Treatment of Multiple

Sclerosis

MNI grand rounds

Joshua Chalkley D.O. M.S.

Faculty Disclosures I have none

Objectives

Introduce concepts in treatment

Review established treatments

Introduce emerging therapeutic options

Treatment of Multiple Sclerosis

• MS is a complicated disease state

• Multiple Sclerosis is not a classic Autoimmune disease

• Multiple sclerosis is an inflammatory neurodegenerative disease which the immune systems plays an important role

A little History

• Debate over the initial case of MS

• First described in a detailed journal of Augustus d’Estes 1794-1845

• Some credit Linwana Holland 1380

MS Through the Ages

History Howard Weiner and Stephen Hauser treated MS

patients with systemic induction cyclophosphamide

First concept of disease modifying therapy

Immune regulation played key role in the treatment of

disease

Very controversial at the time they were highly criticized

given most experts in the field felt MS was likely related

to a latent virus

Weiner et al., 1983

Curing MS

• Three main goals in the treatment of MS

• Stop attacks and prevent disease progression

• Aid in repair and recovery of the CNS

• Prevent MS

• Weiner states we are doing a good job of one of these three goals and for all extensive purposes MS is now “curable” in some populations

Weiner et al., 2009

Treatment Approach

• Traditional approach choose first line therapy with minimal risk and if the patient progresses or has relapse switch to stronger treatment

• Pick the most effective treatment from the onset, in a hope of arresting the disease

Approach to MS Patient Bactericidal vs bacteriostatic?

Likely have the most impact if the disease is treated aggressively from the beginning

Most of our current agents modulate the immune system

Some of the newer drugs change in the immune system and likely have long lasting effects on immune function

Some of the newer drugs kill certain cell lines

No Evidence of Disease

Activity No new symptoms

No change in exam

No change in functional status

No change in MRI

Lofty goal we are not meeting this in the real world

Climb 7 year outcomes showed only 7.9% met this

criteria at 7 years

Rostein et al,.

2015

Interferon Multiple preperations of interferon beta

All are injections

All are beta interferons

All work by regulating T cell response although exact mechanism is unknown

They all work to reduce antigen presentation and T cell proliferation

All effective in reducing relapse rates in relapse remitting multiple sclerosis, both through clinical relapse and radiographically

Coyel et al., 2004

Pros Very good safety profile

Over 25 years of clinical data

Very effective

Multiple preparation choices

Cons Injectable

Neutralizing antibodies can render these drugs ineffective over time

Flu-like symptoms

Depression

Liver disease

Psychiatric disease

Limited role in current treatment

Glatiramer Acetate 1994

Works through unknown mechanism but is likely a mimics myelin, also likely regulates T cell response through an unknown mechanism

Made from a polymer of 4 amino acids found in myelin basic protein, which likely fools the immune system in mounting an attack against the drug

Once a day injection

Very effective in the treatment of MS

Johnson et al., 1995

Pros Very safe, no major side effects, no routine labs

Long safety record and effective

Cons Daily injections

Can cause pain

Panic attack like reaction

Lipodystrophy

Natalizumab First non injectable

Infusion every month

Works by cell adhesion on a alpha4- integrin receptor

inhibiting T-cell migration into the CNS

Very effective in the treatment of MS

This is considered one of the most potent of all the MS

drugs

Coleman et al 2005

Pros Extremely effective

Once monthly infusion

Overall good safety profile

Often effective in pt who were refractory to other drugs

Rapid effects in the CNS

Cons Serious side effects

PML- we will discuss this more

Increased risk of infections

Likely increased risk of melanoma

Cases of intraocular melanoma

PML

Natalizumab associated PML 731 cases of Natalizumab associated PML as of June

2017 (Biogen Idec)

JC virus titers are important for initiating treatment

Need to check these every 6 months

Natalizumab associated PML is about 30% fatal has much better outcome than with other diseases

If JC virus titer is negative risk of PML is minimal

Predilection for frontal lobes, often presents with subtle bhx changes

Berger et al., 2013

Risk Stratification The risk of developing PML under most circumstances is

fairly low

Risk of developing PML depends of JC virus status, duration

of treatment, and prior immunosuppressant use

If JC virus titer is negative, and there is no hx of previous

immunosuppression then overall risk is 0.01/1000 pts

If JC virus titer is positive, and there is hx of previous

immunosuppressant use and treatment duration is greater

than 25 months then risk is 11.1/1000

Chalkley et al., 2014

PML Risk Initial data likely underestimated the risk of PML

Berger and Fox reexamined current data in 2016

If all three risk factors were present, treatment over two

years, JCV positive, and prior exposure to

immunosuppressive therapy

The risk of developing PML is 1/44

Berger et al., 2016

CASE 1 44 year old male comes to clinic with new onset ataxia

and left leg weakness. His right disk is pale with right

RAPD. MRI of the brain shows several scattered white

matter lesions along with C4 enhancing lesion. 12 OCB

were seen in the CSF and he had hx of optic neuritis in

his early thirties with no clinical relapses. NMO is

negative infectious workup is clean what do you want

to do

CASE 1

Case Continued He was started on Glatiramer and did well for 7 months

when he had clinical relapse with enhancing lesions in

the spinal cord and brain. JC virus titer was negative at

this time. He was switched in interferon and a month

later had another serious relapse with enhancing

lesions in the brain and spinal cord. He is now wheel

chair bound and weak on his right side. Thoughts from

the crowd

Fingolimod First oral medication for MS

Sphingosine-1-phosphate receptor modulator

Traps developing T cells in peripheral lymph tissue

Very effective in the treatment of MS

Over a 50% reduction in total relapse rates

Cohen et al., 2010

Fingolimod Very effective, was far superior to IFN in initial clinical

trails (Cohen, NEJM 2010)

First oral drug approved for MS

Initial clinical trials had two deaths in the fingolimod

group secondary to infections, and an unexplained

death

May also have significant effect on brain atrophy

Cohen et al.,2010

Radue et al., 2015

Pros Once a day oral medication

Very effective

Good overall safety profile

Most experts believe this to be the most potent of the

oral drugs

Cons Difficult to get started

Associated with fatal bradycardia

Associated with two fatal infections

Systemic varicella

9 cases of PML

Lymphadenopathy

Macular Edema

Increase risk of skin cancer

Rare fungal infections, Kaposi sarcoma

Teriflunomide Second oral preparation

Inhibits pyrimidine de nova synthesis which

consequently inhibits rapidly dividing cells including T

cells

Also blocks transcription factors including NF-kB

Very effective

Once a day oral medication

O’Conner et al., 2011

Pros Oral med

Effective

To date no serious life threatening complications

Easy to start

Minimal monitoring

Improved disability progression

May work better late in the disease

O’Conner et al., 2011

Cons Its new and not used as much as the other medications

Alopecia

Nausea

Can cause liver damage

Category X for pregnancy

Also passed in significant levels in semen? (risk in

males)

Dimethyl fumarate Newest oral drug

Unknown how it protects in MS

Rapidly attacked by glutathione, then has multiple

possible immune reactions including up regulating anti-

inflammatory stress protein HO-1

Used for Psoriatic arthritis for 10 years in Europe

Gold et al., 2012

Pros 10 years of safety data

Safe

Well tolerated

Effective

Oral preparation

Cons Flushing

GI upset

Lymphopenia

Hepatic toxicity

PML risk

PML Cases in both formulations for MS and psoriasis

All cases were associated with absolute lymphocyte

counts less than 600 except one

Recommend stopping the drug in lymphocyte counts

less than 600

One case of PML with normal lymphocyte counts

Alemtuzumab

• Approved for refractory MS

• Humanized monoclonal Antibody with directed affect against CD52

• Binds to CD52, which is present on more than 95% of T cells, B cells, monocytes, eosinophils

• Actual CD52 function is unknown

• Initially designed for the treatment of leukemia

Cohen et al., 2012

Effects on the immune system

• Causes prolonged lymphocyte depletion (B cells, T cells, monocytes) for up to 5 years

• Within an hour after dose lymphocytes and monocytes are no longer detectable

• Median recovery time CD4 T cells 61 months, CD8 cells 30 months, monocytes 3 months, B cells 3 months

Cohen et al., 2012

Alemtuzumab

• Initial clinical trials were very impressive

• CAMMS223 trial, and CARE MS-I, CARE MS-II showed statistically significant reduction in relapse rate, Mean EDSS, contrasting lesions, and increase in disease free activity

• Outperformed IFNB-1a in all trials

Cohen et al.

2012

Adverse Events

• Infusion reactions, 3% serious

• Increased risk of infection- mostly simple infections nasopharyngitis, UTI, herpes, (acyclovir is given 1 month post therapy)

• Autoimmune disorders- thyroid disease most common 18%, thrombocytopenia, renal disease, pancytopenia with one death in trials

Pros

• Overall great efficacy

• Induction therapy with no ongoing injections

• One of the strongest treatments for MS

• Long lasting effects on the immune system

Cons Long acting effects on the immune system

Serious risk of autoimmune disorders

May have long term unknown consequences

Difficult infusion

Unclear dosing

Unclear what to do in case of relapse

Daclizumab

• Humanized IgG1 MAD against IL-R chain (CD25)

• IL-2R is expressed on active T and B cells

• Approved for treatment of renal transplant rejection

• Approved this year for MS

Milo et al., 2014

Daclizumab

• Approved in 2016

• Select trial showed significant decrease in Relapses, along with decrease in new lesion burden

• One death in this trial due to autoimmune hepatitis

• Injection every 6 weeks

Gold et al., 2013

Pros Novel mechanism of action

Well tolerated

Very effective in trials

Outperformed interferon beta-1a

cons Very new

Rash

Autoimmune reactions

Hepatic injury

As with all monoclonals side effects may be long term

and far reaching

Laquinimod

• Oral quinoline-3 carboxamide • Three phase III clinical trials show efficacy in

terms of disability progression(Allegro, Bravo, Concerta)

• Phase III trials showed decreased disability but no not decreased MRI activity, or relapse rates when compared to interferon

• Given unique model of action may be a favorable combination drug

• Continued debate

Comi et al., 2012

Anti-CD20 Most effective therapies to date have targeted T cells,

however increasing clinical data for the role of B cells in

treatment

CD20 is a transmembrane protein which functions as a

CA+ permeable cation channel

CD20 is present on greater than 95% of B cells

It is also found on a small subset of normal/neoplastic T

cells

Rituximab Chimeric anti-CD20 monocloncal antibody

Approved for non-Hodgkin lymphoma and refractory

RA, used off label in MS

Causes rapid depletion of B cells

Initial studies show significant decrease in contrasting

lesions, and relapse rates

Also being studied in progressive MS

Castillo et al., 2013

Rituximab In trials sub group analysis effective in progressive patients

less than 55

Rituximab success spawned other B cell therapies in MS

Salzer and colleagues looked at large retrospective group

which showed decreased relapse rates, decreased disability

with very little in terms of side effects

Apling and colleagues looked at aggressive MS patients

who stopped natalizumab due to JCV status and compared

fingolimod to Rituximab, Rituximab pts were more stable

with fewer side effects

Slazer et al., 2016

Apling et al., 2016

Pros Very effective

Safe

Long term data available from other disease states

Well tolerated with few side effects

Cons Small risk of increased infection

Small risk of PML although this difficult to ascertain,

never seen in pure MS populations

Allergic reaction

Headache

Ocrelizumab Approved this year for MS

Humanized form of Rituxan

Very effective in MS, outperformed interferon in trials

Was effective in both RRMS and PPMS in trials

Some debate over its true effectiveness in progressive

MS

Novel Anti-CD20

Ofatumumab

Ocaratuzumab

Veltuzumab

Obinutuzumab

SMIP-small, modular immuno-pharmaceutical

All are being studied in the treatment of RRMS

Ocrelizumab Opera I, II, phase two clinical trials showed clinically

significant, and showed treatment effect

ORATORIO- phase three clinical trial on primary

progressive MS

Appears to slow disease progression in primary

progressive MS

Chateway et al., 2011

Ocrelizumab Pros

Very Effective

Possibly new avenue for progressive MS

No daily injection or pill

Anti-CD20 Cons

Unknown side effects

Single doses cause long term effects on the immune

system which can not be easily reversed

Cyclophosphamide First drug to show promise in the treatment of MS

Still used off label in MS

Alkylating chemotherapeutic agent binds to DNA and

interferes with mitosis, and cell replication

Decreases pro-inflammatory T helper cell, and

cytokines, causes the secretion of anti-inflammatory

Th2 cytokines IL-4 and IL-10 in both CSF blood

Weiner et al., 1983

Cyclophosphamide Good induction therapy

Very effective

Lots of toxic side effects

Nausea, hair loss

Infertility

Hemorrhagic cystitis, bladder cancer

Increased risk of lymphomas, leukemia, transitional cell carcinoma

Infections

Biotin High dose biotin

Several small phase II studies showing it improves EDSS in progressive MS

Activates Acytel Coenzyme Decarboxolase a rate limiting step in Myelin synthesis

All had EDSS 4.5-7

13 participants improved,

Studies were small

Larger studies are underway Tourbah et al., 2016

More than just inflammation So far all the drugs we use for MS down regulate the

immunes response

There are still a role for neuroprotection inflammation

Although MS was initially thought to be primarily a white matter disease there is growing evidence MS effects grey matter as well and there is non-inflammatory aspects that contribute to disease progression as well as disability

This growing data may provide newer avenues for treatment

Cortical Disease Cortical lesions

Hormonal Therapy PRIMS study followed several women with MS

throughout pregnancy and found significant decrease

in relapse rates in the third trimester. This was thought

to be closely related to estrogen levels

Estrogen treatment has been shown to affect cytokines,

chemokines, matrix metalloproteinase-9 (MMP-9),

antigen presentation and dendritic cell function

One phase I study showed promise, and there are

several phase II/III ongoing studies using estradiol

Vukusic et al., 2004

Vitamin D Multiple studies have shown MS in correlation with low

levels of vitamin D

Vitamin D levels are also inversely linked with disease activity, although these studies are mixed

It’s hard to say which came first the chicken or the egg

Studies with aggressive vitamin D supplementation show a mixed results

Vitamin D is easy to replace and safe, but evidence is mixed on its overall effectiveness

Thouvenot et al., 2014

Vitamin D

Vitamin D Vitamin D may be a downstream consequence of

multiple sclerosis on the genetic level

Ramasamy purposed link between MS and rs2248359-

C increases CYP24A1 which is also linked to Vitamin D

metabolism

Ramasamy et al., 2014

Antivirals There has always been speculation MS is secondary to a

viral cause

Some speculation this may be due to ongoing viral infection and not just the initiating event

Multiple case reports of MS remission following antiviral therapy (most were associated with HIV infection but not all)

human endogenous retroviruses

Two separate studies failed to show statistical significance with raltegravir

Fumaric Acid?

Chalkley et al., 2014

Combination therapy Intriguing concept

One three year study combining interferon and

glatiramer which showed no statistical significance

These studies have been difficult to start after the initial

PML cases with natalizumab

Benefits vs side effect profile

Lublin et al., 2013

Selection of Agents No perfect drug

All come with side effects and benefits

How confident are you of the diagnosis

You have to match the patient to the medication

These have not been studied head to head

There is meta-analysis data supporting Natalizumab, Rituximab, Fingolimod, Alemtuzumab, as superior

Problems when comparing across trials

All are considered first line except (Natalizumab, alemtuzumab, and daclizumab)

Weiner et al., 2009

Berger et al., 2014

My personal approach Take this slide with a grain of salt given it is more

expert opinion vs hard data

I tend to be more aggressive in the beginning given this

is when we can make the biggest impact on disease.

I do not think the step wise approach is as effective

This is being studied and I will let you know in 10 years

Treatment approach Its clear from the data all patient should be on treatment with

relapsing disease

If you have clear progression of disease or relapse need to switch to a strong agent

Silent MRI change is more difficult

I would not switch from similar strength agents

If patient is showing ongoing activity need to be aggressive

I tend to be more aggressive in high risk populations

Pt with brain stem or spinal cord disease, presentation with primary motor symptoms, male sex, minority race, short time between attacks

Case 1 44 year old male comes to clinic with new onset ataxia

and left leg weakness. MRI of the brain shows several

scattered white matter lesions along with C4 enhancing

lesion. 12 OCB were seen in the CSF and he had hx of

optic neuritis in his early thirties with no clinical

relapses. NMO is negative infectious workup is clean

what do you want to do

Case continued He was stared on glatiramer and did well for 7 months

when he had clinical relapse with enhancing lesions in

the spinal cord and brain. JC virus titer was negative at

this time. Switched in inferon and a month later had

another serious relapse with enhancing lesions in the

brain and spinal cord. He is now wheel chair bound and

weak on his right side. Thoughts from the crowd

Case continued Pt was stared on natalizumab and did very well. He

had stabilization of disease clinically and by MR. After

12 months of therapy JC titer was highly positive. What

now?

CASE 2 19 year old female presents to clinic after having three

week hx of painful vision loss in her right eye. Her right

eye visual acuity is 20/200, with right RAPD, and right

upgoing toe with brisk reflexes throughout. MRI of the

brain shows scattered white matter lesions, along with

11 OCB in the CSF. She has a hx of multiple sexual

partners with high risk sexual bhx and was recently

hospitalized for a suicide attempt two months ago,

along with heavy drug and alcohol abuse. Any thoughts

Case three 23 year of female presents to clinic with a PMH of

RRMS on glatiramer for two years. She is doing well in

college with no relapses since starting treatment. She

is tolerating the medication well but states she would

like to try “one of those pills for MS.” Thoughts

THANK YOU Questions