest FDA-approved disease-modifying therapies
–
–
–

Natalizumab
Fingolimod
Teriflunomide
Drugs in late-phase trials
–
–

Balancing efficacy with safety
The “old guard” medications vs newer agents
Dimethyl fumarate, alemtuzumab, daclizumab, laquinimod,
and ocrelizumab
Combination therapies: teriflunomide + IFN-β, CombiRx trial
Individualizing therapy
–
The role of MRI and other biomarkers in guiding therapies
2
9 FDA-Approved MS
Disease-Modifying Therapies
Drug
Approved
Type of MS
1st/2nd
Line
1993, 2009
Relapsing MS, CIS
1st
Glatiramer acetate SQ QD
1996
RRMS, CIS
1st
Interferon -1a IM weekly
1996
Relapsing MS, CIS
1st
Mitoxantrone IV q3mo
(dose limit)
2000
Worsening RRMS,
SPMS, progressive
relapsing MS
2nd
IFN -1a SQ TWI
2002
RRMS
1st
2004/2006
Relapsing MS
2nd
Fingolimod oral QD
2010
Relapsing MS
1st
Teriflunomide oral QD
2012
Relapsing MS
1st
Interferon -1b
(2 products) SQ QOD
Natalizumab IV q4wk
Abbreviations: CIS, clinically isolated syndrome; MS, multiple sclerosis; RRMS, relapsing-remitting
MS; SPMS, secondary-progressive MS. Graphic courtesy of Anne H. Cross, MD.
3
More Treatments Are Good,
But It Makes Treatment Choices
More Difficult!
Graphic courtesy of Anne H. Cross, MD.
4
Treatment Decisions—A
Balancing Act
Benefits
Impact
Disease course
Disability outcomes
Tolerance
Convenience
Graphic courtesy of Anne H. Cross, MD.
Risks
Short-term safety
Long-term safety
Pregnancy
Financial costs
5
Role of MRI in Guiding Initial
Medication Decisions

Improves diagnostic certainty
–

Helps to gauge the aggressiveness of the MS
–
–
–

Spinal cord MRI
Number and extent of T2 lesions on early MRI
Infratentorial lesions
Degree of cerebral atrophy − requires careful
measurement
Helps to gauge MS activity
–
Number of contrast-enhancing lesions

Although correlation of Gd+ lesions with future disability
not clear
6
Advantages of The “Old Guard”
Interferon-βs and Glatiramer Acetate

Highly efficacious in a sizeable proportion of
relapsing-remitting MS patients

Known safety profiles – years, decades

No immunosuppression

Glatiramer acetate (GA) is Pregnancy
Category B

No blood monitoring needed for GA
7
Disadvantages of The “Old Guard”
IFN-βs and GA


Partial efficacy against relapses
Effect on long-term disability less clear
–






Immediate IM IFN β-1a at time of clinically isolated
syndrome reduced relapse rate over 10 years but did
not improve disability outcomes1
Neutralizing antibody formation with IFNs
Injections: site reactions, lipoatrophy, infections
“Flu-like” illness with IFN-βs
Nonadherence in up to 40%−50%2,3
Blood monitoring needed for IFN-βs
IFN-βs are Pregnancy Category C
1. Kinkel RP, et al. Arch Neurol. 2012;69:183-190. 2. Klauer T, et al. J Neurol. 2008;255:87-92.
3. Wong J, et al. Can J Neurol Sci. 2011;38:429-433.
8
Long-Term Outcome Considerations






Age of patient and expected lifespan?
How aggressive does the disease appear?
How long can the patient be on the
medication?
Future and present childbearing potential?
Concomitant illnesses?
Does the medication increase risk of future
neoplasm?
9
Newer Drugs
10
Natalizumab
11
Transmigration of Inflammatory Cells
Lymphocyte
Lectins
Chemokine
VLA-4, LFA-1,
Mac-1,
(integrins)
Chemokine R
Blood
Addressins
ICAM-1, VCAM-1
(Ig superfamily)
Step 1 (“rolling”)
Step 2
Chemokines
Graphic courtesy of Anne H. Cross, MD.
MMPs
Step 3
Inside the CNS12
Natalizumab for Relapsing MS


Humanized monoclonal antibody to α4-integrins
(part of VLA-4)1
Blocks interactions of α4β1 and α4β7 on
leukocyte surface with VCAM-1 on endothelium
and fibronectin in extracellular matrix1
–


Suppressing cell transmigration through the blood–
brain barrier and trafficking into tissues
Initially approved 2004, “generally
recommended for patients who have had an
inadequate response to, or unable to tolerate, an
alternate MS therapy”2
Available only through the TOUCH program2
1. Engelhardt B, et al. Neurodegener Dis. 2008;5:16-22.
2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.
13
Natalizumab—Boxed Warning

“[Natalizumab] increases the risk of progressive
multifocal leukoencephalopathy (PML), an
opportunistic viral infection of the brain that
usually leads to death or severe disability”1

As of October 3, 2012, 298 cases of PML with
104,300 exposures to natalizumab worldwide2

3 risk factors for PML1
–
Longer treatment duration, particularly >2 years
–
Prior immunosuppressant treatment
–
Presence of anti-JCV antibodies
1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.
2. Biogen Idec. Tysabri Update. October 18, 2012.
14
PML—Biomarkers to Stratify
Risks with Natalizumab
Anti-JCV Antibody Positive +
Natalizumab
Exposure

No
Yes
1–24 months
<1/1000
2/1000
24–48 months
4/1000
11/1000
Antibodies to JCV indicate prior JCV exposure and risk of PML
–

Prior Immunosuppressant Use
Absence of anti-JCV antibodies indicates low, but not 0, risk
Examples of prior immunosuppressants include mitoxantrone,
azathioprine, methotrexate, cyclophosphamide, mycophenolate
mofetil
FDA. Drug Safety Communication. Accessed 12/21 at:
http://www.fda.gov/drugs/drugsafety/ucm288186.htm.
15
AFFIRM Trial—Natalizumab vs Placebo
Annualized Relapse Rate,
Primary Endpoint at 1 Year
Adjusted Annualized
Relapse Rate
0.9
0.81
Placebo (n = 315)
0.8
Natalizumab (n = 627)
0.7
0.6
0.5
P <.001
0.4
0.3
0.26
0.2
0.1
0
Polman CH, et al. N Engl J Med. 2006;354:899-910.
16
AFFIRM Trial—Natalizumab vs Placebo
Risk of Sustained
Progression of Disability (%)
Sustained Progression of Disability,
Primary Endpoint at 2 Years
35
30
Placebo (n = 315)
29
25
20
Natalizumab (n = 627)
P <.001
17
15
10
5
0
Polman CH, et al. N Engl J Med. 2006;354:899-910.
17
AFFIRM—Natalizumab Compared
with Placebo
Secondary Imaging Endpoints
83%
New or enlarging T2 lesions at year 2
92%
Gd+ lesions at years 1 and 2
Polman CH, et al. N Engl J Med. 2006;354:899-910.
18
Patients Free of Clinical and
Radiologic Disease Activity* (%)
AFFIRM—Proportion of Patients
Without Disease Activity at 2 Years
Post-Hoc Analysis
50
45
40
35
30
25
20
15
10
5
0
Placebo (n = 304)
37
Natalizumab (n = 600)
P <.0001
7
*No relapses, sustained disability progression, Gd+ lesions, or new or enlarging T2-hyperintense lesions.
19
Havrdova E, et al. Lancet Neurol. 2009;8:254-260.
It’s Time to Move
The Goalposts Toward
Disease Activity-Free
Status!
Graphic courtesy of Anne H. Cross, MD.
20
MRI Can Be Used to
Monitor Treatment

MRI can detect “breakthrough” disease
–
New lesion or enhancing lesion

Enhancing lesion or new T2 lesion >12 months on IFN-β
suggests future nonresponsiveness to IFN-βs1,2

Equivalent studies not done with glatiramer acetate,
natalizumab, fingolimod, or teriflunomide
–

But progression of MRI lesions on any of these medications
raises the question of efficacy for individual patient
Timing of baseline MRI is a question
–
Consider waiting until 1–2 months on new therapy to ensure
that next MRI truly reflects the new medication effects
1. Tomassini V, et al. J Neurol. 2006;253:287-293. 2. Rudick RA, et al. Ann Neurol. 2004;56:548-555.
21
Case 1—Mr. R History and
Presentation

44-year-old male architect

1-year history of personality changes

Lost job 6 months prior to presentation

Around same time, he developed weakness
and tingling when taking showers

Abnormal gait noticed by wife
22
Case 1—Initial MRI Findings

>20 Gd+ lesions

Many T1-weighted
hypointensities
(“black holes”)

Significant brain
volume loss
Graphic courtesy of Anne H. Cross, MD.
23
Case 1—CSF and Neurocognitive
Findings

Cerebrospinal fluid (CSF) analysis
– 9 oligoclonal bands restricted to CSF
– IgG Index 0.85
– 10 mononuclear cells

Formal neurocognitive testing
– Severe deficits in learning, memory, and
reasoning
24
Case 1—First-Line Treatment
Decision

Initial laboratory tests and baseline
evaluations normal
– Dermatology, ophthalmology

Negative for anti-JC virus antibodies

Began natalizumab 300 mg IV every 4 weeks
25

Case 1—Follow-Up at 4 and 6
Months
MRI after 4 months
–
–
–

All enhanced lesions
disappeared
No new MS lesions
Cerebral volume loss
remained, along with
sizeable burden of
disease on T2 and T1
weighted MR imaging
Neurocognitive testing
after 6 months
–
–
–
Minimal improvement
Failed driving test
Unable to return to work
Graphic courtesy of Anne H. Cross, MD.
26
Case 1—Ongoing Management

Continues to take natalizumab

Monitoring plans
– Liver function tests and complete blood count
every 3 months
– Anti-JC virus antibodies every 6 months
– MRI yearly
– Dermatology and ophthalmology exams yearly
27
Fingolimod
28
Fingolimod—Mechanism of Action
Blood
Efferent
lymph
Lymph node
S1P
gradient
= lymphocyte




Down-modulates sphingosine-1-phosphate receptors1
Leaves T- and B-cells unable to migrate along a sphingosine-1phosphate gradient between lymph tissue and blood1
Retains otherwise healthy lymphocytes in lymph nodes1
No effect on lymphocyte induction, proliferation, memory1,2
1. Brinkmann V, et al. Am J Transplant. 2004;4:1019-1025. 2. Pinschewer DD, et al. J Immunol.
2000;164:5761-5770. Graphic courtesy of Anne H. Cross, MD.
29
Fingolimod Crosses the Blood-Brain
Barrier—May Have Beneficial CNS Effects

Fingolimod may be phosphorylated in the CNS1

Fingolimod modulates sphingosine-1-phosphate
(SIP) receptors: 1, 3, 4, and 5 (all but SIP2) 2

S1P receptors throughout body, including on glia and
neurons in the CNS3

S1P5 agonists enhance blood-brain barrier function
of cultured human endothelial cells4

Increased brain-derived neurotrophic factor
production by neurons in mouse model5
1. Foster CA, et al. J Pharmacol Exp Ther. 2007;323:469-475. 2. Brown BA, et al. Ann Pharmacother.
2007;41:1660-1668. 3. Aktas O, et al. Nat Rev Neurol. 2010;6:373-382. 4. van Doorn R, et al.
J Neuroinflamm. 2012;9:133. 5. Deogracias R, et al. Proc Natl Acad Sci USA. 2012;109:14230-14235.
30
FREEDOMS—Fingolimod vs Placebo
for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.45
0.4
Placebo
FNG 1.25 mg
FNG 0.5 mg*
0.4
0.35
0.3
0.25
0.2
P <.001 for both
0.16
0.18
0.15
0.1
N = 1272
mean age 36–37 y,
mean EDSS 2.3–2.5
0.05
0
*FDA-approved dose.
Abbreviations: EDSS, Expanded Disability Status Scale; FNG, fingolimod.
Kappos L, et al. N Engl J Med. 2010;362:387-401.
31
FREEDOMS—Fingolimod 0.5 mg*
Compared with Placebo, 2 Years
Secondary Endpoints
30%
Sustained disability progression (3 months)
30%
Reduction in rate of decrease in
MRI brain volumes
89.7% vs 65.1%
Free of Gd+ lesions
*FDA-approved dose.
Kappos L, et al. N Engl J Med. 2010;362:387-401.
32
TRANSFORMS—Fingolimod vs
IFN β-1a IM for 1 Year
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.35
IFN beta-1a 30 µg/wk
FNG 1.25 mg
FNG 0.5 mg*
0.33
0.3
0.25
0.2
P <.001 for both
0.2
0.16
0.15
0.1
N = 1280
mean age 35–36 y,
mean EDSS 2.2–2.4
0.05
0
*FDA-approved dose.
Abbreviations: EDSS, Expanded Disability Status Scale; FNG, fingolimod.
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
33
TRANSFORMS—Fingolimod 0.5 mg*
Compared with IFN β-1a, 1 Year
Secondary Endpoints
No Difference
Sustained disability progression (3 months)
35%
Mean new or enlarged T2 lesions
55%
Mean Gd+ lesions
In 1.25-mg arm, 2 deaths from herpes infections (encephalitis, disseminated varicella zoster).
*FDA-approved dose.
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
34
FREEDOMS II—Fingolimod vs Placebo
for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.45
0.4
0.4
Placebo
FNG 0.5 mg*
0.35
0.3
0.25
0.2
0.15
0.1
P <.001
0.21
N = 1083
Mean age 40–41 y,
mean EDSS 2.4–2.5,
higher BMI than
FREEDOMS
0.05
Note: Showing
only the 0.5 mg
dose.
*FDA-approved dose.
Abbreviations: BMI, body mass index; EDSS, Expanded Disability Status Scale; FNG, fingolimod.
35
0
Calabresi PA, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Poster P491.
FREEDOMS II—Fingolimod 0.5 mg*
Compared with Placebo, 2 Years
Secondary Endpoints
17% (NS)
Disability progression (3 months)
33%
Proportion of brain volume loss
Adverse effects, FNG 0.5 mg vs placebo: herpes zoster: 2.5% vs 0.8%; basal
cell skin cancer: 2.8% vs 0.6%; hypertension 8.9% vs 3.1%. No deaths.
*FDA-approved dose.
Abbreviations: FNG, fingolimod; NS, nonsignificant.
Calabresi PA, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract P491.
36
Fingolimod—Contraindications

Within past 6 months: 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- or
3rd-degree atrioventricular block or sick sinus
syndrome, unless patient has a functioning
pacemaker

Baseline QTc interval ≥500 ms

Treatment with Class Ia or Class III
antiarrhythmic drugs
Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
37
Fingolimod—Other Precautions

Monitor pulse and blood pressure after 1st dose
>6 hours
–
If heart rate has not reached nadir after 6 hours, continue
monitoring
–
Patients on drugs that prolong QT or that cause bradycardia
should be monitored with EKG overnight

Obtain EKG prior to and at end of dosing

Monitor for signs/symptoms of infections
–
Avoid live vaccines

Perform ophthalmologic exam at baseline and at 3–4
months (macular edema)

Obtain pulmonary function tests, if indicated

Contraception during and for 2 months after stopping
Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
38
Case 2—Mrs. M History and
Presentation

54-year-old female real estate agent
– Works full time, right-handed

MS began at age 40 with optic neuritis

Initially took glatiramer acetate for
5 years
– Single mild relapse and lipoatrophy

Switched to an interferon-β
39
Case 2—History and Presentation

Developed fatigue

Timed 25-Foot Walking (T25FW) worsened
– 7 seconds, 2010
– 8.4 seconds, 2011
– 9 seconds, early 2012

Neutralizing antibodies, negative

No history of heart disease, lung disease, or
hypertension
40
Case 2—MRI Findings

Brain MRI showed
findings compatible
with MS

Patient had a mild to
moderate burden of
disease
– A few “black holes”
– No enhancing lesions
Graphic courtesy of Anne H. Cross, MD.
41
Case 2—Evaluation and
Switching Therapy

Laboratory tests
–
–
–
–




Complete metabolic profile (CMP), including liver
function tests – normal
CBC – normal
Varicella zoster +IgG
Pregnancy test – negative
Dermatology and ophthalmology evaluations –
normal
12-lead EKG with rhythm strip – normal
Initiated fingolimod at standard 0.5 mg/day dose
1st dose observation March 2012 (after
approximately 4-week wash-out period)
42
Case 2—Follow-Up

Patient tolerating fingolimod well

Fatigue improved

Monitoring plans
– Ophthalmology exam at 3–4 months, then yearly
– Lab tests monthly for first 3 months, then every
3 months

Her total lymphocyte count 3 months after starting
fingolimod was 400/mL
– Yearly MRI
– Yearly dermatology evaluation
43
Teriflunomide
44
Teriflunomide—Overview

Approved fall 2012 for relapsing MS
– 1st-line agent
– Oral – 7 mg or 14 mg daily

Antiproliferative and anti-inflammatory1

Not considered “immunosuppressive”1

Active metabolite of leflunomide, approved
for rheumatoid arthritis in 19981
1. Claussen MC, et al. Clin Immunol. 2012;142:49-56.
45
Teriflunomide—Mechanism
of Action

Inhibits the pyrimidine synthesis enzyme, dihydroorotate dehydrogenase (DHODH)

2 pathways of pyrimidine synthesis
–
de novo synthesis used in activated lymphocytes
–
Salvage pathway used by resting lymphocytes

8-fold increase in pyrimidine synthesis required for
proliferation of activated lymphocytes

Without DHODH, sufficient pyrimidine cannot be
synthesized to support proliferation

Does not eliminate resting lymphocytes
Claussen MC, et al. Clin Immunol. 2012;142:49-56.
46
TEMSO—Teriflunomide vs Placebo
for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.6
0.54
0.5
P <.001 for both
0.4
0.37
Placebo
TFN 7 mg
TFN 14 mg
0.37
0.3
N = 1086
Mean EDSS 2.68
0.2
0.1
0
Abbreviations: EDSS, Expanded Disability Status Scale; TFN, teriflunomide.
O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.
47
TEMSO—Teriflunomide Compared
with Placebo, 2 Years
Secondary Endpoints
23.7% (7 mg) and 29.8% (14 mg)
Sustained disability progression (3 months)
48% (7 mg) and 69% (14 mg)
Combined unique and active MRI lesions
O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.
48
TOWER—Teriflunomide
vs Placebo for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.6
0.5
0.4
Placebo
TFN 7 mg
TFN 14 mg
0.501
P = .0183
0.389
P = .0001
0.319
0.3
N = 1165
Mean EDSS 2.7
0.2
0.1
0
Abbreviations: EDSS, Expanded Disability Status Scale; TFN, teriflunomide.
49
Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.
TOWER—Teriflunomide
Compared with Placebo, 2 Years
Secondary Endpoints
31.5% (14 mg)*
Sustained disability progression (3 months)
52% (14 mg) and 38% (placebo)
Relapse-free at study end
*7 mg, nonsignificant.
50
Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.
Teriflunomide—Additional Trials

TENERE1
– Teriflunomide vs IFN β-1a TIW
– No difference in failure rate (confirmed relapse
or stopping therapy for any reason)
– No difference in annualized relapse rate with
14 mg dose; 7 mg dose did less well

TERACLES2
– Add-on to IFN-β, ongoing

TOPIC3
– Clinically isolated syndrome, ongoing
1. Vermersch P, et al. CMSC-ACTRIMS 2012; May 30-June 2, 2012; San Diego, California.
2. ClinicalTrials.gov ID: NCT01252355. 3. ClinicalTrials.gov ID: NCT00622700.
51
Teriflunomide—Boxed Warnings
and Contraindications

Boxed warnings
– Hepatotoxicity
– Teratogenicity, based on animal studies

Contraindications
– Pregnancy
– Known severe hepatic impairment
– Currently taking leflunomide

Can be eliminated using cholestyramine or
activated charcoal
Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.
52
Teriflunomide—Adverse Effects

Gastrointestinal discomfort1
–

Other1
–
–
–
–

Nausea, diarrhea, pain
Hair thinning
Liver enzyme elevation
Weight loss
Hypertension
Reported with leflunomide2
–
–
–
Cases of pulmonary infection, including TB
1 PML case in systemic lupus erythematosus patient
who had been on multiple immunosuppressants
No increase in malignancies
1. Aubagio [PI]. Cambridge, MA: Genzyme Corporation; 2012.
2. Warnke C, et al. Neuropsychiatr Dis Treat. 2009;5:333-340.
53
Case 3—Ms. L History and
Presentation

48-year-old female department store manager
–



MS began at age 38 with numbness in 1 leg
Had several attacks, most with >80% recovery
before disease-modifying therapy
Started IFN β-1a SC 44 ug TIW about 2 years
after diagnosis
–

Thin, right-handed
Has taken it since, with few neurologic problems
Complained at visit earlier this year about
injection-site reactions
–
Admitted missing about 25% of injections
54
Case 3—MRI Findings

MRI was compatible
with MS
– Mild to moderate
lesion burden

No enhancing
lesions

No “black holes”
Graphic courtesy of Anne H. Cross, MD.
55
Case 3—Evaluation and
Switching Therapy

Laboratory tests
– CMP with liver function tests – normal
– CBC with differential – normal
– Pregnancy test – negative

TB skin test – negative

Blood pressure – 112/70

Initiated teriflunomide at 14 mg/day

No wash-out from interferon-β
56
Case 3—Follow-Up

Very happy taking it after 2 months
– Although concerned about possible hair loss

Monitoring plan
– Liver function tests every month for 6 months
then every 2–3 months
– CBC every 2–3 months
– Blood pressure check every 2–3 months
– MRI brain yearly
57
What’s in the Pipeline?
Graphic courtesy of http://opsweb.phmsa.dot.gov/pipelineforum/facts-and-stats/index.html.
58
MS Pipeline
Agent
*Dimethyl fumarate
(BG-12), oral1
*Alemtuzumab, IV1
(SC under evaluation2)
Laquinimod, oral1
Daclizumab, IV1
Ocrelizumab, IV1
Mechanisms of Action
Activates Nrf2, prevents
oxidative stress
Anti-CD52 (depletes T- and
B-cells and monocytes)
Th2 shift
Anti-CD25 (increases CD56+
natural killer cells)
Anti-CD20 (depletes B-cells)
*Under review by FDA. Abbreviation: Nrf2, nuclear factor erythroid 2-related factor.
1. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137.
2. Perumal JS, et al. Mult Scler. 2012;18:1197-1199.
Graphic courtesy of Anne H. Cross, MD.
59
Dimethyl Fumarate (BG-12)—
Overview

240 mg BID or TID, oral

Activates nuclear factor erythroid 2-related
factor 2 (Nrf2) transcriptional pathway1

Nrf2 antioxidant response pathway regulates
phase 2 detoxifying enzymes crucial to
countering oxidative stress1

Not considered immunosuppressive
1. Linker RA, et al. Brain. 2011;134:678-692.
60
DEFINE—BG-12 BID and TID
vs Placebo for 2 Years
Proportion of Relapsers, Primary Endpoint
50
Placebo
BG-12 240 mg BID
BG-12 240 mg TID
46
Proportion of Patients
Who Relapsed (%)
45
40
35
P <.001 for both
30
27
25
26
N = 1234
20
15
10
5
0
Gold R, et al. N Engl J Med. 2012;367:1098-1107.
61
DEFINE—BG-12 BID and TID
Compared with Placebo, 2 Years
Secondary Endpoints
53% (BID) and 48% (TID)
Annualized relapse rate
38% (BID) and 34% (TID)
Sustained disability progression (3 months)
85% (BID) and 74% (TID)
New or newly enlarged T2 lesions
90% (BID) and 73% (TID)
New Gd+ lesions
Gold R, et al. N Engl J Med. 2012;367:1098-1107.
62
CONFIRM—BG-12 BID and TID
vs Placebo vs GA for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.45
0.4
0.4
P = .01
0.35
0.3
0.25
0.2
0.29
P <.001 for both
0.22
0.2
Placebo
BG-12 240 mg BID
BG-12 240 mg TID
GA
N = 1417
0.15
0.1
0.05
Trial not designed to
test superiority/
noninferiority of GA
0
Abbreviation: GA, glatiramer acetate.
Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.
63
CONFIRM—BG-12, BID and TID, and
GA Compared with Placebo, 2 Years
Secondary Endpoints
34% (BID), 45% (TID), and 29% (GA)
Proportion of patients who relapsed
21% (BID), 24% (TID), and 7% (GA) – NS for all
Sustained disability progression (3 months)
71% (BID), 73% (TID), and 54% (GA)
New or enlarging T2 lesions
57% (BID), 65% (TID), and 41% (GA)
New T1 hypointensities
Abbreviation: NS, nonsignificant.
Fox RJ, et al. N Engl J Med. 2012;367:1087-1097.
64
BG-12—Adverse Effects

Adverse effects with incidence ≥5% higher in
BG-12 vs placebo
–
–
–




Flushing (hot flashes)
Gastrointestinal effects – diarrhea, nausea, upper
abdominal pain
Rash
No increase in serious infections or malignancies
No opportunistic infections reported
Mean lymphocyte count decreases by
25%–30% over year 1, then plateaus
Liver transaminases increase first 6 months
Selmaj K, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 484.
65
Alemtuzumab—Overview

Monoclonal antibody to CD521

Humanized IgG11
–


Cell lysis via antibody-dependent cellular cytolysis1
CD52
–
12 amino acid glycosylated surface protein on T- and
B-cells, natural killer cells, monocytes, and some
dendritic cells1-3
–
Role of CD52 not fully known1
–
Cross-linking leads to T-cell activation4
Route of administration – IV; SC under evaluation5
1. Hu Y, et al. Immunology. 2009;128:260-270. 2. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137.
3. Buggins AG, et al. Blood. 2002;100:1715-1720. 4. Hederer RA, et al. Int Immunol. 2000;12:505-516.
66
5. Perumal JS, et al. Mult Scler. 2012;18:1197-1199.
CARE-MS I—Alemtuzumab IV
vs IFN β-1a SC for 2 Years
Annualized Relapse Rate
0.45
0.4
0.35
0.39
P <.0001
0.3
0.25
0.2
0.15
0.1
0.05
0
0.18
Sustained Progression of
Disability at 6 Months (%)
Co-Primary Endpoints
12
11.12
IFN β-1a 44 µg
SC TIW (n = 187)
ALZ 12 mg/day
IV (n = 376)*
10
8
6
4
2
8.00
P = .22
Naive RRMS
patients,
mean age 33 y,
mean baseline
EDSS 2.0
0
*Alemtuzumab given once daily for 5 days at baseline and once daily for 3 days at 12 months.
Abbreviations: EDSS, Expanded Disability Status Scale; ALZ, alemtuzumab.
Cohen JA, et al. Lancet. 2012 Oct 31. [Epub ahead of print].
67
CARE-MS II—Alemtuzumab IV
vs IFN β-1a SC for 2 Years
0.6
0.52
0.5
0.4
0.3
0.2
0.1
0
IFN β-1a 44 µg
SC TIW (n = 202)
ALZ 12 mg/day
IV (n = 426)*
25
P <.0001
0.26
Sustained Progression of
Disability at 6 Months (%)
Annualized Relapse Rate
Co-Primary Endpoints
21.13
20
P = .008
15
10
5
12.71
RRMS patients
with relapse on
prior DMT,
mean age 35 y,
mean baseline
EDSS 2.7
0
*Alemtuzumab given once daily for 5 days at baseline and once daily for 3 days at 12 months.
Abbreviations: ALZ, alemtuzumab; EDSS, Expanded Disability Status Scale.
Coles AJ, et al. Lancet. 2012 Oct 31. [Epub ahead of print.]
68
Alemtuzumab—Adverse Effects


CARE-MS I1
–
Infusion reactions (90%, 3% serious)
–
More infections with alemtuzumab (mainly mild/moderate)
–
Herpetic infections 16% vs 2%
–
Secondary autoimmunity (ITP, thyroid)
–
2 with thyroid papillary carcinoma
CARE-MS II2
–
Similar to CARE-MS I
–
90% had infusion reaction
–
Increase in mild to moderate infection
–
Secondary autoimmunity (ITP 1%, thyroid 16%)
Abbreviation: ITP, immune thrombocytopenia.
1. Cohen JA, et al. Lancet. 2012 Oct 31. [Epub ahead of print].
2. Coles AJ, et al. Lancet. 2012 Oct 31. [Epub ahead of print.]
69
Prolonged Alterations of
Lymphocytes with Alemtuzumab

Follow-up of initial 37 MS patients receiving
single dosing of alemtuzumab in 1990s

Median time to recover to lower limit of
normal range after single dose
– 35 months for CD4+ T-cells
– 20 months for CD8+ T-cells
– 7.1 months for B-cells

CD4+ and CD8+ T-cells did not recover to
baseline in most patients
Hill-Cawthorne GA, et al. J Neurol Neurosurg Psychiatry. 2012;83:298-304.
70
Alemtuzumab—Secondary
Autoimmunity

Data from 5-year extension of CAMMS223
phase II trial1
– Immune thrombocytopenic purpura, 3%

1 fatality
– Thyroid autoimmunity, 30% vs 4% for IFN β-1a
– Goodpasture’s Disease (anti-GBM disease)


1 patient identified by monitoring 39 months after the
2nd annual cycle of alemtuzumab
Higher serum IL-212,3 and CCL213 may predict
future autoimmunity, even before
alemtuzumab initiation
Abbreviation: Glomerular basement membrane.
1. Coles AJ, et al. Neurology. 2012;78:1069-1078. 2. Jones JL, et al. J Clin Invest. 2009;119:2052-2061.71
3. Jones JL, et al. Mult Scler J. 2011:17(suppl10):S459.
Other Drugs for MS in Late
Phase Trials
72
Laquinimod—Overview

Oral synthetic chemical1
–

Penetrates intact blood-brain barrier and into
CNS tissues2
–



Structure based on linomide, which was effective in
MS but had cardiopulmonary toxicity
May act in both the periphery and in the CNS itself
Increased serum BDNF levels in RRMS1
Decreased inflammatory gene expression on
human cells in vitro through decreased NFκB3
Decreased MHC class II on human PBMC in
vitro3
1. Thöne J, et al. Am J Pathol. 2012;180:267-274. 2. Brück W, Wegner C. Insight into the mechanism of
laquinimod action. J Neurol Sci. 2011;306:173-179. 3. Gurevich M, et al. J Neuroimmunol 2010;221:87-73
94.
ALLEGRO, Phase III—Laquinomod
vs Placebo for 2 Years
Annualized Relapse Rate, Primary Endpoint
Annualized Relapse Rate
0.45
0.4
0.39
0.35
0.3
0.25
P = .002
Placebo
LAQ 0.6 mg QD
0.30
N = 1106
0.2
0.15
0.1
0.05
0
Abbreviation: LAQ, laquinomod.
Comi G, et al. N Engl J Med. 2012;366:1000-1009.
74
ALLEGRO—Laquinimod Compared
with Placebo, 2 Years
Secondary Endpoints
36%
Sustained disability progression (3 months)
37%
Gd+ lesions
30%
Cumulative new or enlarging T2 lesions
Comi G, et al. N Engl J Med. 2012;366:1000-1009.
75
BRAVO, Phase III—Laquinimod vs Placebo
(IFN β-1a IM, Active Comparator) for 2 Years
Annualized Relapse Rate, Primary Endpoint
Main comparator was oral placebo
Annualized Relapse Rate
(Adjusted)
0.4
0.37
P = .026
0.35
0.3
0.25
0.29
Placebo
LAQ 0.6 mg QD
N = 1331
0.2
0.15
0.1
0.05
0
Abbreviation: LAQ, laquinimod.
76
Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148.
BRAVO—Laquinimod Compared
with Placebo, 2 Years
Secondary Endpoints
33.5%
Sustained disability progression (3 months)*
27.5%
Brain volume loss
*28.7% reduction with IFN β-1a, P = .09.
77
Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148.
CONCERTO, Phase III—Laquinimod
0.6 mg/day and 1.2 mg/day vs
Placebo for 2 Years

Primary endpoint – sustained disability
progression in 2 years

Not yet recruiting

Estimated final completion date – 2018
ClinicalTrials.gov ID: NCT01707992.
78
Laquinimod—Adverse Effects in
ALLEGRO


Transient elevations in ALT/AST to >3 times
upper limit of normal: 5% vs 2%
Common adverse effects
–
–
–
–

Abdominal pain
Back pain
Cough
Arthralgias
Proportion with serious adverse events
– Placebo 9.5%
– Laquinimod 11.1%
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Comi G, et al. N Engl J Med. 2012;366:1000-1009.
79
Daclizumab—Overview

Humanized monoclonal antibody to IL-2 receptor
alpha sub-unit1

Formerly FDA-approved to limit transplant rejection,
but removed from US market by manufacturer in
20092

Mechanisms of action not fully understood3

Increases CD56bright natural killer cell subset3

Subcutaneous injections every 2–4 weeks

Phase III MS studies of daclizumab “High Yield
Process” (HYP) ongoing4
1. Saidha S, et al. Ann N Y Acad Sci. 2012;1247:117-137. 2. FDA. Dear Healthcare Professional letter.
9/2009. Accessed 11/16 at:
http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM194907.pdf. 3. Stüve O, et al.
Lancet Neurol. 2010;9:337-338. 4. ClinicalTrials.gov ID: NCT01064401.
80
CHOICE, Phase II—Daclizumab vs
Placebo + IFN-β for 24 Wk
New/Enlarging Gd+ Lesions, Primary Endpoint
Mean New or Enlarging
Gd+ Lesions (Adjusted)
5
4.5
4
4.75
Placebo + IFN
Low-dose DAC + IFN
High-dose DAC + IFN
P = .51
3.58
3.5
3
2.5
2
1.5
N = 230
P = .004
1.32
1
0.5
0
Low-dose DAC = 1 mg/kg q4wk; high-dose DAC = 2 mg/kg q2wk. Abbreviation: DAC, daclizumab.
Wynn D, et al. Lancet Neurol. 2010;9:381-390.
81
SELECT and SELECTION, Phase II—
Daclizumab HYP vs Placebo

SELECT1
–
–

SELECTION2
–
–
–


Daclizumab 150 mg or 300 mg SC vs placebo
1 year
1-year extension of SELECT
Placebo group re-randomized to daclizumab
Daclizumab groups re-randomized to either continuous
dose or wash-out period followed by resumption of dose
Report of 1 death from autoimmune hepatitis at the
300 mg dose2
Reports of autoimmune complications in 2 others2
Abbreviation: HYP, high-yield process.
1. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract
149. 2. Giovannoni G, et al. Paper presented at: ECTRIMS/ACTRIMS 2011; October 19–20, 2011;
82
Amsterdam, Netherlands. Abstract 169.
Ocrelizumab—Overview

Fully humanized monoclonal antibody
anti-CD201

Depletes B lymphocytes primarily through
increased antibody-dependent cell-mediated
cytolysis1

Similar to rituximab, not identical1
– Rituximab chimeric, ocrelizumab fully humanized

Ongoing phase III studies
– OPERA I2 and II3 – relapsing-remitting MS
– ORATORIO4 – primary-progressive MS
1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. ClinicalTrials.gov ID: NCT01247324.
3. ClinicalTrials.gov ID: NCT01412333. 4. ClinicalTrials.gov ID: NCT01194570.
83
Phase II—Ocrelizumab vs Placebo
vs IFN β-1a IM for 24 Weeks
Gd+ T1 Lesions, Primary Endpoint
8
6.9
Total Number Gd+
T1 Lesions (Mean)
7
6
5.5
Placebo
Low-dose OCR
High-dose OCR
IFN
5
4
N = 218
3
2
1
P <.0001
for both
0.6
0.2
0
Low-dose OCR = 600 mg; high-dose OCR = 2000 mg; both given in 2 infusions on days 1 and 15.
IFN = IFN β-1a IM 30 µg/wk.
Abbreviation: OCR, ocrelizumab.
Kappos L, et al. Lancet. 2011;378:1779-1787.
84
Phase II—Ocrelizumab 600 mg
Compared with Placebo, 24 Weeks
Secondary Endpoints
80%
Annualized relapse rate
0.0 vs 1.4
Mean new or enlarging T2 lesions
Kappos L, et al. Lancet. 2011;378:1779-1787.
85
Ocrelizumab—Adverse Effects

No opportunistic infections in MS trials1,2

But increased serious and opportunistic
infections, including deaths, in phase III trials
for rheumatoid arthritis (RA)3
– RA trials were shut down
– Increased infections in RA trials driven by sites in
Asia, and higher dose1
1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. Hauser S, et al. ECTRIMS 2012; October 10-13,
2012; Lyon, France. Abstract S30.006. 3. Roche. Press release. March 8, 2010. Accessed 11/27 at:
http://www.roche.com/media/media_releases/med-cor-2010-03-08.htm.
86
Combination Therapies
87
Teriflunomide Added to IFN-β

Phase II – teriflunomide 7 mg or 14 mg vs
placebo plus IFN-β for 24 weeks1
– N = 118, on stable doses IFN-β; randomized 1:1:1
– >80% Gd+ lesions with both doses vs placebo
– Trend toward dose-dependent reduction in
annualized relapse rate with both doses


Best at 14 mg dose: 57.9% (not sufficiently powered)
Phase III – TERACLES study is ongoing2
1. Freedman MS, et al. Neurology. 2012;78:1877-1885. 2. ClinicalTrials.gov ID: NCT01252355.
88
CombiRx Trial—GA + IFN β-1a
30 µg IM vs Either Alone

3-year, multicenter, randomized, double-blind
trial

N = 1008, relapsing-remitting MS
– Randomized 2:1:1 (IFN + GA; IFN; GA)

Conclusion: annualized relapse rate and
disability progression not improved for
the combination of the 2 vs the better of the
2 alone
Lublin F, et al. Paper presented at: 64th AAN; April 21–28, 2012; New Orleans, LA. Abstract PL02.001.
89
CombiRx Trial—Preliminary Findings
Outcome at
3 Years
IFN + GA
IFN
GA
Annualized relapse
rate*
0.12
0.16
(P = .02)
0.11
(P = .27)
Proportion relapsing
23.1%
26%
(P = .19)
20.5%
(P = .21)
Proportion clinical
activity-free
58.7%
60.3%
(P = NS)
60.2%
(P = NS)
Proportion
cumulative unique
lesion activity-free
49.2%
32.2%
(P <.0001)
32.5%
(P <.0001)
Proportion disease
activity-free (clinical
and imaging)
33.3%
21.2%
(P = .0004)
19.4%
(P <.0001)
*Primary endpoint.
Lublin F, et al. Paper presented at: 64th AAN; April 21–28, 2012; New Orleans, LA. Abstract PL02.001.
90
Case 4—Mr. J History and
Presentation

52-year-old male
– Hypertension, 20 pack/year cigarettes, no
alcohol abuse

In 2001, brought to ER after generalized
tonic-clonic seizure in 2001
– No prior history of seizures or other neurologic
diseases

Admitting labs negative, including drug
screen
91
Case 4—MRI Findings

Initial brain MRI
showed 2 ringenhancing lesions

Larger lesion had
sufficient mass
effect to shift
midline
Graphic courtesy of Anne H. Cross, MD.
92
Case 4— CSF Findings






Protein 52 mg/dL
Glucose 65 mg/dL
IgG Index 0.95
3 oligoclonal bands
10 white blood cells (96% lymphs)
CSF cytology negative
93
Case 4—Continued Evaluation

Referred to a neurosurgeon
– Underwent biopsy

Final biopsy report
– “T-cells, B-cells, macrophages, including foamy
macrophages, sharply demarcated areas of
demyelination on LFB-PAS; relative axonal
sparing on Bielschowsky stain”

Diagnosis – multiple sclerosis
Abbreviation: LFB-PAS, Luxol Fast Blue-Periodic Acid Schiff.
94
Case 4—Follow-Up at 11 Years

Followed in MS clinic for 11 years

On IFN β-1b since diagnosis

Continues to be employed full-time

2 mild relapses since treatment began

No recurrence of seizures
– Discontinued phenytoin after 3 years
95
Our challenge is to figure out
how to predict at onset which
therapy will work best in each
individual patient.
96
Important Factors for Choosing the
Right Agent at the Right Time




Aggressiveness of MS
Subtype of MS
Age of patient
Other medical problems
– Migraines, depression, hypertension, cardiac,
alcohol/liver, cancer, history of tuberculosis


Family history – if positive, what diseasemodifying therapies have they taken and
what was the response?
Discussions with patient: lifestyle, risk
97
Future Outlook

In 1 year
–
–

Expect at least 1 new drug to be FDA approved
May have different formulations of and less-frequent
dosing than older medications – GA TIW, IFN β-1a IM
monthly
In 5 years
–
–
–
Expect 2–3 new drugs, including more options for
very aggressive MS
Expect more ways to stratify risks of developing
adverse events in individual patients from specific
medications
May have medications effective in progressive MS
subtypes
98
Within 15 Years…..
…..individually tailored
MS therapies?
99
Concluding Thoughts

9 FDA-approved medications for relapsing
subtypes of MS
– 6 different mechanisms of action

Goals of MS therapy may be changing
– To halt all clinical and radiologic activity may
be achievable in many

Good prospects for the future
100