Transcript MS Overview Nurses_SDTP

Disease Modifying
Treatments
Joseph R. Berger, M.D.
Professor of Neurology
Chief of the MS Division
Perelman School of Medicine
University of Pennsylvania
What is MS?
• A chronic disease that affects the central nervous system
(CNS-brain and spinal cord)
• MS is thought to be immune mediated
– The Immune system becomes activated and incorrectly targets
the CNS
• Associated with relapses and remissions
– Relapses: new or returning neurological symptoms that last at
least 24 hours and are not associated with another cause such
as a fever.
• Worsening or progression of disability is possible over time
• The cause is unknown but research strongly suggests that
certain factors increase the risk of developing MS
Model of MS Immunopathogenesis:
Targets for Therapy of CNS Autoimmune Disease
4. Invasion
1. Activation
3. Attraction
Th
2. Adhesion
5. Reactivation
BBB
Periphery
CNS
Bar-Or 2008
CIS
RRMS
SPMS
Clinical Threshold
T2 Burden
Axonal
loss
D MTR
Brain
Volume
MRI
Relapses and Disability
Clinical and MRI Course in MS
Gado +
Time
Bar-Or A, 2002
Evolution of MS lesions over time
Brain Atrophy (Shrinkage) in Untreated MS
Black Holes and Their Contribution to
Brain Atrophy
Possible MS Risk factors
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Genetic susceptibility
Smoking
Childhood and adolescent obesity
Low Vitamin D
History of Epstein Barr infection
Other close family members with MS
Living in a temperate climate
However, having these risk factors does not guarantee
that a person will develop MS
MS Epidemiology - Genetics
• Family history as a risk factor
• Higher rates if index case is female
• Relationship
– General population
0.1%
– Sibling
2.0% (20 X)
– Fraternal twin
2-12%
– Identical twin
21-70%
– Child of MS patient
1.0%
– Aunt/Uncle
2.0%
– Niece/Nephew
0.4%
– Conjugal
rare
What happens to the Myelin and nerve fibers
in MS?
What Causes MS?
Exact cause is not known, but is thought to be a complex
interplay of genetic predisposition and environmental factors
Genetic
Predisposition
Environmental
Trigger
Immune mediated
response
Inflammation/Damage/destruction
of myelin and axons
Who gets MS?
• Usually diagnosed between 20 and 50
– Less frequently diagnosed in young children and older
adults
• More common in women than men (3:1)
• More common in temperate areas (further from the
equator) although in some recent studies the geographic
gradient is becoming less apparent.
MS Symptoms vary between individuals and are
unpredictable
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Other symptoms:
Sexual dysfunction
Spasticity
Gait, balance, and
coordination problems
• Tremor
How is MS diagnosed?
• MS is a clinical diagnosis:
– Medical history of symptoms referable to the CNS
– Neurological findings on examination
– Laboratory tests: MRI, lumbar puncture, serum analysis,
evoked potentials
• Requires dissemination in time and space
– Space: Objective evidence of lesions, typical of MS, in two or
more distinct areas of the CNS
– Time: Two clinical events that occurred at different points in
time
– No better explanation for the symptoms and findings
MRI Findings in MS
T2
Spinal
Cord
T2FLAIR
T1/Gd
postcontrast
Active inflammation
Goals of MS Management
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Optimal treatment of relapses
Effective symptom management
Disease modification
Ability to live well with MS
Who is on the MS “Management
Team”?
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Neurologist
Urologist
Nurse
Advanced Practice Nurse
Physician Assistant
Physical therapist
Occupational therapist
Speech/language
pathologist
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Physiatrist
Psychiatrist
Psychotherapist
Neuropsychologist
Social worker/Care
manager
• Primary care physician
• Pharmacist
Optimal MS Management
Wellness
strategies:
Rehabilitation
Team approach
Exercise, smoking
cessation, diet, weight
management,
preventive health
Optimal
management
Medications
for symptoms
and relapses
Knowledge
Disease
Modifying
Therapies
How are relapses treated?
• Not all relapses require treatment
– Symptoms that interfere with function (e.g., visual or
motor) are usually treated
• High dose IV glucocorticoids are treatment of choice for
acute relapses
– Length of treatment varies
– High-dose oral steroids are used by some neurologists
• When needed, rehabilitation to help restore/maintain
function
Association for Research in
Nervous and Mental Disease
December 10th-11th, 1948
Robert Foster Kennedy
One should no more tell our patients they
have multiple sclerosis than we should
tell them they have inoperable
cancer…When I have to make the
diagnosis of multiple sclerosis, I make it
to the relations, not to the patient; and I
try to defend the patient from hearing the
name because once the name is heard, it
is vested with lamentable result.
Robert Foster Kennedy, M.D.
Association for Research in
Nervous and Mental Disease
December 10th-11th, 1948
And I certainly agree with him that
the diagnosis should never be told
to the patient unless it is absolutely
essential to that patient for the
arrangement of his life, and that the
facts should be explained to the
family.
H. Houston Merritt, M.D.
Changing MS Treatment Landscape
Laquinimod
IFNβ-1b
(Betaseron®)
Natalizumab
(Tysabri®)
IFNβ-1a
(Avonex®)
ONO-4641
IFNβ-1b
(Extavia®)
Alemtuzumab
BG-12
(Tecfidera™)
Glatiramer acetate injection
(Copaxone®)
Mitoxantrone
(Novantrone®)
Teriflunomide
(Aubagio™)
Fingolimod
(Gilenya™)
Ofatumumab
IFNβ-1a
(Rebif®)
1995
2000
Daclizumab
Ocrelizumab
2005
2009
2010
2011
2012
2013
Rituximab
Approval date
FDA-approved therapies
Currently not
approved
Clinical Trial Landscape in MS
S1P-R
Modulators
mAbs
Ph 2
Ponesimod
MT-1303
Ceralifimod/
ONO-4641
Rituximab*
Ofatumumab*
Atacicept
Secukinumab
Vatelizumab
VAY736
MOR103
GNbAC1
Ph 3
Fingolimod*
Siponimod
RPC-1063
Daclizumab*
Ocrelizumab
Natalizumab*
Neuroprotective
Anti-LINGO
Amiloride*
Ibudilast
Idebenone
Erythropoietin*
Statins*
Antiepileptics*
Riluzole*
Biotin*
Others
Vitamin D
Mesenchymal
stem cells
Masitinib
Trichuris Suis
Ova (TSO)
Laquinimod
DMF*
* Extension trials
Each Efficacy Measure Is Important in Evaluating
Treatment Outcome in Clinical Trials
MRI* - Pathology
• T2 lesion area
• MRI activity
Relapses
Disability
• EDSS/IDSS
• No. progressions
Progression
of disease
Prognostic value
O’Riordan, Brain 1998
Relapse rate
% relapse-free
Time to 1st/2nd
Severity
Prognostic value
Weinshenker 1989
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The ultimate goal:
Delay progression
*The exact relationship between MRI findings and the clinical status of patients is unknown.
How important is early treatment?
• The MS Coalition recommends that treatment with a
disease modifying agent initiated as early as CIS
confirmed.
– Irreversible axonal damage occurs even in the earliest stages of
the illness.
– Tx is most effective when started early when inflammation is most
likely to occur
• No treatment has been approved for primary-progressive
MS.
Approximately 60% of people with MS are on a DMT
BENEFIT TRIAL: Immediate v Delayed Betaseron
Delay in Conversion From CIS to CDMS
Patients Without CDMS (%)
100
90
25th
percentile
80
255
618
70
60
363 days
Delayed
Betaseron
50
0
0.5
1.0
Time (years)
*At
25th
Immediate
Betaseron
percentile
Kappos L, et al. Neurology. 2006;67:1242-1249.
1.5
2.0
Current Opinion of the
Hypothetical Effect of Treatment
Natural course of disease
Disability
Later intervention
Later
treatment

Intervention at diagnosis
Treatment
at diagnosis

Disease onset
Time
Disease Modifying Treatments (DMT’s)
• Modify the inflammatory immune activity
– Reduce the number of new relapses
– Delay worsening (progression)
– Limit new areas of damage in the CNS
• 12 FDA approved DMT’s
– 6 injectable treatments
– 3 oral treatments
– 3 infusion treatments
• 11 are approved for relapsing forms of MS;
• Novantrone is approved for secondary progressive MS and
worsening relapsing MS
• Lemtrada is recommended for those who have had insufficient
benefit from at least two other medications.
• Certain interferons and Copaxone are approved for people who
have had one neurological event suggestive of MS
Injectable DMT’s
• Interferon beta’s
– Betaseron
– Extavia
Interferon beta -1b
– Rebif
– Avonex
Interferon beta -1a
– Plegridy
Pegylated Interferon beta -1a
Interferon beta-1a and 1b
• Reduce the ability of certain immune system cells from
becoming activated
• Reduce the ability of certain immune system cells from
entering the CNS
• Reduces relapse rate
• Reduce new CNS inflammation
• Delay progression
Interferon Administration
• Betaseron and Extavia
– Subcutaneous injection (under the skin) every other day
• Rebif
– Subcutaneous injection given three times/week
• Avonex
– Intramuscularly (into a large muscle) once weekly
• Plegridty
– Subcutaneous injection once every 2 weeks
• Auto – injector devices are available for each of the
interferon DMT’s
Interferon Side Effects
Side effects are similar among the interferons
– Flu-like symptoms following injection, which lessen over time
for many.
– Injection site reactions.(subcutaneous injections)
– Less common:
• Allergic reactions
• Depression
• Liver abnormalities
• Low white blood cell counts.
• Seizure
• Heart problems
Interferon beta Warnings/Precautions
• Individuals with a history of depression or a seizure
disorder should be closely monitored while on this
medication
• This medication should be used with caution in people with
depression
• Rare but significant allergic reactions have been reported
with this medications
• Skin infections or areas of severe skin damage can occur
with subcutaneous injections; injection sites should be
rotated on a regular basis
• People with cardiac problems should be monitored closely
• Blood counts and liver function should be monitored
Copaxone – glatiramer acetates
• A mixture of 4 protein building blocks (amino acids)
• Copaxone shifts the immune system response to one
that is less inflammatory
• Reduces relapse rate
• Reduces new CNS inflammation
• 2 formulations
– 20 mg given daily by subcutaneous injection
– 40 mg given three times per week by subcutaneous injection
Copaxone Side Effects
• Injection site reactions
• Less common:
– Immediate post injection reaction that can occur immediately
following the injection ands lasts 15-30 minutes. This may
consist of:
• Vasodilation (dilation of blood vessels
• Chest pain
• Heart palpitations
• Shortness of breath,
• Flushing
Copaxone Warnings/Precautions
• Immediate post-injection reaction
– Generally occurs after the first few months of treatment and may
occur more than once in a given individual.
• vasodilation (dilation of blood vessels), chest pain, heart palpitations,
shortness of breath, flushing
• Transient chest pain — without any long-term effects —
may also occur one or more times, either as part of the
post-injection reaction or separately.
• Permanent depressions under the skin at injection sites can
occur because of destruction of the fatty tissue.
– In addition, areas of severe skin damage can occur.
– Careful rotation of injection sites is recommended so that no
single area is injected more than one time per week.
Oral DMT’s
• Gilenya (fingolimod)
– 0.5 mg capsule taken once daily
• Aubagio (teriflunomide)
– 7 mg or 14 mg tablets taken once daily
• Tecfidera (dimethyl fumarate)
– 240 mg capsule taken twice daily
Gilenya
• Restricts certain immune system cells called
lymphocytes from exiting the lymph nodes and thus
keeps them out of the bloodstream.
• Reduces relapse rate
• Delays worsening
• Limits new inflammation in the CNS
Gilenya Side Effects
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Headache
Flu
Diarrhea
Back pain
Liver enzyme elevations
Cough
Less common
– Slowed heart rate following first dose (requires monitoring for
6 or more hours after the first dose
– Infections
– Macular edema
Gilenya Warnings
• Slowed heart rate for several hours after the first dose:
– All patients should have an electrocardiogram (ECG) prior to the
first dose,
– Monitoring required for six hours after the first dose with hourly
pulse and blood pressure measurement, and then given a repeat
ECG.
• Reduction in the number of white blood cell
• Possible respiratory difficulties
• A vision test is recommended prior to starting treatment
and about 3 months later
• Possible liver enzyme abnormalities
• Potential for reactivation of herpes viruses including VZV
• One case of PML
Aubagio
• Reduces the number of white blood cells – some
which are considered to cause MS inflammation
• Reduces relapse rate
• Delays worsening
• Reduces new CNS inflammation
Aubagio Side Effects
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Hair thinning (tends to be temporary)
Diarrhea
Flu
Nausea
Abnormal liver tests (must be monitored closely)
Unusual numbness or tingling in the hands or feet
(paresthesias).
• Less common: lowered levels of white blood cells,
which can increase the risk of infections; increase in
blood pressure; severe liver damage
Aubagio Warnings
• Aubagio can cause liver damage.
– Blood tests are needed on a regular basis including
before and monthly after starting treatment .
• Aubagio can cause major birth defects for up to two years
after the medication is discontinued.
– Pregnancy test before starting the medication
– Use of effective birth control while taking Aubagio
– If pregnancy occurs while on Aubagio, stop taking
Aubagio immediately and undergo treatment to remove
the medication rapidly from the body.
– Men who plan to father a child should stop taking the
medication and undergo treatment to remove the
medication rapidly from the body before they and their
partners try to conceive.
Aubagio Warnings/Precautions
• Aubagio can increase a person’s risk of infections.
– Complete blood count prior to starting treatment
– Monitor for infection while on treatment.
– TB test before starting treatment.
– If positive TB test, TB treatment before taking Aubagio
– Aubagio can cause damage to peripheral
– Aubagio can cause acute kidney failure and elevated
potassium in the blood.
• Kidney function should be monitored in anyone who
experiences symptoms of renal failure or elevated
potassium levels.
• Aubagio can cause elevations in blood pressure; blood
pressure should monitored and managed during treatment.
Tecfidera
• Shifts the immune system to a less inflammatory
response
• May reduce oxidative stress, which is known to cause
damage in MS
• Reduces relapse rate
• Delays worsening
• Reduces new CNS inflammation
Tecfidera Side Effects
• Flushing (sensation of heat or itching and a blush on
the skin)
• Gastrointestinal issues (nausea, diarrhea, abdominal
pain)
• Rash
• Protein in the urine
• Elevated liver enzymes
• Reduction in blood lymphocyte (white blood cell)
counts.
Tecfidera Warnings/Precautions
• Tecfidera® (dimethyl fumarate) can cause a reduction
in blood lymphocyte (white blood cell) counts.
– Check blood cell count before starting Tecfidera
– A CBC including lymphocyte count should also be obtained
after 6 months of treatment, every 6 to 12 months thereafter,
and as clinically indicated.
• PML (progressive multifocal leukoencephalopathy
– Occurred in one person who had been on Tecfidera for 4
years and a very low white blood cell count
• Severe allergic reactions
– Difficulty breathing, hives and itching, swelling of the throat
and tongue.
Infused DMT’s
• Tysabri (natalizumab)
– 300 mg intravenously (IV) every 4 weeks
• Novantrone (mitoxantrone)
– 12 mg/m2 IV every 3 months (with a lifetime maximum dose
of 140 mg/m2
• Lemtrada (alemtuzumab)
– 12 mg IV daily on 5 consecutive days and then 12 mg IV on
three consecutive days one year later.
Tysabri
• Blocks lymphocytes (a type of white blood cell) from
entering the CNS
• Reduces relapse rate
• Delays disability
• Reduces new CNS inflammation
Tysabri Warnings
• Tysabri must be infused in an approved infusion
center.
• PML (progressive multifocal leukoencephalopathy),
which is caused by the common JC virus. PML is a
serious CNS infection that can cause significant
disability and may cause death
• Liver damage
• Herpes infections
Novantrone
• An immunosuppressant medication that suppresses
the production of white blood cells
• Delays worsening
• Reduces relapse rate
• Reduces new CNS inflammation
Novantrone Warnings/Precautions
• The total lifetime dose is limited in order to avoid
possible heart damage.
• People taking Novantrone should have tests of their
heart function before each dose and periodically after
treatment has ended.
• It cannot be used in people with pre-existing heart
problems, liver disease, and certain blood disorders.
• Acute myelogenous leukemia (AML), a type of cancer
Lemtrada
• Depletes the numbers of certain immune system cells
that a molecule on their cell surface known as CD 52
• Reduces relapses rate
• Delays worsening
• Reduces new CNS inflammation
Lemtrada Warnings/Precautions
• ~25% develop autoimmune conditions, e.g, immune
thrombocytopenia (ITP, a rare bleeding condition) and antiglomerular basement membrane disease (which impacts the
kidneys)
• Possible serious and life-threatening infusion reactions (while the
medication is being given and for 24 hours after each infusion)
• Increased risk of malignancies (thyroid cancer, melanoma, and
blood cancers).
• A person with an active infection should not start treatment until
the infection is controlled.
Because of the risks associated with Lemtrada, this treatment is only
available from certified prescribers and pharmacies, and people
taking the medication, as well as the healthcare facility administering
the medication, must be enrolled
Annualized Relapse Rates:
Annualized Relapse Rate
Proportional Treatment Effects
1992–2001
43.3% ▼
2002–2008
57% ▼
Summary
• The FDA has approved 12 medications for the
treatment of relapsing MS
• All treatments have been found to be effective
• Starting treatment early in the disease process has
been found to be most effective
• DMT’s should be continued unless there is continued
MS activity or intolerable side effects
• Stopping and/or switching a DMT should occur only for
medical reasons and after consultation with your
neurology provider
More Research Needed