Precision Medicine with Polypharmacy in

Multiple Sclerosis:
What Does It Mean in Practice?

Robert K. Shin, MD, FANA, FAAN Marijean Buhse, PhD, RN, NP-C, MSCN
Professor, Department of Neurology, Clinical Professor,
Georgetown University Stony Brook University School of Nursing
Director, Georgetown Multiple Sclerosis and
Neuroimmunology Center,
Georgetown University Medical Center

Jacquelyn L. Bainbridge, PharmD, FCCP,

MSCS, FAES
Professor of Neurology, Department of Clinical
Pharmacy
University of Colorado, Anschutz Medical
Campus
Faculty Disclosures
 Jacquelyn L. Bainbridge, PharmD, FCCP, MSCS, FAES
served as faculty for this activity. She has served on an
advisory board for Genentech.

 Marijean Buhse, PhD, RN, NP-C, MSCN served as faculty

for this activity. She has received consulting fees from
Biogen and Genzyme. She has served on the Speaker’s
Bureau for Biogen and Genzyme.

 Robert K. Shin, MD, FANA, FAAN served as faculty for

this activity. He has received consulting fees from Biogen,
Bristol-Myers Squibb, EMD Serono, Mallinckrodt, Novartis,
and Sanofi Genzyme. He has served on the Speaker’s
Bureau for Biogen, Bristol-Myers Squibb, EMD Serono,
Mallinckrodt, Novartis, and Sanofi Genzyme.
2
Learning Objectives
 Summarize approaches to providing personalized
medicine for MS diagnosis and management while
minimizing drug interactions with medications for
common comorbidities

 Appraise current data on biomarkers for differentiating

MS from other disorders and MS phenotypes

 Evaluate algorithms and predictive models for MS

management

3
Q: Which of the following biomarkers do you feel will be the
most useful in the management of MS?

A. Brain MRI T2 lesion volume

B. Brain MRI brain volume measurements

C. Optical Coherence Tomography (OCT)

D. Serum Neurofilament Light (NfL)

E. Symbol Digit Modality Testing (SDMT)

4
Properties of a Biomarker

 Measurable indicator of the presence of a

disease state
 Measurable indicator of the severity of a
disease state

5
Diagnosis of Multiple Sclerosis

 Dissemination in SPACE
 Dissemination in TIME

6
Dissemination in SPACE

7
Dissemination in SPACE

8
Dissemination in TIME

9
Dissemination in TIME

10
MRI Disease Activity

11
 Diagnosis of Multiple Sclerosis:
2017 Revision of the McDonald Criteria

 If the 2017 McDonald Criteria are fulfilled

and there is no better explanation for the
clinical presentation, the diagnosis is MS.

12
Thompson AJ, et al. Lancet Neurol. 2017;17(2):162-173.
Patient Case: Relapsing MS

 1967: right optic neuritis

 1968: left-side weakness, right-side
numbness
 1970s: several exacerbations, treated w/
ACTH
 Relapses in 11/97, 1/99 and 2/99
 Beta-interferon treatment initiated in 1999
 2005: hospitalized with paraplegia and
incontinence

13
Relapsing MS?

14
Neuromyelitis Optica Spectrum Disorder
(NMOSD)

 Optic neuritis
 Transverse myelitis
 Area postrema syndrome
 80% serum AQP4-IgG (NMO-IgG) positive

15
16
Optic Neuritis?

 APQ4-IgG negative
 Myelin oligodendrocyte glycoprotein (MOG)
-IgG positive (1:100)
 Diagnosed with MOG antibody-associated
disorder (MOGAD)

17
Myelin Oligodendrocyte Glycoprotein
Antibody-Associated Disorders (MOGAD)

 Optic neuritis
 Transverse myelitis
 Acute disseminated encephalomyelitis (ADEM)
 May overlap clinically with NMOSD
 Associated with serum MOG-IgG

18
Neurofilament Light Chain

19
Biomarkers in Multiple Sclerosis

 MRI
• Diagnosis
– Dissemination in SPACE
– Dissemination in TIME
• Disease activity
 Autoantibody testing
• Aquaporin 4 (AQP4-IgG)
– Neuromyelitis Optica Spectrum Disorder (NMOSD)
• MOG-IgG
– MOGAD
 Neurofilament light
• Serum neurofilament light chain (NFL)
– Marker of neuronal injury

20
Polypharmacy and
Comorbidities
Objectives

 Discuss the burden of and factors

contributing to polypharmacy in relapsing
MS
 Identify the potential for drug interactions
with DMTs and medications for
comorbidities
 Describe the implication for management
and treatment decisions

22
Q: How many medications are considered
“polypharmacy”?

A. ≥3

B. ≥4

C. ≥5

D. ≥6

E. ≥7

23
 Polypharmacy in Multiple Sclerosis Patients

 Polypharmacy definition: use of ≥5 medications

 Frahm and colleagues (2019)
• Evaluated frequency of polypharmacy in MS
population (56.5% of patients)
• DMTs, antihypertensives, GI meds, thrombosis
prophylactics, osteoporosis and sedatives used
most frequently
• Unmonitored multidrug use can lead to adverse
outcomes, higher costs, and non-adherence,
especially in those with disability

Frahm N, et al. Sci Rep. 2019;9(1):3743. 24

Factors in How Drug Interactions Happen

 Pharmacokinetic
• What the body does to the drug
 Pharmacodynamic
• What the drug does to the body
 Protein binding
• Highly protein bound drugs
• ~ >90%

25
 Cytochrome P450 Isozyme system (CYP)

 Most involved with drug metabolism in liver

 Enzymes have broad substrate specificity, and
individual drugs may be substrates for several
enzymes
 60% of all clinically prescribed drugs are
metabolized by CYP3A4
 Enzyme inhibition vs enzyme induction
 CYP2C9
CYP2C19 oxidative metabolism
CYP2D6 ~80% of drugs
CYP3A4
Doring B, et al. Drug Metab Rev. 2014;46(3):261-282. 26
 Common Primary Symptoms in MS

27
Crayton H, et al. Neurology. 2004;63:s12-s18. For educational purposes only.
 Treatment Options for Comorbidities

Comorbidity Treatment Options

Spasticity oral/intrathecal baclofen, tizanidine, diazepam, clonazepam, dantrolene,

clonidine, gabapentin, botulinum toxin
Fatigue modafinil, armodafinil, fluoxetine, 4-aminopyridine, amantadine

Cognitive dysfunction cholinesterase inhibitors, NMDA receptor antagonists, CNS stimulants

Depression SSRI, SNRI, mirtazapine, tricyclics, bupropion

Bladder dysfunction anticholinergics, alpha-1 blockers, beta-agonists

Sensory and pain carbamazepine, gabapentin, pregabalin, topiramate, duloxetine, capsaicin

(neuropathic) cream, tricyclics
Sexual dysfunction PDE5 inhibitors, estrogen cream, methyltestosterone

Walking/mobility issues dalfampridine

 Caution with additive CNS depressant, QTc prolonging or serotonergic effects with
using multiple agents that have these effects in combination
 Stimulants may counteract effects of antihypertensive medications
 Caution with using strong inhibitors or inducers together (eg, carbamazepine)
 Consider all comorbidities when selecting agent 28
 DMTs Approved by the FDA

Injectable Oral Infusions

Glatiramer Acetate Dimethyl Fumarate Alemtuzumab
(Copaxone; Glatopa) (Tecfidera) (Lemtrada)
Interferon β-1a IM Diroximel Fumarate Natalizumab
(Avonex) (Vumerity) (Tysabri)
Interferon β-1a SQ Monomethyl Fumarate Ocrelizumab
(Rebif) (Bafiertam) (Ocrevus)
PEG INF β-1a SQ Fingolimod Ofatumumab*
(Plegridy) (Gilenya) (Arzerra – approved for CLL)
Interferon β-1b Siponimod Mitoxantrone**
(Betaseron; Extavia) (Mayzent) (Novantrone)
Ozanimod
(Zeposia)
Teriflunomide
(Aubagio)
Cladribine
(Mavenclad)
* Not approved for MS – under regulatory review. 29
**Rarely used around the world; not at all used in the VA system
 Metabolism and Elimination of DMTs

Drug Metabolism/Elimination
IFN β-1a Inactivated in body fluids and tissue
IFN β-1b
Glatiramer acetate Hydrolyzed locally
Natalizumab Broken down into peptides and AAs in body fluids
Alemtuzumab
Ocrelizumab
Dimethyl fumarate Hydrolysis. No CYP involvement in metabolism
Elimination: exhalation of CO2 (major)
Renal and fecal (minor)
Diroximel fumarate Inactivated by esterases in the GI tract, blood, and tissue
Eliminated: renally and respiratory
Monomethyl fumarate Tricarboxylic acid cycle to active metabolites
Elimination: renal, fecal, respiratory exhalation (major)

70% of drugs are metabolized by CYP 3A4, 2D6, 2C, therefore if a drug is not a
substrate/inducer/inhibitor of those CYPs or P-Glycoprotein, the drug-drug interactions will be minimal.
30
MicroMedex Solutions. Available at: http://micromedex.com/.
 Metabolism and Elimination of DMTs

Drug Metabolism/Elimination
Teriflunomide Hydrolysis to minor metabolites
Highly protein bound
Inhibits: BCRP (CYP2C8, OATP1B1 (influx))
Induces: CYP1A2
Substrate: BCRP
Eliminated: biliary and renal
Fingolimod Hepatic via CYP4F2
Highly protein bound
Substrate: CYP2D6, CYP2E1, CYP3A4 (all minor)
Excreted: renal and fecal
Siponimod Hepatic via CYP2C9, CYP3A4
Highly protein bound
Substrate: CYP2C9 and CYP3A4

70% of drugs are metabolized by CYP 3A4, 2D6, 2C, therefore if a drug is not a
substrate/inducer/inhibitor of those CYPs or P-Glycoprotein, the drug-drug interactions will be minimal.
31
MicroMedex Solutions. Available at: http://micromedex.com/.
 Metabolism and Elimination of DMTs

Drug Metabolism/Elimination
Ozanimod Highly protein bound
Major active metabolites: CC112273, CC1084037
Minor active metabolites: RP101988, RP101075, and RP101509
Active metabolite substrates: CYP2C8, BCRP, MAO-B
Active metabolites inhibit MAO-B
Substrate: CYP3A4 and CYP2C8
Elimination: renal and fecal
Cladribine Metabolism not fully characterized; extensive whole blood,
phosphorylation
Substrate: P-gP, BCRP, ENT1, and CNT3
Elimination: renal
Mitoxantrone* Hepatically into inactive metabolites
Elimination: renal and fecal

*Rarely used around the world; not at all used in the VA system 32
MicroMedex Solutions. Available at: http://micromedex.com/.
 Injectable DMT Drug Interactions

 IFN-beta products – data do not suggest any

significant interactions with therapies commonly
used in MS
 Glatiramer acetate – data do not suggest any
significant interactions with therapies commonly
used in MS
 Live attenuated virus vaccines - (smallpox, rubella,
mumps, poliovirus, measles, influenza – flu mist,
varicella, zoster, yellow fever, adenovirus, dengue
tetravalent, rotavirus, typhoid*, cholera*, BCG*)
may result in an increased risk of secondary
transmission of infection by the live vaccine and
reduced effectiveness of immunization
MicroMedex Solutions. Available at: http://micromedex.com/.
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020
*Whole-cell vaccines, bacterial: not available in the US 33
 Oral DMT Drug Interactions (Fumarates)

 Dimethyl fumarate – renally-cleared medications may affect PK; no potential

drug interactions were identified in in vitro CYP inhibition and induction
studies or in P-glycoprotein studies. Administration of dimethyl fumarate and
diroximel concurrently are contraindicated due to ↑ monomethyl fumarate
levels. Post-marketing reports of hepatotoxicity.

 Diroximel fumarate – metabolism is via esterases in the GI tract, blood and

tissues, the active metabolite monomethyl fumarate is excreted primarily by
the respiratory system. No identified drug interactions. Do not use with
dimethyl fumarate (same active metabolite). Can start diroximel fumarate the
day after discontinuing dimethyl fumarate. Hepatotoxicity may occur. Less GI
side effects and less flushing.

 Monomethyl fumarate – metabolite of both dimethyl fumarate and diroximel

fumarate. No identified drug interactions.

 Live attenuated virus vaccines - may result in an increased risk of secondary

transmission of infection by the live vaccine and reduced effectiveness of
immunization

MicroMedex Solutions. Available at: http://micromedex.com/.

https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020
34
 Fingolimod
 Substrate of: CYP2D6, CYP2E1, CYP3A4, CYP4F12, minor, CYP4F2 major
 Highly protein bound
 Drugs that slow heart rate: beta blockers, diltiazem use with caution
 Drugs that prolong the QT interval (can cause torsades de pointes in patients with bradycardia): citalopram,
chlorpromazine, haloperidol, methadone, erythromycin, ziprasidone, saquinavir, bepridil, thioridazine, pimozide) –
monitor overnight with continuous ECG in a medical facility
 Concomitant use with class Ia or III antiarrhythmic drugs are contraindicated
• 1a = quinidine, procainamide, disopyramide
• III = amiodarone, bretylium, sotalol, ibutilide, azimilide, dofetilide, dronedarone
 Ketoconazole: inhibits CYP 3A4 which increases fingolimod concentration by 70%
 Carbamazepine, rifampin, phenytoin, phenobarbital, St. John’s wort will decrease fingolimod
 6-hr first-dose observation period
 Live attenuated virus vaccines - may result in an increased risk of secondary transmission of infection by the live
vaccine and reduced effectiveness of immunization
 Risk of infection; reduction of lymphocyte count to ~20-30% of baseline: at risk for Herpes viral infections. Herpes
simplex encephalitis, and varicella zoster meningitis, varicella (chickenpox) documentation or antibody + or
vaccination prior to start. HPV, PML and cryptococcal meningitis or disseminated infection has been seen with
fingolimod- monitor
 Monitor for malignancies – cutaneous, lymphoma
 Monitor for posterior reversible encephalopathy syndrome (PRES) – reported with fingolimod
 May have additive immunosuppressive effects with anti-neoplastic, immune-modulating, or immunosuppressive
therapies – use de novo
 Monitor liver function tests

CBC = complete blood count; LFTs = liver function tests; MOA = mechanism of action; PFTs = pulmonary function tests.
Not an extensive list.
Fingolimod (GILENYA®) [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.; MicroMedex Solutions. Available at: http://micromedex.com/.;
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020
35
 Siponimod
 CYP2C9 genotyping required
 Contraindicated in patients with CYP2C9*3/*3 genotype, MI with in the last 6 months, unstable angina, stroke, TIA, decompensated heart
failure, class III or IV heart failure
 CYP2C9*1/*3 or *2/*3 maintenance dosage (after the initiation dose)1 mg orally daily. CYP2C9*1/*1, *1/*2, or *2/*2 maintenance dosage
(after the initiation dose) is 2 mg orally daily
 Extensively metabolized by CYP2C9 (80%) followed by CYP3A4 (18%);
• Avoid use or monitor with moderate CYP2C9 and strong CYP3A4 inducers not recommended, this concomitant drug regiment can
consist of moderate CYP2C9/strong CYP3A4 dual inducer (rifampin or carbamazepine), or a moderate CYP2C9 inducer in
combination with a separate strong CYP3A4 inducer. Caution should be used for concomitant use with a moderate (modafinil,
efavirenz) or strong CYP3A4 inducers is not recommend for patients with CYP2C9*1/*3 and *2/*3 genotype.
• Avoid use or monitor with moderate CYP2C9 and moderate or strong CYP3A4 inhibition. This can consist of a moderate
CYP2C9/CYP3A4 dual inhibitor (fluconazole) or a moderated inhibitor in combination with a separate –moderate or strong CYP3A4
inhibitor
 It is not an enzyme inducer or enzyme inhibitor
 Fluconazole: inhibits CYP2C9 and CYP3A4 leads to a 2 to 4 fold increase in the AUC
 Rifampin: induces CYP3A4 and CYP2C9 and decreased siponimod AUC and Cmax by 57 % and 45 % respectively in CYP2C9*1/*1
patients
 Rifampin and efavirenz: moderate inducer of CYP3A4 reduced the AUC of siponimod by up to 78% and 52% respectively across CYP2C9
genotypes
 Drugs that lower heart rate: beta blockers, diltiazem, verapamil, ivabradine, digoxin use caution
 Has not been studied in patients taking QT prolongation drugs see fingolimod slide, recommended cardiology consult
 Highly protein bound
 Live attenuated virus vaccines - may result in an increased risk of secondary transmission of infection by the live vaccine and reduced
effectiveness of immunization
 Risk of infection; reduction of lymphocyte count to ~20-30 of baseline: At risk for Herpes viral infections. Herpes simplex encephalitis, and
varicella zoster meningitis, Varicella (chickenpox) documentation or antibody + or vaccination prior to start. Cryptococcal meningitis or
disseminated infection has been see with other SP1 receptor modulators and with siponimod- monitor. PML has not been reported with
siponimod , however it has occurred with other SP1 receptor modulators.
 May cause increase in liver function tests – monitor
 Monitor for posterior reversible encephalopathy syndrome (PRES) – not seen with siponimod but other SP1s
 May have additive immunosuppressive effects with anti-neoplastic, immune-modulating, or immunosuppressive therapies – use de novo
 First dose 6-hour monitoring in patients with sinus bradycardia (HR <55), first or second degree Mobitz type I AV block, or history of MI or
heart failure unless patient has a functional pacemaker

Siponimod (Mayzent®) [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.; MicroMedex Solutions. Available at: http://micromedex.com/.;
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020 36
 Ozanimod
 Substrate for: CYP2C8, CYP3A4 ozanimod; Substrate for: CYP2C8, BCRP/ABCG2, MAO-B
active metabolites – inhibitors/inducers may alter systemic exposure to ozanimod
 Ozanimod is not an enzyme inducer or enzyme inhibitor of CYP450 system
 Active metabolites are an inhibitor of MAO-B
 Major interaction: tricyclics - eg, nortriptyline, amoxapine, amitriptyline, (prolong QT interval),
cyclosporine, MAOI – phenelzine, rasagiline, linezolid, safinamide, selegiline; BCRP
inhibitors – eg, velpatasvir; SNRI’s – duloxetine, milnacipran, nefazodone, desvenlafaxine,
venlafaxine, etc., strong CYP2C8 inhibitors – gemfibrozil, etc., opioids…, SSRIs – fluoxetine,
paroxetine, sertraline, citalopram, escitalopram, QT prolongation drugs antiarrhythmics, first-
generation antipsychotics. Essentially, ozanimod is not recommended with strong CYP2C8
inducers and inhibitors and BCRP inhibitors.
 Live attenuated virus vaccines - may result in an increased risk of secondary transmission of
infection by the live vaccine and reduced effectiveness of immunization
 Immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase risk of
adverse effects
 PML not reported in the MS population
 Antivirals/antiretrovirals (lamivudine, zalcitabine, ribavirin, stavudine and zidovudine) reduce
intracellular phosphorylation and potentially reduce the efficacy of ozanimod

Ozanimod (Zeposia®) [package insert]. Summit, NJ: Celgene Corporation; 2020; MicroMedex Solutions. Available at: http://micromedex.com/.;
https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020 37
 Cladribine
 Contraindicated in patients with current malignancy, pregnant women, and
women and men of reproductive potential who do not plan to use effective
contraception during active treatment and for 6 months after the last dose,
HIV infection, active chronic infections (e.g., hepatitis or tuberculosis) and
women intending to breastfeed on a cladribine treatment day and for 10
days after the last dose
 Substrate for: P-gP, BCRP, ENT1, CNT3 – inhibitors/inducers may alter
systemic exposure to cladribine
 Not an inducer or inhibitor of Cytochrome P450 system
 Live attenuated virus vaccines - (smallpox, rubella, mumps, poliovirus,
measles, influenza – flu mist, varicella, zoster, yellow fever, adenovirus,
dengue tetravalent, rotavirus, typhoid*, cholera*, bacillus of Calmette and
Guerin*) may result in an increased risk of secondary transmission of
infection by the live vaccine and reduced effectiveness of immunization
 Immunomodulatory, immunosuppressive, or myelosuppressive drugs may
increase risk of adverse effects
 PML not reported in the MS population
 Antivirals/Antiretrovirals (lamivudine, zalcitabine, ribavirin, stavudine and
zidovudine) reduce intracellular phosphorylation and potentially reduce the
efficacy of cladribine
ENT1 = equilibrative nucleoside transporter 1; CNT3 = concentrative nucleoside transporter 3
MicroMedex Solutions. Available at: http://micromedex.com/.; Cladribine (Mavenclad®) [package insert]. Rockland, MA: EMD Serono,
Inc.; 2019; https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020
*Whole-cell vaccines, bacterial: not available in the US
38
 Teriflunomide
 Induces CYP1A2
• Major: clozapine, warfarin (decreased anticoagulant effectiveness – unknown
mechanism of action + CYP1A2)
• Moderate: olanzapine, tizanidine, fluvoxamine, tacrine, haloperidol, imipramine,
naproxen, duloxetine, cyclobenzaprine
 Inhibits CYP2C8
• Pioglitazone (Moderate) or rosiglitazone and leflunomide or its metabolites
results in increased pioglitazone or rosiglitazone exposure
• Major: Repaglinide and leflunomide or its metabolites (increased exposure of
repaglinide)
• Major: Leflunomide and methotrexate may result in increased exposure of
methotrexate and increased risk of hepatotoxicity and bone marrow toxicity
• Major: Teriflunomide and CYP2C8 substrates (paclitaxel, montelukast,
enzalutamide, dabrafenib, dasabuvir) results in increased exposure of these
CYP2C8 substrates
• Major: Tucatinib (CYP2c* substrate) with a moderate CYP2C8 inhibitor may
increase tucatinib exposure and risk of toxicities
• Major: Rosuvastatin with leflunomide or its metabolites increased exposure of
rosuvastatin
• Major: Teriflunomide and OAT3 substrate causes increased OAT3 substrate
(furosemide, cefaclor, acyclovir, ciprofloxacin, valacyclovir, baricitinib) exposure
MicroMedex Solutions. Available at: http://micromedex.com/. https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020 39
*Whole-cell vaccines, bacterial: not available in the US
 Teriflunomide (cont.)
 Inhibits CYP2C8 (cont.)
• Major: Teriflunomide and OATP1B1/1B3 substrate causes increased
OAT1B1/1B3 substrate (Glyburide, simvastatin, atorvastatin, bosentan,
pitavastatin, grazoprevir, letermovir, elagolix, revefenacin) exposure
• Major: Teriflunomide and BCRP substrates (sulfasalazine, irinotecan, topotecan,
tenofovir alafenamide) may result in increased exposure of BCRP substrates
• Major: Amiodarone with a CYP2C8 inhibitor as exposure to amiodarone may be
increased. Amiodarone has a long half life so drug interactions may persist of
weeks to months after discontinuation
• Major: Selexipag (CYP2C8 substrate) and a moderate CYP2C8 inhibitor may
result in an increase in selexipag exposure. If used together reduce the selexipag
dosing to once daily. Change dosing back after CYP2C8 inhibitor discontinued
• Major: Leflunomide (prodrug) and teriflunomide (its active metabolite), increased
exposure of teriflunomide. CONTRAINDICATED
 Highly protein bound
 Live attenuated virus vaccines - (smallpox, rubella, mumps, poliovirus, measles,
influenza – flu mist, varicella, zoster, yellow fever, adenovirus, dengue tetravalent,
rotavirus, typhoid*, cholera*, bacillus of Calmette and Guerin*) may result in an
increased risk of secondary transmission of infection by the live vaccine and
reduced effectiveness of immunization

MicroMedex Solutions. Available at: http://micromedex.com/. https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020 40

*Whole-cell vaccines, bacterial: not available in the US
 Infusible DMT Drug Interactions

 Alemtuzumab – no formal drug interaction studies have been

performed. An immune response may interfere with subsequent
diagnostic serum tests that utilize antibodies. PML reported.
• Ozanimod, siponimod, tofacitinib result in ↑ immunosuppression
 Ocrelizumab – no CYP drug interactions. Immunomodulatory,
immunosuppressive may cause concomitant
immunosuppression. PML reported.
 Natalizumab – potential for ↑ risk of PML and other infections
with concomitant immunosuppressants (eg, 6-mercaptopurine,
azathioprine, cyclosporine, methotrexate, corticosteroids, or
TNF-α inhibitors)
 Live attenuated virus vaccines - may result in an increased risk
of secondary transmission of infection by the live vaccine and
reduced effectiveness of immunization

Alemtuzumab (Campath®) [package insert]. Cambridge, MA: Millennium and ILEX Partners, LP; 2020; Natalizumab (Tysabri®) [package
insert]. Cambridge, MA: Biogen; 2020; https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf, accessed 7-13-2020
41
Implication for Management and Treatment
Decisions
 Document medication history and allergies
 Screen all patients for drug interactions
 Consult pharmacist for options specific to
individual patients
• Antidepressants, antipsychotics, drugs used for
systemic comorbidities
 If the patient has genetic testing, use precision
medicine to guide therapy
• Antidepressants, antipsychotics, siponimod
 Utilize shared decision-making techniques

42
Summary

 High risk for polypharmacy within the MS

patient population can lead to adverse
outcomes, higher costs, and non-adherence
 Medications to treat comorbidities often pose
drug interaction risks
 Medications to treat MS often interact with the
CYP450 and drug transporter systems
resulting in a large range of possible drug
interactions

43
Treatment Precision:
Newly Diagnosed and
Relapsing MS
Why Treat?

 Decrease the number and severity of relapses

 Decrease lesions in CNS
 Decrease progression
 Decrease cognitive loss
 Prevent/minimize neuronal damage

45
Giovannoni G, et al. Mult Scler Relat Disord. 2016;9 Suppl 1:S5-S48. 46
 Overview of DMTs

 Most target T and B cells and cytokines

 Therapies differ in their ability to
• penetrate the blood brain barrier
• act locally on inflammation and
neurodegeneration
 Aim to increase benefits by:
• increasing the anti-inflammatory activity
• decreasing burden of disease

Alroughani R, et al. Neurol Ther. 2019;8(1):13-23. 47

 DMTs Approved by the FDA

Injectable Oral Infusions

Glatiramer Acetate Dimethyl Fumarate Alemtuzumab
(Copaxone; Glatopa) (Tecfidera) (Lemtrada)
Interferon β-1a IM Diroximel Fumarate Natalizumab
(Avonex) (Vumerity) (Tysabri)
Interferon β-1a SQ Monomethyl Fumarate Ocrelizumab
(Rebif) (Bafiertam) (Ocrevus)
PEG INF β-1a SQ Fingolimod Ofatumumab*
(Plegridy) (Gilenya) (Arzerra – approved for CLL)
Interferon β-1b Siponimod Mitoxantrone**
(Betaseron; Extavia) (Mayzent) (Novantrone)
Ozanimod
(Zeposia)
Teriflunomide
(Aubagio)
Cladribine
(Mavenclad)
* Not approved for MS – under regulatory review. 48
**Rarely used around the world; not at all used in the VA system
 How to Choose Treatment?

 Increasingly complex
 Practical considerations
 Identification of an ‘optimal choice’
• Efficacy
• Side effects
• Requirements for starting and monitoring
• Treatment adherence
• Previous DMTs
Klotz L, et al. Ther Adv Neurol Disord. 2019 Apr 1. [Epub ahead of print]. 49
 How to Choose Treatment? (cont’d)

 MRI and clinical exam

 Number of recent relapses
 Symptoms
 Age
 Gender – pregnancy
 Patient lifestyle
 Patient preferences
 Comorbidities
• Smoking
• Depression
Clanet MC, et al. Mult Scler. 2014;20(10):1306-1311.
Tomassini V, et al. Mult Scler. 2019;25(9):1306-1315. 50
 Disease Course

 Clinical course highly variable

 Relatively mild disease with mild disability

 Relapsing course – usual

 Aggressive MS - “early, unexpected acquisition

of disability followed by frequent relapses
(often with incomplete resolution) and highly
active disease seen on MRI” .
Rush CA, et al. Nat Rev Neurol. 2015;11(7):379-389. 51
Treatment Discussions

 Open conversations
 Discuss why one treatment may be better
for patient
 Set treatment expectations
 Address patient concerns/hesitancy:
• Fear of treatment
• Disease denial
• Outright refusal
• Costs

52
 Shared Decision-Making

 Clinicians and patients work together to

make decisions and treatments based on
clinical evidence that balances risks and
expected outcomes with patient preferences
and values
 More than one reasonable option
 Builds trust
 Decision for treatment risk is shared
 Offers individualized assessment of risk

https://www.healthit.gov/sites/default/files/nlc_shared_decision_making_fact_sheet.pdf 53
When to Start, What to Use, For How Long?

 Depends upon disease course

 Any relapses on treatment?
 Adherence to medications?
 New lesions on MRI?
 New cognitive changes?

54
 Reasons for Non-Adherence

 Patient perception – only mild disease

 Cost
 Side effects
 Avoidance coping

Schoor R, et al. J Clin Psychol. 2019;75(3):380-391. 55

Strategy of Therapy

 When do you change treatment?

 Treatment failures
• New lesions
• Non-adherence
• New relapse
 Escalation vs induction

56
57
Monitoring Treatment Results

 Adverse drug reactions

 Non-adherence
 New relapses
 Progression of symptoms
 Scheduled MRIs
 Bloodwork
 REMs programs
 Usual health screening and vaccinations
58
Summary

 MS should be treated as early as possible

 Numerous DMTs to choose from
 Patients should be counseled on need for DMTs
 Treatment expectations should be discussed
 Treatment efficacy should be closely monitored
 Safety issues should be identified immediately
 Adherence is an ongoing problem

59
Q&A
Tune into our Upcoming Sessions
Multiple Sclerosis Research to Practice I:
Neuropathology and Biomarkers

Multiple Sclerosis Research to Practice II: High-Efficacy

DMTs
Monday, September 14th from 1:00-3:00pm ET

Speakers
Ellen M. Mowry, MD Daniel Ontaneda, MD, MSc
Professor of Neurology and Epidemiology Assistant Professor of Medicine/Neurology
Johns Hopkins University Cleveland Clinic Lerner College of Medicine of
Case Western Reserve University

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Thank You!