Eric Williamson, MDAssociate Prof. Neurology at UCLA &

Director, MS Center of Excellence, West Los Angeles VA

The Current State of Disease Modifying Therapy Use in Multiple Sclerosis

Presented August 2019 PVA Healthcare Summit and Expo

Disclosures● Eric Williamson, MD has the following financial or non-financial

interests/affiliation/arrangements with a commercial interest or interests to disclose: Biogen: Consulting, EMD Serono: Consulting, Genzyme: Consulting, Teva: Consulting, Novartis: Research Support

● This continuing education activity is managed and accredited by Affinity CE in cooperation with PVA. Affinity CE,PVA, as well as all accrediting organizations, do not support or endorse any product or service mentioned in this activity. Disclosure will be made when a product is discussed for an unapproved use.

● Affinity CE staff and PVA Staff, as well as planners and reviewers, have no relevant financial or non-financial interests to disclose.

● Commercial Support was not received for this activity.

Learning OutcomesAt the conclusion of this activity, the participant will be able to:

●Define what evidence of disease activity means.

●Explain what discontinuous therapy is.

●Describe the understood risk(s) and safety monitoring associated with each therapy discussed.

Symptoms vs. Relapses vs. Progression• MS symptoms are chronic or ongoing indicators of

dysfunction in the brain, spinal cord, +/- optic nerve*

• MS relapses are sudden flare-ups of disease activity (including new or worsening symptoms) that typically last several days or more, which we attribute to inflammation

• Disability attributed to MS must exclude other explanations, health issues & aging and implies loss of ability explained only by the primary disease process• typically measured by a scale or outcome measure

such as walking distance/need for assistive device

*we will omit discussion of symptomatic therapies today

Key Decisions in Tx/mgmnt of MS

Initiating immune therapy

Changing therapy

At all Times - Evaluating clinical response and therapeutic options

while weighing understood benefit/risk, safety, side effect & tolerance issues

MS subtypes● In most, disease “starts” as relapsing-remitting (RR) = clinical

episodes of central nervous system dysfunction followed by variable recovery & periods of remission ● >85% of patients begin with a Relapsing form of disease● 100% of pediatric MS patients begin with RRMS

● Relapsing stage may be followed by uninterrupted disability worsening not explained by other factors or health issues = Secondary progressive (SPMS)

● Some adult patients (5-15%) start with gradual worsening from onset without clear relapses = Primary progressive (PPMS)

Disease Activity

Previously: any evidence of

relapsing disease = RRMS

More recently: idea of progressive dz with OR w/o Dz activity

Disease Courses in MS

Best Description: characterize dz activity and/or progression by time

RRMS

PPMS

Dis

abili

ty

Time

Time

Dis

abili

tyRRMS—>SPMS

PMS with Dz activity or RMS with Progression

Time

Time

Dis

abili

tyD

isab

ility

Adapted from Lublin FD et al. Neurology. 1996;46:907-911. (http://lww.com)

Subclinical disease activity

Challenges of MS Treatment● Dz is difficult to predict, prognosticate, measure● Exacerbations, remission, variable recovery & disability progression

● Varied pathology: myelin loss, inflammation, axon loss, degeneration

● Symptom management and DMT utilization, the latter to:● Prevent relapses/Reduce Inflammation And hopefully to

● Slow any Progression of Disability

Issues with Disease Modifying Therapies

● tolerability● adherence● safety● monitoring● variable efficacy and response

● Many choices, including between● conventional step-care [escalation] ● early top-down approach [induction]

(ie standard vs. flipped pyramid re efficacy/safety)

Immune dysregulation —> modulation

● CNS tissue demonstrates immune cell infiltration, activation and inflammation (particularly early in the disease course)

● Adaptive immune responses offer targets and all the approved therapies reduce inflammation, relapses

● There may be downstream effects of modulation and we can not only predispose to infections but upset the balance between pro- and anti-inflammatory processes

● Reactivation of latent viruses● Interactions btwn cancer biology and immunotherapy

Evolution of Treatment:

● Pre 1992: steroids/ACTH

● Platform therapies: injectables

● 2nd generation of DMTs: more potency, new complications…Mitoxantrone (n.b. for “PMS”): heart failure + then 2005: Progressive Multifocal Leukoencephalopathy with natalizumab

● With time and additional agents, concern about infectious complications heightened and new side effect profiles recognized

● Now: “Progressive indications”● Primary Progressive Dz or● Secondary Progressive Dz with disease activity

Steroids:

Corticosteroids, including ACTH (steroid receptor agonist), used for decades before DMTs, extensively in other diseases● In MS, can accelerate recovery from acute attacks/relapses● Anti-inflammatory and/or immunosuppressive

● Increase risk of infections over longer periods of time/with chronic use and may exacerbate latent infections or mask signs of infxn even in the short term

● Detrimental effects on bone health, endocrine system longterm

*Use with caution with new DMTs, where serious infections more of a risk: herpetic infections, JCV/PML

disease-modifying therapies by route● glatiramer acetate (Copaxone®; generic equivalents) [injectable]● interferon beta-1a (Avonex®, Plegridy™, Rebif®) [injectable]● interferon beta-1b (Betaseron® and Extavia®) [injectable]

● cladribine (Mavenclad®) [oral] ● dimethyl fumarate (Tecfidera™) [oral]● fingolimod (Gilenya™) [oral]● teriflunomide (Aubagio®) [oral]● saponimod (Mayzent®) [oral]

● alemtuzumab (Lemtrada™) [infusion]● mitoxantrone (Novantrone®) [infusion]● natalizumab (Tysabri®) [infusion]● ocrelizumab (Ocrevus) [infusion]

DMTs by frequency of administrationDMT FrequencyInterferon-Beta

1a’s1b’s

Glatiramer Acetate 20mg40mg

Weekly, biweekly, three times per weekEvery other day or three times per week

DailyThree times per week

FingolimodSaponimodTeriflunomideDimethyl Fumarate

DailyDailyDailyTwice Daily

NatalizumabOcrelizumab

MonthlyEvery 6 months (after first two 1/2 doses over 2 weeks)

Cladribine Weight-based dosing at month 1 and 2, may repeat 12 months thereafter but not more than 2 years continuous

AlemtuzumabMitoxantrone

5 days once yearly (some patients won’t receive >2 doses)q3months, do not exceed ~12 doses lifetime

Platform Therapies

● Widespread use, retain large market share as a group and most patients will not change due to efficacy concerns

● Do not alter the immune system in ways that suppress the body’s:● ability to fight off infections, respond to vaccinations, or function

● Safe with respect to serious infectious side effects (SEs)● Rare reports of local infxns, abscess formation with injections

● Are metabolized in part by the liver and require screening for rare occurrence of lymphopenia (interferons > glatiramer)

The “other” 2nd gen DMT: Mitoxantrone

● Powerful antineoplastic, also used in leukemia● Cytotoxic, capable of broad immunosuppression● Approved in 1996 for aggressive or PROGRESSIVE dz,

but use has waned over time● Dose-limited cardiotoxicity+

● Long term infectious concerns and reports of hematologic malignancy

● In trials, mild increase in UTIs, URTIs

Natalizumab

● Dramatic Improvement in Efficacy (and compliance) vs. platforms

● Initial studies:● UTI’s, Rhinopharyngitis ● Fatal case of herpes encephalitis

● Shortly after approval for use in both diseases, PML reported in association with natalizumab treatment for Crohn’s and MS

● As of 2019, >800 reported cases of PML

● Often used pending JCV+ status, with time limitation● Herpes, Varicella are other recognized complications

Progressive Multifocal Leukoencephalopathy (PML)

● Cardinal features: ● Rapid Demyelination + Deterioration● Cognitive/behavioral changes,

weakness, visual, other Sx’s

● Diagnosis established by: ● (1) a compatible clinical picture● (2) typical brain MRI ● (3) PCR detection of JCV in CSF

● Disorders of cell-mediated immunity increase risk, esp. HIV ● Restoration of immune system can arrest PML, but No Treatment● Immune reconstitution can cause as much or more damage

*Risk with other agents is substantially less than with natalizumab

Ocrelizumab

● Depletes B and pre-B cells ● Dramatic anti-inflammatory effect, including MRI● Modest effect in Progression of disability

● UTIs 2x more common than placebo ● Serious complications outside trials: viral disease

incl reactivation of hepatitis, cases of PML (handful with ocre. in MS but 100s with ritux)

● PML incidence considerably lower than with NTZ, but RTX fatality rate > 90% + if dosed within 3 mo

● The 6 plus PML cases to date with ocrelizumab had prior NTZ (or fingolimod, in once case)

*Across ocrelizumab trials, 6 cases breast CA vs. zero cases in placebo groups

Alemtuzumab

● Potent and lasting effect on relapsing disease● profound reduction of B and T lymphocytes

● B cells recover inside 3 months, T’s over years

● 1/3 develop thyroid disorder, other autoimmune problems incl renal dz, ITP

● In comparison studies vs IFN-β-1a:● Modest increases in UTIs, URTIs and severe infxns in 4 vs 1%

● Reports of mucocutaneous herpes, candidiasis and varicella zoster● patient in endemic region developed tuberculosis (TB), another a +skin test ● PML with alemtuzumab: 2 cases in chronic lymphocytic leukemia and 1 in

lung transplant pt (background of malignancy/IS) but none in MS to date● More recently, listeria diet and/or prophylaxis recommended

Fingolimod

● The first oral to market and robust efficacy● Bradycardia requiring first dose observation● Rare cases of macular edema

● Trial Data:● acute infections of respiratory, urinary tract● severe infections in 2-6%:

● fatal case each of HSV encephalitis and disseminated VZV infection● + primary VZV case in extension = VZV status testing, boosters

● Additional reports of HSV, recurrent zoster, VZV encephalitis & vasculitis ● >Ten fingolimod-PML cases without NTZ, additional cases post-NTZ● crypto and other opportunistic infections were later added to label

Saponimod● Close cousin of Fingolimod

● Need for first dose cardiac monitoring removed if no prior concern of cardiac dz

● Received indication for Secondary Progressive MS with disease activity, in addition to being approved for relapsing disease

Teriflunomide

● Another once daily oral DMT● limits pyrimidine synthesis in rapidly proliferating cells

● = hair thinning in 10% of patients● Pregnancy “category X”● Blocks activation, proliferation of T&B lymphocytes

● Small numbers of UTIs, URTIs and 3 cases of pyelonephritis in trials● closely related to leflunomide – providing additional info:

● Cases of pulmonary tuberculosis, Pneumocystis jieroveci, pulmonary infections = TB screening

● Rare PML with leflunomide (one SLE, one RA) in patients with immunosuppressant drugs prior

Dimethyl Fumarate

● Reasonable efficacy● Induces apoptosis of certain T cells, other MOA?● Can upset stomach or cause flushing in >50% ● Significantly reduces some lymphocyte counts

● Comparable rates of rhinopharyngitis, bronchitis, URTIs, UTIs, sinusitis, gastroenteritis across placebo and comparator arms with frequency of serious infections low across all groups at 1-2%

● As many as five cases published re PML associated with use of fumaric acid esters in other disease and now at least 6 in MS in DF without NTZ● Risk thought to include “profound” lymphopenia [+age/duration?]

Daclizumab● Injectable CD25 targeting medication● Rare but serious liver problems● Common skin issues● Minor infections ●but then, encephalomyelitis cases = pulled in 2018

Cladribine

● Two treatment courses● Discontinuous● Approved for RRMS and

Active secondary progressive MS [sea change?]● with inadequate response to prior Tx

● safety profile includes infections and rare but scattered malignancies from trials

What should you be checking/monitoring?(at a minimum...)

●Inteferons LFTs, CBC

●Glatiramer acetate

●Fingolimod EKG then FDO, OCT, VZV IgG; lymphs (care <200) ●Saponimod above PLUS CYP2C9 *3/*3 genotype, MINUS FDO

●Teriflunomide TB; LFTs

●Dimethyl fumarate lymphos q3-6months (caution <500)

●Cladribine lymphocyte counts before/during/after

●Natalizumab JCV index, regular imaging

●Alemtuzumab TB, VZV, HIV, hepatitis; monthly CBC, q3mo TSH, CMP(/renal)

●Ocrelizumab hepatitis screening

VZV testing and immunizing

● Prior to use of: fingolimod, alemtuzumab, natalizumab, ocrelizumab, others ??

● If IgG status is negative, recommendation is two boosters a month apart and to wait another month before starting drug

● Should we give immunization while on drug?● Should we be rechecking Immune status, how often?

*Examining effects of DMTs on immunity needs to be evaluated, especially when discussing use of B cell depletors

JCV antibody status

● Beneficial to know change in status, possibly index value(s) in the setting of natalizumab use

● Viral replication during the weeks or months leading up to PML could provide stimulus for antibody production

● Observations of moderate to high, or rising, JCV antibody titers may support using the titer levels to further stratify risk

● Natalizumab treated PML patients with samples available months prior to PML often show higher anti-JCV levels

● Unclear how to use in other situations or with other DMTs, as is the effect of these therapies on said values

other concerns●malignancy? - rec general cancer screening or more?

● HPV vaccination, PCR’s, cervical smears?

●other vaccinations● MMR● pneumo/meningo-coccus● H. flu

*It is reasonable in specific populations, to add additional screening - particularly for potent immune suppressing or long term strategies

We need to better identify and describe disease activity to Treat appropriately

• Early diagnosis and treatment are important:▪ Significant, irreversible damage can occur early▪ Available treatments reduce number of relapses along with

MRI activity and may slow progression

• The cause of disability progression in the absence of inflammation is still unknown

• Treatment includes: symptom management, along with relapse management and rehabilitation, but also necessitates emotional support in addition to disease modification

• We encourage regular disability measurements, questions about ability, walking, exercise tolerance in addition to imaging and routine clinical follow up

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