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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 …