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10/11/2017
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Pharmacotherapy UpdateMultiple Sclerosis
Yolande Hanssens
SIG Leader Medicine Information
Hamad Medical CorporationPharmacy Department - Clinical Service Unit
Doha - Qatar
Heidelberg/October 2017
Pharmacotherapy UpdateMultiple Sclerosis
• Introduction
• Classification
• Therapeutic management of RRMS*
Disease Modifying Drugs (DMDs)
Patient tailored treatment
Special patient groups
• Summary & take home messages
*RRMS = Relapsing Remitting Multiple Sclerosis
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MS - Intro• Progressive, chronic idiopathic autoimmune driven
disorder of the nervous system
widespread inflammation affecting the brain and spinal cord
plaques (MRI)
• Unpredictable
• Symptoms
from numbness and tingling to blindness and paralysis
• Age 20-50, M:2F, genetic factors? North Europeans?
• > 2.3 million
• No cure
• Relapsing-Remitting MS (RRMS)
About 85%
• Secondary-Progressive MS (SPMS)
Symptoms worsen more steadily over time, with or without the occurrence of relapses and remissions.
RRMS SPMS at some point
• Primary-Progressive MS (PPMS)
About 10%
slowly worsening symptoms from the beginning, with no relapses or remissions
• Progressive-Relapsing MS (PRMS)
About 5%
steadily worsening disease state from the beginning, with acute relapses but no remissions, with or without recovery
MS – Classification
Hooper K. Managing Progressive MS. New York, NY: National Multiple Sclerosis Society; 2011.Multiple Sclerosis: Just the Facts New York, NY; National Multiple Sclerosis Society; 2011.
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MS International Federation; www.msif.org
Types of MS at Diagnosis
Clinical Evolution
RIS = Radiological Isolated SyndromeCIS = Clinical Isolated SyndromeRRMS = Relapsing Remitting MSR-SPMS = Relapsing Secondary Progressive MSSPMS = Secondary Progressive MS
TIME WINDOW
to
STARTTREATMENT
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Therapeutic Management
• No Cure
• DMDs for RRMS
Mode of Action & Major Adverse Events
Documented Treatment Effects
Patient Tailored Therapy
Special Patient groups
& Overall Pharmaceutical Care Considerations
DMD = Disease modifying DrugRRMS = Relapsing Remitting MS
EDDS = Expanded Disability Status ScaleMSFC = Multiple Sclerosis Functional CompositeNEDA = No Evidence of Disease Activity
Ocreluzimabi.v. 2017
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DMDs for RRMS• Interferon β (Rebif®, Betaseron®, Avonex®, Plegridy®)
• Glatiramer acetate (Copaxone®)
• Teriflunomide (Aubagio®)
• Dimethyl fumarate (Tecfidera®)
• Fingolimod (Gilenya®)
• Natalizumab (Tysabri®)
• Alemtuzumab (Lemtrada®)
• Ocrelizumab (Ocrevus®)
DMD = Disease modifying DrugRRMS = Relapsing Remitting MS
Interferon β
• MOA - unknown
• (PEG)Interferon Beta-1a
IM (Avonex®) & SubQ (Rebif ®, Plegridy®) Chinese hamster ovary cells
• Interferon Beta-1b
SubQ (Betaseron®)
E coli
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Interferon β - ConcernsRelated to adverse effects
• Anaphylaxis/hypersensitivity reactions
• Autoimmune disorders
• Bone marrow suppression
• Flu-like symptoms
• Hepatic effects obtain liver function tests at 1, 3, and 6 months post
therapy initiation and periodically thereafter.
• Injection site reactions
• Neuropsychiatric disorders
• Thrombotic microangiopathy
Glatiramer Acetate
• MOA - thought to induce and activate T-lymphocyte
suppressor cells specific for a myelin antigen & to interfere with the antigen-presenting function of certain immune cells opposing pathogenic T-cell function
• SubQ - 20 mg once daily OR 40 mg 3x/week
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Glatiramer - ConcernsRelated to adverse effects
• Hypersensitivity reactions• Immune response• Lipoatrophy including skin necrosis • Systemic reactions
anxiety, chest pain, constriction of the throat,
dyspnea, flushing, palpitations, urticaria
usually self-limited and transient
generally occur several months after initiation of
treatment.
Teriflunomide
• MOA - immunomodulatory agent that inhibits
pyrimidine synthesis, resulting in anti-proliferative and anti-inflammatory effects
- may reduce the number of activated
lymphocytes in the CNS
• PO – 7 to 14 mg once daily
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Teriflunomide - ConcernsRelated to adverse effects
• Dermatologic reactions: Cases of serious skin reactions, including cases of Stevens-Johnson syndrome and fatal toxic epidermal necrolysis have been reported with teriflunomide
• Hepatotoxicity - [US Boxed Warning]
• Hypersensitivity reactions - Anaphylaxis and severe allergic reactions may occur
• Hypertension• Infections • Interstitial lung disease• Malignancy• Pancreatitis• Peripheral neuropathy• Renal effects - Transient acute renal failure
Teriflunomide - Concerns
Other
• Drug elimination procedure - up to 2 years to reach low levels of teriflunomide metabolite serum concentrations. drug elimination procedure using cholestyramine
or activated charcoal for more rapid elimination BUT return of disease activity
• Teriflunomide is also found in semen
• Immunizations - before initiating therapy
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Dimethyl fumarate
• MOA - believed to result from its anti-inflammatory
and cytoprotective properties via activation of the Nrf2* pathway
• PO – 120 mg BID; after 7 days to 240 mg BID
*Nrf2 = nuclear factor (erythroid-derived 2)-like 2
Dimethyl fumarate - Concerns
Related to adverse effects• Dermatitis/irritation• Flushing• Gastrointestinal events• Hepatotoxicity• Hypersensitivity reactions- Anaphylaxis and angioedema may occur after the first dose or at any time during treatment• Lymphopenia• Proteinuria• Progressive multifocal leukoencephalopathy (PML) -
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Dimethyl fumarate - Concerns
Related to adverse effects• Dermatitis/irritation• Flushing• Gastrointestinal events• Hepatotoxicity• Hypersensitivity reactions • Lymphopenia• Proteinuria
• Progressive multifocal leukoencephalopathy (PML)associated with persistent (>6 months) lymphopenia, with a majority of cases occurring in patients with lymphocyte counts <500/mm3 and anti-JCV (John Cunningham virus) antibody >0.9 withhold therapy immediately at the first sign or
symptom suggestive of PML (eg, progressive weakness on one side of the body or clumsiness of limbs; vision disturbances; mental status changes) and perform a diagnostic evaluation (MRI findings may appear before clinical signs/symptoms).
Fingolimod
• MOA – Sphingosine 1-Phosphate (S1P) Receptor Modulator;
blocks the lymphocytes' ability to emerge from lymph nodes
the amount of lymphocytes available to the central
nervous system is decreased
reduces central inflammation.
• PO – 0.5 mg PO once daily
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Fingolimod- Concerns
Related to adverse effects• Atrioventricular (AV) block• Bradycardia• Cryptococcal infections• Hepatic effects• Herpes infection • Hypersensitivity reaction• Hypertension• Immune suppression• Macular edema• Malignancy• Neurotoxicity• Progressive multifocal leukoencephalopathy (PML) • Respiratory effects• QT prolongation
Fingolimod- Concerns
Other specific warnings/precautions
Discontinuation of therapy rebound syndrome
may occur within 4 to 16 weeks of stopping fingolimod treatment in patients with multiple sclerosis of varying severity and duration relapses have occurred despite the initiation of other disease-
modifying therapies Rebound symptoms: back and extremity pain,
confusion, constipation, diplopia, facial muscle spasms, fatigue, increased leg weakness, nausea,paraparesis and paresthesias
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NatalizumabAlemtuzumab Ocrelizumab
• Monoclonal Antibodies with different MOA
• IV with different treatment schedules
Natalizumab : 300 mg every 4 weeks
Alemtuzumab : 12 mg daily for 5 consecutive days (total 60 mg), followed 12 months later by 12 mg daily for 3 consecutive days (total 36 mg); total duration of therapy: 24 months
Ocrelizumab : 300 mg on day 1, 300 mg 2 weeks later and 600 mg once every 6 months
NatalizumabAlemtuzumab Ocrelizumab
• Monoclonal Antibodies with different MOA
• Need for pre-medication methylprednisolone (1000 mg IV) 30 minutes prior to each
infusion
an antihistamine (eg, diphenhydramine) 30 to 60 minutes prior each infusion
may also consider premedication with paracetamol
assess for infection; delay administration for active infection
monitor patient during (and after) infusion
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Natalizumab, Alemtuzumab Ocrelizumab - Concerns
Related to adverse effects
• Hepatotoxicity
• Herpes infection & other infections
• Hep B reactivations
• Hypersensitivity reaction/antibody formation
• Immune reconstitution inflammatory syndrome (IRIS)
• Malignancy
• Lab test abnormalities
• Progressive multifocal leukoencephalopathy (PML)
• Auto-Immune effects
• Bone marrow suppression
• GI toxicity
EDDS = Expanded Disability Status ScaleMSFC = Multiple Sclerosis Functional CompositeNEDA = No Evidence of Disease Activity
Ocreluzimabi.v. 2017
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Overview of the efficacy of MS therapies currently
available: NEDA# at 2 years
Data cannot be directly compared between trials because of different study designs and/or populations
P-value study drug vs comparator; *<0.05; **<0.001; ***<0.0001.1. Traboulsee A et al. Neurology 2016;86 [PL02.004]; 2. Cohen AJ et al. Lancet 2012;380:1819–28; 3. Havrdova E et al. Lancet Neurol 2009;8:254‒60; 4. Bevan CJ, Cree BAC. JAMA Neurol 2014;71:269‒70; 5. Coles AJ et al. Lancet 2012;380:1829–39; 6. Giovannoni G et al. Neurology 2012;78 [PD5.005]; 7. Freedman M et al. Neurology 2012;78 [PD5.007]
Trial Study drug
% patients
achieving
NEDA#
Comparator
% patients
achieving
NEDA#
OPERA I1*** Ocrelizumab 48 sc IFN β-1a 29
OPERA II1*** Ocrelizumab 48 sc IFN β-1a 25
CARE-MS I2* Alemtuzumab 39 sc IFN β-1a 27
AFFIRM3*** Natalizumab 37 Placebo 7
FREEDOMS4** Fingolimod 33 Placebo 13
CARE-MS II5*** Alemtuzumab 32 sc IFN β-1a 14
DEFINE6* Dimethyl fumarate 28 Placebo 15
TEMSO7** Teriflunomide 22.9 Placebo 14.3
#NEDA = No Evidence of Disease Activity
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Comi G, Radaelli M, Soelberg Sorensen P. Lancet 2017;389: 1347-56.
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Switching Therapy &Wash-Out Periods Required for Treatment Switch in MS Patients
Michel L, et al. Update on treatments in multiple sclerosis. Presse Med. 2015
Treatment 1 Treatment 2 Wash-Out
Dimethyl Fumarate Fingolimod NatalizumabAlemtuzumab
until lymphocyteslevel returnsto normal levels
Fingolimod Teriflunomide NatalizumabAlemtuzumab
until lymphocyteslevel returns tonormal levels(1 to 2months)
Teriflunomide Fingolimod NatalizumabAlemtuzumab
accelerated eliminationprocedure or 3.5 months
Natalizumab FingolimodTeriflunomideDimethyl Fumarate
1-3 months
Any Drug IFN or GA No wash-out required
IFN1 or GA2 Any Drug No wash-out required
1IFN = Interferon; 2GA = Glatiramer Acetate
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Patient &
Disease Profile
Shared
Decision
&
Patient
Tailored
Treatment
Therapy Issues
Patient
Preferences
Geographic &
Economic Factors
• Age, gender, family status
• Disease activity/disease type
• Stage of disease
• Treatment history
• Comorbidities & concurrent treatment
• Efficacy
• Safety
• Tolerability
• Administration (route/frequency)
• Monitoring requirements & frequency
of monitoring
• Sociodemographic profile (lifestyle,
work status, family status)
• Convenience
• Risk tolerance
• Likelihood of adherence
• Access to medication
• Approved usage
• Cost
Treatment decisions for RRMS are multifactorial:
Need for Systematic Approach
Female Pregnancy Lactation
MS & Pregnancy
Effects of pregnancy on MS
↓ Rate of relapse especially during 3rd
trimester
↑ Rate of relapses in first 3 months post
partum
Confavreux C et al. NEJM. 1998:285-91
Vukusic S et al. Brain. 2004:1353-60
Before 1st Trim 2nd Trim 3rd Trim 1st 3 months post
0.7 0.5 0.6 0.2 1.2
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MS & Pregnancy
Effects of pregnancy on MS
No acceleration in the rate of disability or disease progression postpartum
Epidural anesthesia No adverse event
on rate of relapse
Breastfeeding or progression of MS
Confavreux C et al. NEJM. 1998:285-91
Vukusic S et al. Brain. 2004:1353-60
MS & Pregnancy
MS does not seem to impair fertility
Effect of Assisted Reproductive Technology (ART)
? ↑ risk of MS disease activity
? Roles of extra hormones (GnRH agonist, FSH,
progesterone) or rapid changes in hormone levels
Hellwig K, Correale. J Clin Immunol. 2013:219-24
Correale J et al. Ann Neurol. 2012:682-94
Voskuhl RR. Ann Neurol. 2012:631
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MS & Pregnancy
Effect of MS on Pregnancy Outcomes
↑ rate of caesarian delivery
Lower infant birth weight
No ↑ in complications
ectopic pregnancies
birth defects
spontaneous abortions
MS in offspring : 2.5% (single MS) vs
30.5% (dual MS)
Kelly VM et al. Neurology. 2009:1831-6
Dahl J et al. Neurology. 2005:1961-3
Mueller BA et al. Am J Obstet Gynecol. 2002:446-52
Ebers G. Lancet Neurol. 2008:268-77
MS & Pregnancy
Treatment of RRMS during Pregnancy
To stop or NOT to stop?
Washout period
DMD Washout period
Glatiramer acetate none
Interferons zero to one month
Dimethyl fumarate zero to one month
Natalizumab one to three months
Fingolimod two months
Alemtuzumab three to four months
Teriflunomide* washout protocol using po cholestyramine or activated charcoal (<0.02mg/ml)
*Also found in semen
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Safety during pregnancy of drugs used to treat RRMS
Category B - No evidence of human risk in controlled studies
Glatiramer acetate
Category C - Risk cannot be ruled out
Alemtuzumab
Dimethyl fumarate
Fingolimod
Interferon beta-1a (Avonex®, Rebif®)
Interferon beta-1b (Betaseron®)
Natalizumab
Category X - Contraindicated in pregnancy
Teriflunomide
Modified from: Damek DM, Shuster EA, Mayo Clin Proc 1997; 72:977 (UptoDate-SEP2017)
MS & Breastfeeding
Effect of breastfeeding on MS None
Effect of MS on breastfeeding Meds!
Interferon β and glatiramer acetate “OK”?
Others to avoid
Coyle PK. Continuum (Minneap Minn). 2014:42-59
Hale TW et al. Breastfeed Med. 2012:123-5
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Conclusions
• Management of patients with MS/RRMS is very complex
• Early treatment influences the course over time
• There is a clear difference in safety profile among the current DMDs The risk-benefit ratio needs to be individualized
• Baseline assessment and monitoring are required for most of the DMDs in MS
• Teratogenicity & carcinogenicity are important factors in the choice of DMD
• Cost …