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Multiple Sclerosis UpdateAmanda Stahnke, PharmD, BCACP

University of Missouri-Kansas City School of Pharmacy

Kansas City Veterans Affairs Honor Annex

Kelsey Morris, PharmD

University of Kansas Health-System

Disclosure and Conflict of Interest

• Amanda Stahnke and Kelsey Morris declare no conflicts of

interest, real or apparent, and no financial interests in any

company, product, or service mentioned in this program,

including grants, employment, gifts, stock holdings and

honoraria.

Pharmacist and Technician Objectives

At the conclusion of this program, the pharmacist and

technician will be able to:

1. Discuss the basic etiology, pathophysiology, and diagnosis

of multiple sclerosis (MS)

2. Discuss recently approved disease modifying therapies

(DMTs)

3. Identify potential candidates for newly approved DMTs

Pre-Test Questions

1. The __________ Criteria is utilized in practice to determine

the diagnosis of MS.

a) Summer

b) McDonald

c) Sclerosis

d) Farmer

Pre-Test Questions

2. Which of the following therapies is contraindicated in

pregnancy and requires completion of an elimination protocol if

pregnancy occurs?

a) Ocrelizumab

b) Fingolimod

c) Dimethyl fumarate

d) Teriflunomide

3. Which of the following disease modifying therapies

(DMTs) carries a Black Box Warning for progressive

multifocal leukoencephalopathy (PML)?

a) Natalizumab

b) Teriflunomide

c) Glatiramer acetate

d) Peginterferon

Pre-Test Questions

Background

REFERENCES: Pharmacotherapy, 9th Ed. 2014;835-854.

Porth’s Pathophysiology, 9th Ed. 2014;476-479.

http://www.msconnection.org/Blog/September-2014/MS-Genetics-Research-Hits-Home.

Etiology/Risk factors

• Environmental– Epstein-Barr Virus (EBV)

– Cytomegalovirus (CMV)• Negative risk factor

– Geography

• Vitamin D deficiency

• Genetics

• Smoking

REFERENCES: J Rehabil Res Dev 2006;43(1):123-132.

Pathophysiology

REFERENCES: Pharmacotherapy, 9th Ed. 2014;835-854.

Rehabil Res Dev 2006;43(1):123-132.

Neurodegener Dis Manag. 2016;6(1):37-47.

N Engl J Med, 2017;376:221-234.

• T-cells:

– Expression of alpha-4 integrin (adhesion molecule)

– Cytokine and nitric oxide production

– Matrix metalloproteinase production

• B-cells:

– Antigen presentation

– Autoantibody production

– Cytokine regulation

– Formation of ectopic lymphoid aggregates in the

meninges

Pathophysiology

REFERENCES: Nat Rev Clin Oncol. 2014;11:536-547.

Nature Clinical Practice Neurology. 2008;4:557-567.

Pathophysiology

Diagnosis

MRI = magnetic resonance imaging

• History

– Birthplace, Family history (FHx), Travel, Past medical history

(PMH), Signs and symptoms- acute exacerbation

• Laboratory tests

• Neurological Exam

• Cognitive Exam

• Lumbar puncture

– Oligoclonal bands

REFERENCES: http://www.radiologyassistant.nl/en/p4556dea65db62/multiple-sclerosis.html.

Diagnosis

REFERENCES: Ann Neurol. 2011;69(2):292-302.

Diagnosis

2010 McDonald Criteria

Acute exacerbation history MRI history Additional data needed

2 exacerbations 2 lesions None

2 exacerbations 1 lesion DIS or wait for additional

exacerbation

1 exacerbation 2 lesions DIT or wait for additional

exacerbation

1 exacerbation 1 lesion DIS and DIT or wait for

additional exacerbation

Continuous progression of

disease over 1 year

2 of the 3:

1. DIS (non-spinal cord

lesions)

2. DIS (2 or more T2 lesions

on spinal cord)

3. Oligoclonal bands and/or

elevated IgG index present

in CSF

MRI = magnetic resonance imaging, DIS = dissemination in space (1 or more T2 lesion in 2 of 4 regions of the CNS typical of MS (periventricular, juxtacortical, infratentorial, or spinal cord), DIT

= dissemination in time (presence of gadolinium-enhancing and non-enhancing lesions simultaneously or new lesions on a repeat MRI (T2 or gadolinium-enhancing), CSF = cerebrospinal fluid

REFERENCES: Neurology. 2014;83:1-9.

Classification

RRMS- Active PPMS- Not active, Progressing PPMS or SPMS - Active, Progressing

• Phenotypes:– Clinically isolated syndrome (CIS)

– Radiographically isolated syndrome (RIS)*

– Relapsing remitting MS (RRMS)

– Secondary progressive MS (SPMS)

– Primary progressive MS (PPMS)

• Modifiers:– Active or Not active

– Progressing or Not progressing

REFERENCES: Neurology. 1983;33:1444-1452.

Expanded Disability Status Scale (EDSS)

0 = Normal neurologic exam

1.0-1.5 = No impairment

2.0-2.5 = Impairment is minimal

3.0-3.5 = Impairment is mild to moderate

4.0-4.5 = Impairment is relatively severe

5.0-5.5 = Increasing limitation in ability to walk

6.0-6.5 = Walking assistance is needed

7.0-7.5 = Confined to wheelchair

8.0-8.5 = Confined to bed/chair; self-care with help

9.0-9.5 = Completely dependent

10.0 = Death due to MS

Disease Management

• Acute exacerbation treatment– Steroids

• Methylprednisolone 500-1000mg/day IV or 500-2000mg PO for 3-5 days

• Other therapy- IVIG, plasmaphoresis, ACTH (Acthar®)

• Disease modifying therapies– Mainstay of management

• Symptom management– Depression, fatigue, bowel/bladder dysfunction, gait

abnormalities, …IVIG = intravenous immunoglobulin, ACTH = Adrenocorticotropic hormone

REFERENCES: http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Managing-MS/Relapse-Management.

Lancet. 2015;386:974-981.

NICE. 2014. nice.org.uk/guidance/cg186.

Disease Management Goals

• Decrease attack/exacerbation rate

– Decrease annualized relapse rate (ARR)

• Slow progression of disease

– Disability, MRI findings, Cognition

• Prevent/limit ADRs

• Effectively manage symptoms

REFERENCES: Multiple Sclerosis Coalition. 2017.

Disease Modifying Therapies (DMTs)

ARR = Annualized Relapse Rate

Therapy Maintenance Dosing ARR

Interferons

o β-1a

o β-1b

o All require titration

o Avonex® 30mcg IM qweek

o Rebif® 22 or 44mcg subcut three times per week

o Peginterferon (Plegridy®) 125mcg subcut q2weeks

o Betaseron® or Extavia® 0.25mg subcut every other day

18%

33.2%

36%

34%

Glatiramer acetate (Copaxone®) 20mg subcut daily [generic available (Glatopa®)]

40mg subcut three times weekly

29%

34%

Mitoxantrone (Novantrone®) 12mg/m2 IV q3months 66%

Natalizumab (Tysabri®) 300mg IV q4weeks 68%

Fingolimod (Gilenya®) 0.5mg PO daily 48-54%

Teriflunomide (Aubagio®) 7 or 14mg PO daily ~31%

Dimethyl fumarate (Tecfidera®) 240mg PO BID, requires titration 44-49%

Alemtuzumab (Lemtrada®) 12mg IV for 5 days, repeated in 1 year for 3 days 49-55%

Daclizumab (Zinbryta®)

Ocrelizumab (Ocrevus®)

New Multiple Sclerosis Therapies

Daclizumab

REFERENCES: Lancet. 2013;381:2167-2175.

• FDA approved: May 2016– Indication: Relapsing forms of multiple sclerosis

• MOA: humanized monoclonal antibody which binds to the CD25 subunit of the high-affinity interleukin-2 (IL-2) receptor– Prevents signaling at the high-affinity IL-2

receptor

– Allows for increased IL-2 availability for signaling at the intermediate-affinity IL-2 receptor

Daclizumab (Zinbryta®)

SELECT


SELECT: Treatment Groups and Study Design

SELECT: Primary Endpoint

• daclizumab 150mg group: 54% reduction in ARR

• daclizumab 300mg group: 50% reduction in ARR


SELECT: Secondary Endpoints


• More patients relapse free at 52 weeks

• Significantly fewer new Gd+-enhancing lesions at 52 weeksGd+ = gadolinium


SELECT: Adverse Events

Placebo

(N = 204)

Daclizumab

HYP 150mg

(N = 208)

Daclizumab

HYP 300mg

(N = 209)

Adverse events of interest Number of patients (%)

Infections 89 (44) 104 (50) 112 (54)

Serious infections 0 6 (3) 3 (1)

Cutaneous events 27 (13) 38 (18) 45 (22)

Serious cutaneous events 0 2 (<1) 3 (<1)

Death 0 1 (<1) 0

Incidence of ALT or AST abnormalities Number of patients (%)

1-3 x ULN 64 (31) 54 (26) 62 (30)

3-5 x ULN 6 (3) 7 (3) 6 (3)

>5 x ULN 1 (<1) 9 (4) 8 (4)

Injection-site reactionm erythema 3 (1) 4 (2) 4 (2)

Malignancy 1 (<1) 1 (<1) 2 (<1)

DECIDE

REFERENCES: N Engl J Med. 2015;373:1418-1428.

DECIDE: Treatment Groups and Study Design

DECIDE: Primary and Secondary Endpoints

• 45% reduction in ARR with daclizumab vs. INF beta-1a



DECIDE: Adverse Events

Daclizumab HYP

(N = 919)

Interferon Beta-

1a

(N = 922)

Event Number of patients (%)

Infection Nasopharyngitis

Upper respiratory

tract infection

Urinary tract infection

Serious infection

595 (65) 226 (25)

149 (16)

96 (10)

40 (4)

523 (57) 197 (21)

124 (13)

98 (11)

15 (2)

Cutaneous events 344 (37) 176 (19)


DECIDE: Adverse Events

Event Daclizumab

HYP

(N = 919)

Interferon Beta 1-a

(N = 922)

Hepatic laboratory abnormality Number of patients (%)

ALT or AST >3 x ULN 96 (10) 80 (9)

ALT or AST >5 x ULN 59 (6) 31 (3)

ALT or AST >3 x ULN and total

bilirubin >2x ULN

7 (1) 1 (<1)

EMA = European Medicines Agency

Ocrelizumab


• FDA approved: March 2017– Indication: relapsing or primary

progressive forms of multiple sclerosis

• MOA: ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells– CD20 is a cell-surface antigen that is

express on• Pre-B cells

• Mature B cells

• Memory B cells

Ocrelizumab (Ocrevus®)

OPERA I & OPERA II


OPERA I & OPERA II: Treatment Groups

OPERA I & OPERA II:

Primary and Secondary Endpoints


• OPERA I: 46% lower ARR with ocrelizumab vs. INF beta-1a

• OPERA II: 47% lower ARR with ocrelizumab vs. INF beta-1a

• Significantly fewer Gd+ enhancing lesions at 96 weeksGd+ = gadolinium

OPERA I & OPERA II: Adverse Events


ORATORIO

ORATORIO: Treatment Groups


ORATORIO: Primary Endpoint

• 6.4% fewer patients experienced disease progression at 12 weeks vs. placebo


ORATORIO: Secondary Endpoint

• 6.1% fewer patients experienced disease progression at 24 weeks vs. placebo


ORATORIO: Adverse Events

Ocrelizumab

(N = 486)

Placebo

(N =239)

Event Number of patients (%)

>1 infusion-related reaction

(mild-severe)

194 (39.9) 61 (25.5)

Serious infection 30 (6.2) 14 (5.9)

Neoplasms Breast

Basal-cell

Adenocarcinoma of cervix

Anaplastic large-cell lymphoma

Endometrial adenocarcinoma

Malignancy fibrous histiocytoma

Metastatic pancreatic carcinoma

11 (2.3) 4 (0.8)

3 (0.6)

0

1 (0.2)

1 (0.2)

1 (0.2)

1 (0.2)

2 (0.8) 0

1 (0.4)

1 (0.4)

0

0

0

0

Death 4 (0.8) 1 (0.4)


Ocrelizumab: Post-Marketing Updates

Post Test: Question #1

• KS is a 52 year old white female diagnosed with MS 20 years ago.

At the time of diagnosis her MRI showed multiple Gd+ enhancing

and non-enhancing lesions in the infratentorial and along her

spinal cord and her lumbar puncture was (+) for oligoclonal bands.

KS continues to experiences relapses at least yearly and her most

recent MRI demonstrated new Gd+ enhancing lesions in the

juxtacortical and periventricular regions of her brain. She does not

experience worsening of disease outside of relapses.

1. How would you classify KS’s disease course?

a) Secondary-progressive MS- active, not progressing

b) Relapsing-remitting MS- active

c) Clinically Isolated Syndrome

d) Primary-progressive MS- not active, progressing


• KS has now failed the oral option you selected for her

previously (totaling 4 failed therapies). Labs were completed

to assist in further therapy selection.

2. Based on clinical trial data and

recent FDA post-marketing reports,

which of the following therapies would

you avoid in KS?

a) Ocrelizumab

b) Daclizumab

Na 141 mEq/L

K 3.6 mEq/L

Cl 106 mEq/L

CO2 24 mEq/L

SCr 0.74 mg/dL

BUN 14 mg/dL

GLU 88 mg/dL

Ca 9.5 mg/dL

AST 130 U/L

ALT 154 U/L

Vit D 18 ng/mL


3. To date no reports of progressive multifocal

leukoencephalopathy (PML) have been

reported with either daclizumab or

ocrelizumab.

a) True

b) False

Take Home Points

• The exact cause of MS is still unknown, but multiple

risk factors have been identified and several new

therapies have been developed within the last few

years, specifically daclizumab and ocrelizumab.

• The choice of therapy is based upon many factors,

including patient and provider preference, disease

course and severity, patient specific factors, and

medication adverse effects.

Resources & References

• Bainbridge JL, Miravalle A, Corboy JR. Pharmacotherapy, 9th Ed. 2014;835-854.

• Porth’s Pathophysiology, 9th Ed. 2014;476-479.

• http://www.msconnection.org/Blog/September-2014/MS-Genetics-Research-Hits-Home.

• Cudrici C, et al. J Rehabil Res Dev 2006;43(1):123-132.

• Gasperi C, Stüve O, Hemmer B. Neurodegener Dis Manag. 2016;6(1):37-47.

• Hauser SL, Bar-Or A, Comi G, et al. N Engl J Med. 2017;376:221-234.

• Choi SW, Reddy P. Nat Rev Clin Oncol. 2014;11:536-547.

• Dalakas MC. Nature Clinical Practice Neurology. 2008;4:557-567.

• http://www.radiologyassistant.nl/en/p4556dea65db62/multiple-sclerosis.html

• Polman CH, Reingold SC, Banwell B, et al. Ann Neurol 2011;69(2):292-302.

• Lublin FD, Reingold SC, Cohen JH, et al. Neurology. 2014;83:1-9.

• Kurtzke JF. Neurology. 1983;33:1444-1452.

• http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Managing-MS/Relapse-

Management.

• LePage E, Veillard D, Laplaud DA, et al. Lancet. 2015;386:974-981.

• NICE. 2014. nice.org.uk/guidance/cg186.

• Costello K, Halper J, Kalb R, et al. The use of disease-modifying therapies in multiple sclerosis:

principles and current evidence. 2017.

• Gold R, Giovannoni G, Selmaj K, et al. Lancet. 2013;381:2167-2175.

• Kappos L, Wiendl H, Selmaj K, et al. N Engl J Med. 2015;373:1418-1428.

• Montalban X, Hauser SL, Kappos L, et al. N Engl J Med. 2017;376:209-220.

Speaker Contact Information

Amanda Stahnke, PharmD, BCACP

University of Missouri-Kansas City Department of Pharmacy Practice

and Administration- Clinical Assistant Professor

Kansas City Veterans Affairs Medical Center Honor Annex

Patient-Aligned Care Team Pharmacist in Primary Care

[email protected]

Kelsey Morris, PharmD

University of Kansas Healthcare System

Clinical Ambulatory Care Pharmacist: Neurology-Multiple Sclerosis

[email protected]

mailto:[email protected]

mailto:[email protected]

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