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
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: 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: 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®)
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: Primary Endpoint
• daclizumab 150mg group: 54% reduction in ARR
• daclizumab 300mg group: 50% reduction in ARR
REFERENCES: Lancet. 2013;381:2167-2175.
SELECT: Secondary Endpoints
REFERENCES: Lancet. 2013;381:2167-2175.
• More patients relapse free at 52 weeks
• Significantly fewer new Gd+-enhancing lesions at 52 weeksGd+ = gadolinium
REFERENCES: Lancet. 2013;381:2167-2175.
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: Primary and Secondary Endpoints
• 45% reduction in ARR with daclizumab vs. INF beta-1a
REFERENCES: N Engl J Med. 2015;373:1418-1428.
REFERENCES: N Engl J Med. 2015;373:1418-1428.
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)
REFERENCES: N Engl J Med. 2015;373:1418-1428.
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
REFERENCES: N Engl J Med. 2017;376:221-234.
• 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:
Primary and Secondary Endpoints
REFERENCES: N Engl J Med. 2017;376:221-234.
• 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
ORATORIO: Primary Endpoint
• 6.4% fewer patients experienced disease progression at 12 weeks vs. placebo
REFERENCES: N Engl J Med. 2017;376:209-220.
ORATORIO: Secondary Endpoint
• 6.1% fewer patients experienced disease progression at 24 weeks vs. placebo
REFERENCES: N Engl J Med. 2017;376:209-220.
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)
REFERENCES: N Engl J Med. 2017;376:209-220.
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
Post Test: Question #2
• 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
Post Test: Question #3
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
Kelsey Morris, PharmD
University of Kansas Healthcare System
Clinical Ambulatory Care Pharmacist: Neurology-Multiple Sclerosis