Controversy in Management:Case 1: Relapsing MS

Aaron Miller, M.D.

Corinne Goldsmith Dickinson Center for Multiple Sclerosis

Icahn School of Medicine

at Mount Sinai

New York, NY

.

Case 1

• 26-year-old African-American woman, with no PMH, consults you for recommendation about disease management.

• Two months earlier she had developed slurred speech, incoordination of her right hand and impaired balance. Symptoms resolved spontaneously by the time she was able to see a neurologist 10 days later.

• Brain MRI showed a gadolinium enhancing cerebellar lesion, multiple periventricular lesions, hemispheric lesions, juxtacortical and brainstem lesions.

• Neurological examination is normal

Question 1: Her initial neurologist had ordered a battery of serological tests. All were negative except for an ANA that was positive at 1:80. The best diagnosis now is:

• 1. Acute disseminated encephalomyelitis

• 2. Clinically isolated syndrome

• 3. Definite multiple sclerosis

• 4. Lupus cerebritis

• 5. Not multiple sclerosis

• 6. Possible multiple sclerosis

• 7. Probable multiple sclerosis

2011 McDonald Criteria

Clinical Presentation Additional Data Needed for MS Diagnosis

1 attack; objective clinical evidence of ≥ 2 lesions

DIT, demonstrated by: Simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time

or

A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan

or

Await a second clinical attack

1 attack; objective clinical evidence of 1 lesion (CIS)

DIS and DIT, demonstrated by:

For DIS:

1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)

or

Await a second clinical attack implicating a different CNS site

and

For DIT:

Simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time

or

A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan

or

Await a second clinical attack.

Polman CH, et al. Ann Neurol. 2011;69(2):292–302.

Question 2: Would you now recommend the patient begin treatment with a disease-modifying therapy?1. Yes

2. No

REFLEX: Time to Conversion to

McDonald MS or CDMS

CDMS = clinically definite multiple sclerosis

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

D0 D90 D180 D270 D360 D450 D540 D630 D720

Cu

mu

lati

ve

In

cid

en

ce

sc IFN β-1a 44 μg tiw (n = 171)

sc IFN β-1a 44 μg qw (n = 175)

Placebo (n = 171)

88%

76%

62%

sc IFNβ-1a 44µg tiw vs placebo P < 0.001

Risk reduction: 51%

sc IFNβ-1a 44µg qw vs placebo P = 0.008

Number of patients at risk:

sc IFNβ-1a 44µg tiw 171 149 100 87 78 69 63 59 51

sc IFNβ-1a 44µg qw 175 147 87 70 57 50 47 42 31

Placebo 171 135 62 45 41 34 29 25 14

Number of patients at risk:

sc IFNβ-1a 44µg tiw 171 162 156 149 141 139 131 125 108

sc IFNβ-1a 44µg qw 175 168 158 150 145 141 134 130 103

Placebo 171 159 153 132 119 108 102 97 73

2-year

cumulative

incidence

0.0

0.1

0.2

0.3

0.4

0.5

0.6

D0 D90 D180 D270 D360 D450 D540 D630 D720

Cu

mu

lati

ve

In

cid

en

ce

38%

22%

21%

sc IFNβ-1a 44µg tiw vs placebo P < 0.001

Risk reduction: 51%

sc IFNβ-1a 44µg qw vs placebo P = 0.0082-year

cumulative

incidence

Time to McDonald MS Time to CDMS

Comi G, et al. Lancet Neurol. 2012;11:33-41.

Question 3: The patient’s JC virus STRATIFY antibody test is positive with an index of 1.54. Your preferred disease-modifying therapy at this point is:

1. Alemtuzumab

2. Cladribine 7. Interferon-beta

3. Daclizumab 8. Natalizumab

4. Dimethylfumarate 9. Ocrelizumab

5. Fingolimod 10. Rituximab

6. Glatiramer acetate 11. Teriflunomide

Predicting the Course of MS

• Clinical features of onset bout

– Motor worse than sensory

– Polyregional worse than monosymptomatic

– Early bladder involvement poor prognosis

• Incomplete recovery from initial attack

• Short interval between attacks

Prognosis

• Initial MRI

– T2 lesion numbers

– Median EDSS at 20 years = 6 for >10 T2 lesions

– 3 or 4 Barkhof criteria moderate correlation with EDSS at 5 years

Fisniku LK. Brain. 2008;131:808-817.

0

10

20

30

40

50

60

70

0 1-3 4-9 ≥10

% p

ati

en

ts

# of brain lesions

EDSS > 3

EDSS ≥ 6

Choosing Therapy

Aggressive Disease?

Yes No

JCV Ab+ JCV Ab-

Safest PregnancyNon-

injectable

OcrelizumabFingolimod

DMF

Natalizumab

Ocrelizumab

IFN

GAGA

Teriflunomide

DMF

Fingolimod

Natalizumab

Ocrelizumab

Case 1 continued

• The patient begins treatment with interferon-beta-1a subcutaneously 3 times weekly

• Patient remains asymptomatic and MRI brain one year after initiating therapy shows no new lesions

• Two years later, the patient still asymptomatic and neurological examination is normal

Case 1 continued:

• About nine months later (nearly 4 years after beginning interferon), patient reports that she has been experiencing slight imbalance for several weeks.

• Examination shows minimal finger-to-nose dysmetria bilaterally and minimal difficulty with tandem walking.

• New brain and cervical spine MRI are ordered but not done because patient loses her insurance coverage

• The patient remains on interferon-beta-1a

Case 1 continued

• Six months later the patient reports that her right hand shakes when she is stressed, but her neurological examination is normal.

• She reports that she is “tired of the injections” and has been missing approximately one every two weeks

• She says she would like to switch to an oral medication

Case 1 continued

• Quantiferon gold test is negative

• Varicella-zoster-virus antibody titer indicates lack of immunity

• Liver enzymes are normal

• Previous JC virus antibody was positive with index 1.54

Question 4: You would now recommend that the patient:

1. Begin dimethyl fumarate

2. Begin fingolimod

3. Begin teriflunomide

4. Continue interferon-beta-1a

5. Get immunized against varicella-zoster virus and then begin fingolimod one month later

S1P receptor

FTY720 results in internalization of

the S1P1 receptor

This blocks lymphocyte egress

from lymph nodes while sparing

immune surveillance by circulating

memory T cells

LN

Prevents T cell

invasion of CNS

FTY720 traps

circulating

lymphocytes in

peripheral lymph

nodes

Fingolimod (FTY720): Mode of Action

Cohen JA, Chun J. Ann Neurol. 2011;69:759-777.

T cellFTY720-P

FREEDOMS: Key Efficacy Results

Consortium of Multiple Sclerosis Centers (CMSC). Available at:

www.mscare.org/cmsc/Informs-Novartis-on-MS-therapy-FTY720.html.

MRI: decreased number of new and enlarging T2H

and Gd + lesions (P<0.001)

Managing Patients on Fingolimod

• Before Initiation of Treatment

– Baseline CBC and liver panel

– Cardiac status and ECG

– Baseline ophthalmological exam

– Baseline dermatological exam

– Varicella immune status

• Baseline 6-hour monitoring because of potential bradycardia

• On Treatment Monitoring

– Follow CBC, liver panel

– Ophthalmological f/u at 3-4 months and annually

– Annual dermatological exam

– Check BP

• Infections

– 13 reported cases of PML

– Rare cases of cryptococcalmeningitis

– Increased risk of shingles or VZV

Teriflunomide: A Selective Dihydroorotate Dehydrogenase Inhibitor

• An oral disease-modifier for relapsing forms of MS (RMS)

• Blocks de novo pyrimidine synthesis, reducing T- and B-cell proliferation and function in response to autoantigens

• Preserves replication and function of cells (e.g. haemopoietic cells, memory T-cells) living on the existing pyrimidine pool (salvage pathway)

DHO-DH, dihydroorotate dehydrogenase;

Blasting lymphocyte

De novo pathway

DHO-DH

Pyrimidine pools Salvage

pathway

CTP-, UTP-sugars Nucleotides CDP lipids

Glycoproteins, Glycolipids RNA, DNA Phospholipids

Cell-cell contact

Adhesion and

diapedesis

Proliferation

Ig

secretion

Cell membranes

Second

messengers

Non-

lymphoid

cells

Resting lymphocyte

Teriflunomide

Miller A et al. Presented at: American Academy of Neurology (AAN) 2011, April 9-16; Honolulu, HI.

Teriflunomide for RRMS (Phase III TEMSO Study): Key Clinical Outcomes

RRR: 31.2%

P = 0.0002RRR: 31.5%

P = 0.0005

Annualized Relapse Rate

TeriflunomideTeriflunomide

27.30.539

0,370 0,369

0,0

0,1

0,2

0,3

0,4

0,5

0,6

Placebo (n = 363) 7 mg (n = 365) 14 mg (n = 358)

21,720,2

0,0

5,0

10,0

15,0

20,0

25,0

30,0

Placebo (n = 363) 7 mg (n = 365) 14 mg (n = 358)

27.3 23.7%

P = 0.083529.8%

P = 0.0279

EDSS 12 Week Sustained Change

RRR = relative risk reduction

O’Connor P et al. N Engl J Med. 2011;365:1293-1303.

Tolerability Issues with Teriflunomide

• Low incidence of GI symptoms, particularly diarrhea

• Mild hair thinning

• Monthly liver panel x 6 months

• Occasional neutropenia – check CBC periodically

• Check BP

• Category X pregnancy rating

– Accelerated elimination procedure

DMF Has Shown Nrf2 Pathway Activation

DMF = dimethyl fumarate; MMF = monomethyl fumarate

Scannevin R et al. Poster presented at ECTRIMS, October 13-16, 2010. Gothenburg, Sweden. P887.

Feinstein D et al. Poster presented at ECTRIMS, October 13-16, 2010. Gothenburg, Sweden. P879.

Keap1

Maf

Jun

ATF4

Nucleus

- Detoxification enzymes

- Antioxidant enzymes

- NADPH generating enzymes

- GSH biosynthesis enzymes

- Chaperones

- Ubiquitination/proteasome

- Detoxification

- Normalization of

energy metabolism

- Repair/degradation

of damaged proteinsN

rf2

Cytoplasm

OO

O

O DMF (BG-12)

OO

OH

O MMFOR

ARE

DMF: Integrated Efficacy Analysisof DEFINE and CONFIRM

Endpoint (at 2 years)Placebo(n = 771)

DMF BID(n = 769)

Annualized relapse rate (ARR)

Reduction vs placebo

0.37 0.19*

49%

Proportion of patients relapsedHR vs placebo 0.57*

Time to 12-week confirmed disability progressionHR vs placebo 0.68*

Time to 24-week confirmed disability progressionHR vs placebo 0.71*

*Statistically significant vs placebo

Fox RJ et al. Presented at: American Academy of Neurology (AAN) 2013, March 16-23; San Diego, CA. Abstract P07.097.

Safety and Tolerability Issues with Dimethyl Fumarate

• Gastrointestinal symptoms

• Flushing

• Occasional lymphopenia – follow CBC

– 5 cases of PML reported

• Infrequent liver enzyme elevations (follow LFTs)

• Adherence to twice-a-day regimen

• Category C pregnancy rating

Case 1 continued

• Patient decides to remain on interferon; 6 months later her neurological examination is normal except for horizontal nystagmus on left lateral gaze and upbeating nystagmus on upgaze.

• Patient was lost to follow-up for a year because her health insurance lapsed.

• Then she reports her balance is slightly off.

• Exam: horizontal nystagmus on left gaze; upbeating nystagmus on upgaze; minimal intention tremor and dysmetria on finger to nose testing bilaterally and mild heel-knee-shin dysmetria bilaterally

• MRIs: new T2H lesion in the midbrain and enlargement of C spine lesion

Question 5: With regard to patient’s disease-modifying therapy, you would now recommend:

1. Switch patient to alemtuzumab

2. Switch patient to dimethyl fumarate

3. Switch patient to fingolimod

4. Switch patient to rituximab (or ocrelizumab, if available)

5. Switch patient to teriflunomide

Case 1 continued

• The patient begins fingolimod and does well for the next 6 months.

• The patient now decides to take a safari vacation to Tanzania. A travel doctor recommends that she be vaccinated against yellow fever, typhoid fever, and tetanus.

Question 6: You would now recommend that she receive:

• 1. Oral typhoid fever vaccine; tetanus toxoid; but no yellow fever vaccine

• 2. Injectable typhoid fever vaccine; tetanus toxoid; but no yellow fever vaccine

• 3. Injectable typhoid fever vaccine; tetanus toxoid; yellow fever vaccine

• 4. Injectable typhoid fever vaccine; yellow fever vaccine; but no tetanus toxoid

• 5. None of the vaccines

Yellow fever vaccine and MS

• 7 patients studied

• ARR during at risk period 8.57 vs 0.67 outside risk period

• MRI at 3 months post-immunization showed significantly increased T2H and gadolinium-enhanced lesions cf MRIs 12 months prior to and 9 months after immunization

• Increase in MBP and MOG-specific peripheral blood cells secreting pro-inflammatory cytokines

Vaccine safety in MS

• Safe

– Influenza inactivated (not nasal spray)

– Hep B

– Tetanus

• Probably safe

– Human papilloma virus

– MMR

– Varicella

– Rabies

– Inactivated polio

– BCG

• Not Safe

– Yellow fever

– Live attenuated vaccines in immunosuppressed patients

• MMR

• Varicella or zoster

Williamson E, et al. Current Neurol Neurosci Rep. 2016;16:36.

Case 1 continued

• The patient discovers that she is not visiting a yellow fever endemic area and does not need yellow fever vaccine.

• She receives injectable typhoid fever vaccine and tetanus toxoid.

• She leaves for her 12 day safari, but calls you from the airport in Tanzania, panicked that she has left her fingolimod at home.

Question 7: You would now advise the patient:

• 1. Enjoy your vacation and arrange for repeat 1st dose monitoring for fingolimod as soon as you get home.

• 2. Enjoy your vacation and resume your fingolimod as soon as you get home.

• 3. Fly home after 6 days in order to avoid missing a week of fingolimod, which would pose an increased risk of MS relapse and necessitate repeat 1st dose monitoring.

• 4. Make contact with American Embassy in Tanzania to request help in obtaining fingolimod.

• 5. Obtain appointment with local witch doctor to receive anti-MS herbs

Case 1 continued

• Nine months after beginning fingolimod, the patient reports that her legs feel wobbly, as if she were “walking through water.” She experiences increased incoordination in her right hand, especially when writing or holding a cup.

• Neurological exam shows worsened dysmetria in both UEs (worse on right) and HKS dysmetria, also worse on right; gait mildly unsteady

• Repeat brain MRI shows ring-enhancing right periventricular lesion

Question 8: If the patient were JC virus ab negative, you would now recommend that she:

1. Continue fingolimod

2. Switch to alemtuzumab

3. Switch to cladribine

4. Switch to daclizumab

5. Switch to dimethyl fumarate

6. Switch to natalizumab

7. Switch to rituximab (or ocrelizumab, if available)

8. Switch to teriflunomide

Natalizumab Mechanism of Action

O’Connor P. Expert Opin Biol Ther. 2007;7:123-136.

Reduced

Leukocyte

Infiltration

and Brain

Inflammation

Leukocyte

Infiltration

and Brain

Inflammation

Leukocyte

Chemoattractant signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

LeukocyteChemoattractant Signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue VCAM-1

Natalizumab vs Placebo Affirm Study (1801)

Polman C et al. N Engl J Med. 2006;354:899-910.

An

nu

aliz

ed R

elap

se R

ate

(95%

CI)

68%

P<0.0001

Placebon=315

0.81

Natalizumabn=627

0.26

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Natalizumab-associated PML Overall Incidence by Treatment Epoch

749 (746 MS, 3 CD) confirmed PML cases

As of September 1, 2017;

(204 US, 475 EEA, 70 ROW).

749 (746 MS, 3 CD) confirmed PML cases

As of September 1, 2017;

(204 US, 475 EEA, 70 ROW).

749 (746 MS, 3 CD) confirmed PML cases

As of September 1, 2017;

(204 US, 475 EEA, 70 ROW).

749 (746 MS, 3 CD) confirmed PML cases

As of September 1, 2017;

(204 US, 475 EEA, 70 ROW).

Alemtuzumab Targets CD52 on B and T Cells Care-MS Phase III Studies – 12 mg/d x5d at T0 and x3d at T12 mos

CARE – MS1 CARE – MS2

IFN-β1a Alemtuzumab (12mg)

IFN-β1a Alemtuzumab (12mg)

Annual relapse rate 0.39 0.18 0.52 0.26

Risk reduction 54.9% (P<0.0001) 49.4% (P<0.0001)

Sustained disability (% pts)

11 8 21.1 12.7

Risk reduction 30% (P=0.22) 42% (P=0.0084)

Δ EDSS from baseline - 0.14 - 0.14 0.24 - 0.17

Net Δ EDSS 0.41 (P<0.0001)

Cohen JA et al. Lancet. 2012;380:1819-1828.

Coles AJ et al. Lancet. 2012;380: 1829-1839.

Safety Analysis of Care-MS Phase III Studies

• Autoimmune thyroid disorders

• 19.4% in extension; 29.9% total study

• Autoimmune thrombocytopenia (ITP): 1.3%; nephropathy: 0.3% (n=3)

• Infections

– Minor infections more common with alemtuzumab compared with IFN

– Acyclovir prophylaxis seemed to reduce the risk of herpetic infection

– No evidence that neutrophil or lymphocyte counts before a treatment course predicted infection risk

Fox E et al. Presented at American Academy of Neurology (AAN) 2013; March 16-23; San Diego, CA. Abstract S41.001.

Ocrelizumab Superior to IFNβ-1a in Reducing ARR: Phase III Results of OPERA I and II

• Compared with IFNβ-1a, ocrelizumab reduced:

– ARR

– 12- and 24-week CDP (by 40% )

– T1 Gd+ lesions (by 94–95%)

– New and/or enlarging T2 lesion (by 77–83%)

• Safety profile of ocrelizumab:

– Similar to IFNβ-1a

– Most common: IRR (at first dose)

0,292

0,156

0,29

0,155

0

0,1

0,2

0,3

0,4

0,5

IFNβ-1a Ocrelizumab 600 mg

Ad

just

ed A

RR

at

96 W

eeks

(%

)

Primary End Point ARR at 96 weeks

OPERA I OPERA II

46% ARR

P ≤ 0.0001

47% ARR

P ≤ 0.0001

n = 410n = 411 n = 418 n = 417

IFNβ-1a Ocrelizumab

Serious AE 8.7% 6.9%

Malignanciesn = 2

(lymphoma)

n = 4(renal cancer, melanoma, breast

cancer)

Deathsn = 2

(suicide, mechanical ileus)

n = 1(suicide)

Hauser SL et al. Presented at: ECTRIMS 2015; Barcelona, Spain. Abstract 246.

Modified Rio Score: An Approach for Determining Responders and Nonresponders

Score=0

Score=1

Score=2-3

100%

80%

60%

40%

20%

0%

Pro

gre

ss

ion

Pro

ba

bil

ity*

Years

0 1 2 3 4

Modified Rio

Score:

After 1 Year on Treatment

New T2 Lesions

Relapses

0 ≤4 0

1,<4 1

>4 0

2≤4 ≥2

>4 1

3 >4 2

* Probability of disability progression from the first year since treatment started and over the follow-up period (4 years), according to application of the modified Rio score on the “validation set” (observational cohort study, n=222).Figure adapted from Sormani MP et al. Mult Scler. 2013;19:605-612.

The modified Rio score, after 1 year of treatment, was able to predict the probability of

disability progression at 4 years in RRMS patients with 69% accuracy

4

4

Case 1 continued

• The patient switched to rituximab.