Achieving Therapeutic Goals with
Current Treatments
ARS Polling
Which of the following is not recommended as a first-line
treatment for a patient with relapsing-remitting MS?
a) Interferon beta-1b 250 mcg SC QOD
b) Natalizumab 300 mg IV monthly infusion
c) Glatiramer acetate 20 mg SC QD
d) Interferon beta-1a 44 mcg SC TIW or 30 mcg IM
weekly
Therapeutic Goals in MS
• In the absence of a cure for MS, current goals of
disease modifying therapy are to
– Prevent disability
– Prevent relapses
– Prevent development of new or enhancing lesions on MRI
• Additional goals in the management of MS are to
– Relieve symptoms
– Maintain well-being
– Optimize quality of life
Treating Acute Relapse
• IV corticosteroids = standard of care
– Methylprednisolone 500 to 1000 mg/d IV for 3 to
5 days
• May be followed by oral steroid taper
• High-dose oral steroids may be acceptable
alternative
– Phase III randomized OMEGA trial currently
comparing oral and IV steroids
• Plasmapheresis and IVIG for refractory
relapse
Therapeutic Targets in MS
FDA-Approved
Disease-Modifying Agents
First line:
• Interferon beta
– Interferon beta-1b 250 mcg SC QOD (two brands)
– Interferon beta-1a 44 mcg SC TIW
– Interferon beta-1a 30 mcg IM weekly
• Glatiramer acetate
– 20 mg SC QD
Second line:
• Mitoxantrone
– 12 mg/m2 over 5 to 15 min q3mo; lifetime max, 144 mg/m2
• Natalizumab
– 300 mg IV monthly infusion
Current First-Line MS Therapies
• Interferon beta-1a, interferon beta-1b,
glatiramer acetate
– Interferons are FDA approved for relapsing forms
of MS
– Glatiramer acetate is FDA approved for RRMS
• Similar efficacy for relapse rate reduction ~
30%
• Generally very safe and well tolerated
• All require self-injection
Mechanisms of Action for
Interferons
• Reduction of proinflammatory cytokine
secretion
• Promotion of anti-inflammatory cytokine
secretion
• Stabilization of blood-brain barrier
• Enhancement of regulatory T cell activity
• Downregulation of antigen presentation to
T cells
Mechanisms of Action for
Glatiramer Acetate
• Competitive inhibition of antigen presentation
(myelin basic protein) to autoreactive T cells
• Activates regulatory T cells
• Promotes Th1 to Th2 cytokine shift
Head-to-Head Study
EVIDENCE (IFN beta-1a) Trial,
48 Weeks
Patients
Relapse-Free
IFN beta-1a 30
mcg IM QW
IFN beta-1a 44
mcg SC TIW
Difference
P Value
19% in favor of
IFN beta-1a 44
mcg SC TIW
<.009
52%
62%
Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times
per week.
Pantich H, et al. Neurology. 2002;59:1496-1506.
Head-to-Head Study
INCOMIN (IFN beta-1b vs beta-1a)
Trial, 104 Weeks
Patients
Relapse-Free
IFN beta-1b 250
mcg SC EOD
IFN beta-1a 30
mcg IM QW
Difference
P Value
42% in favor of
IFN beta-1b
<.036
51%
36%
Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.
Durelli L, et al. Lancet. 2002;359:1453-1460.
Head-to-Head Study
REGARD (Glatiramer Acetate vs
IFN beta-1a), 96 weeks
Patients
Relapse-Free
Glatiramer
acetate 20 mg
QD
62%
IFN beta-1a 44
mcg SC TIW
62%
Difference
P Value
No difference
<.96
Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week.
Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
Head-to-Head Studies
BECOME and BEYOND
(Glatiramer Acetate
vs IFNDifference
beta-1b)P Value
Patients
RelapseFree
BECOME1
(18 mo)
GA 20 mg QD
70%
IFN beta-1b 250
mcg SC QOD
62%
BEYOND2
(2 years)
GA 20 mg QD
59%
IFN beta-1b 250
mcg SC QOD
58%
IFN beta-1b 500
mcg SC QOD
60%
8% in favor
of GA
NS
1% in favor
of IFN 500
mcg
NS
Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other
day; NS, not significant.
1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897.
Head-to-Head Studies
Bottom Line
• Higher-dose subcutaneous interferons are
more effective than lower-dose intramuscular
interferon
• High-dose subcutaneous interferon
formulations and glatiramer acetate probably
all offer comparable efficacy
Side Effects of Interferons
• Side effects include flu-like symptoms, injection site
reactions/necrosis (SC), liver enzyme elevations,
lymphopenia, depression
• Pregnancy category C
• Warnings: depression/suicide, decreased peripheral
blood counts, hepatic injury, seizures,
cardiomyopathy/CHF, autoimmune disease
• Laboratory tests: periodic CBC with differential, liver
function profile, thyroid function
Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006. Betaseron [package insert] Montville, NJ:
Bayer HealthCare Pharmaceuticals; 2009. Extavia [package insert]. Montville, NJ: Bayer HealthCare
Pharmaceuticals; 2009. Rebif [package insert]. Rockland, MA: EMD Serono; 2009.
•
Interferon therapies are
associated with production of
neutralizing antibodies (NAbs)
to the interferon beta molecule1
– NAbs may reduce radiographic
and clinical effectiveness of
interferon treatment
•
NAb testing
– Sometimes used when deciding
whether to switch from one
interferon to another (usually IM
to SC) in a patient with
suboptimal response
– There are no guidelines on
when to test, which test to use,
how many tests are needed, or
which cutoff titer to apply1
1. Goodin DS, et al. Neurology. 2007;68:977-984.
Probability of NAbs (%)
Neutralizing Antibodies
100
80
60
40
20
0
45
31
24
5
IFN beta-1b 250 mcg SC QOD
IFN beta-1a 22 mcg SC TIW
IFN beta-1a 44 mcg SC TIW
IFN beta-1a 30 mcg IM QW
Data from prescribing information.
Side Effects of Glatiramer Acetate
• Injection-site reactions, vasodilation, rash,
dyspnea, chest pain
• Pregnancy category B
• Warnings: Immediate postinjection reaction,
chest pain, lipoatrophy, skin necrosis
– Postinjection reaction (flushing, chest pain,
palpitations, anxiety, dyspnea, constriction of
throat, urticaria) is self-limited; no treatment
required
• No lab testing required
Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009.
Side Effect Management Tips
Side Effect
Management
Flu-like symptoms
NSAIDs (eg, naproxen 500 mg 1 h before injection + 12 h
later); IFN administration before bedtime; for patients on
IFN beta-1a IM, prednisone 10 mg on day of injection;
switch to glatiramer acetate
Injection-site
reactions and
injection-site pain
Rotate injection sites; administer injection without the
autoinjector; topical anesthetics; application of ice before
injecting; ensure proper product preparation including
warming to room temperature
Difficulty selfinjecting
Have partner administer injection; if “click” of autoinjector
induces anxiety, administer without the autoinjector; call
company nurse for retraining; home health agency might
administer IFN beta-1a IM; switch to a therapy with less
frequent injections
Timing of Therapy May Be Key to
Preventing Disability
First
Pre- Demyelinating
Relapsing-Remitting
Event
clinical
Transitional
Secondary
Progressive
First Clinical Attack
Time
window for
early
treatment
Axonal loss
Clinical threshold
Demyelination
Inflammation
Time (years)
Rationale for Early Treatment
• Time is ticking…
• What is lost by delaying early therapy is not regained
by starting later
Treating CIS
• Treating CIS vs waiting until patient has
clinically definite MS (CDMS)
–
–
–
–
–
Decrease progression to CDMS
Decrease rate of disability progression
Reduced lesion load on MRI
Fewer and less severe relapses
Most clinicians advocate early treatment BUT not
all CIS will develop MS
Placebo-Controlled Trials of
Disease-Modifying Therapy in CIS
Study
Treatment
N
Conversion to CDMS
Followup
On
Tx
Placebo
P
CHAMPS1
Interferon beta-1a
30 μg IM qwk
383
3y
35%
50%
.002
ETOMS2
Interferon beta-1a
22 μg SC once
weekly
309
2y
34%
45%
.047
BENEFIT3
Interferon beta-1b
250 μg SC q48h
468
2y
28%
45%
<.0001
PreCISe4
Glatiramer acetate
20 mg/d
481
3y
61%
77%
.0005
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001;357:1576-1582. 3.
Kappos L, et al. Neurology. 2006;67:1242-1249. 4. Comi G, et al. Lancet. 2009;374:1503-1511.
FDA Approved for CIS
•
•
•
•
Interferon beta-1a 30 mcg IM QW
Interferon beta-1b 250 mcg SC QOD
Glatiramer acetate 20 mg SC daily
Interferon beta-1a 44 mcg SC TIW is
sometimes used off-label
Second-Line MS Therapies
Natalizumab
• Inhibits cell adhesion and leukocyte migration across
BBB
• AFFIRM trial1 of natalizumab vs placebo in RRMS
– 42% reduction in risk of sustained progression of disability in
2 years (P <.001)
– 68% reduction in clinical relapse at 1 year (P <.001)
– 83% reduction in new or enlarging T2 lesions over 2 years
(P <.001)
– 92% reduction in Gd-enhancing lesions at 1 and 2 years
(P <.001)
1. Polman CH, et al. N Engl J Med. 2006;354:899-910.
Second-Line Therapies
Natalizumab
• FDA approved for relapsing MS
• Due to risk of PML, natalizumab is generally reserved
for patients who have not responded to or tolerated
alternate therapies
– PML (JC virus of brain) leads to severe disability or death;
no known treatment
– Available only through very restricted distribution program
(TOUCH Prescribing Program)
• Other warnings: hepatotoxicity, hypersensitivity
reactions, immunosuppression
Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2009.
Mitoxantrone
• Antineoplastic in anthracenedione class
• FDA approved for SPMS, PRMS, worsening RRMS
• Causes cross-links and strand breaks in DNA;
inhibits B cell,
T cell, and macrophage proliferation
• Due to serious side effects, reserve for patients with
rapidly advancing MS despite other diseasemodifying therapies
–
–
–
–
Cardiomyopathy (LVEF elevations in up to 18%; CHF)
Secondary acute myelogenous leukemia (0.25%)
Elevated liver enzyme and glucose levels
Requires frequent monitoring (CBC, liver function tests,
LVEF, ECG)
• Administration should be performed by an oncologist
Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 2009.
Starting an MS Patient on a
Disease-Modifying Agent
• Obtain starter kit from local representative
– If you do not know your local representative, phone the company’s
800 number
• Complete physician portion of Enrollment Form and have patient
complete the patient portion
– Fax form back to manufacturer
• Starter kit will contain educational materials and tools for patient
• Company will verify patient’s insurance benefits
• Company will supply medication and send nurse to the patient’s
home for training on self-injection and proper needle disposal
– The nurse may be an added resource for patients to call with
questions about the product or self-injection
• Titrate interferon dose as indicated on the Enrollment Form
Monitoring
• Follow up 4−6 weeks after initiating therapy
– Assess injection technique and tolerability
• If stable on therapy, re-evaluate every 3−6 months
• Laboratory testing for interferon
– CBC and liver enzyme levels 4–6 weeks after starting
treatment,
3 months later, then every 6 months
• No laboratory testing needed for glatiramer acetate
• Continue on therapy indefinitely unless clear lack of
benefit, intolerable side effects, or better treatment
becomes available
Assess Adherence!
Most Patients Who Discontinue
Do So in First 2 Years
Cohort of patients who stopped therapy
Ye ar 7 Ye ar 8
3%
Ye ar 6 3%
5%
Ye ar 1
22%
Ye ar 5
8%
Ye ar 4
13%
Ye ar 2
27%
Ye ar 3
20%
Rio J, et al. Mult Scler. 2005;11:306-309.
Assess Adherence by Asking
• Patients typically will not tell you they have been
nonadherent if you do not ask
• Ask in nonjudgmental manner that assumes they
have missed some doses
– For example: How many injections do you think you have
missed in the past 2 months?
• Being asked helps motivate patients to adhere
• Assess barriers by asking: What prevents you from
taking your medication?
– NOT: Why aren’t you taking it? (Avoid casting blame)
Address Barriers to Adherence
•
•
•
•
•
•
•
•
•
•
Difficulty self injecting
Adverse events
Unrealistic expectations of therapy (symptom relief)
Lack of acceptance of MS diagnosis and need for
treatment
Financial considerations
“Treatment fatigue”
Depression
Cognitive deficits
Impairment in fine motor skills
Changes to family and support circumstances
Suboptimal Treatment Response
• Worsening clinical status
• Radiologic changes (MRI)
– New Gd enhancement and/or new or enlarging T2 lesions
are signs of disease activity
• No consensus as to when such findings warrant change in
treatment
• Interpret in context of whole clinical picture
• If found on repeat scans, even if patient is clinically stable,
probably warrants change in therapy
– Remember: comparison of serial MRI scans requires
consistent use of standardized MRI protocol (CMSC
protocol)
Suboptimal Response
Potential Causes
• Nonadherence
• Pharmacogenomics: responsiveness to IFN β
related to genetics1
• Variable pathologies with differing responses to
immune therapies
• NAbs
• MS subtype (disease modifying agents do not
work in PPMS)
1. Byun E, et al. Arch Neurol. 2008;65:337-344.
Refer or Consult a Neurologist
• When diagnosis is in doubt
• If a consult is desired regarding selection of
initial therapy
• For patients with poor response or toleration
of first-line therapies
• When considering use of natalizumab or
mitoxantrone
Resources
MS Centers in Oregon
OHSU Multiple Sclerosis Center
3181 SW Sam Jackson Park Rd, Portland, OR 97239
503-494-7321
Providence Multiple Sclerosis Center
9427 SW Barnes Rd, Suite 595, Portland, OR 97225
503-216-1060
VA Medical Center–Portland
3710 SW US Veterans Hospital Rd (153), Portland, OR 97239
503-220-8262 x 57260
Resources
MS Centers in Washington State
Cascadia Multiple Sclerosis Center
11 Bellwether Way, Suite 210, Bellingham, WA 98225
360-752-9919
Evergreen Neuroscience Institute MS Center
12040 NE 128th St, MS #118, Kirkland, WA 98034
425-899-5350
Rockwood Multiple Sclerosis Center
400 East Fifth Ave, Spokane, WA 99202
509-838-2531
Swedish Neuroscience Institute
550 17th Ave, Suite 540, Seattle, WA 98122
206-386-3880
Resources
MS Centers in Washington State
VA MS Center of Excellence–West (VAMC Seattle)
1660 S Columbian Way, Seattle, WA 98108
206-277-4688
Virginia Mason Multiple Sclerosis Center
1100 9th Ave, Seattle, WA 98101
206-223-6600
Western MS Center at University of Washington Medical
Center/MSRRTC
1959 NE Pacific St, Seattle, WA 98195
206-598-3344
Resources
MS Center in Idaho
Idaho Falls Multiple Sclerosis Center
2353 Coronado, Idaho Falls, ID 83404
208-552-4823
Stephen G. Vincent, MD, and Bradford L. Talcott, MD, PhD
ARS Polling
Which of the following is not recommended as a
first-line treatment for a patient with relapsingremitting MS?
a) Interferon beta-1b 250 mcg SC QOD
b) Natalizumab 300 mg IV monthly infusion
c) Glatiramer acetate 20 mg SC QD
d) Interferon beta-1a 44 mcg SC TIW or 30 mcg
IM weekly
Conclusions
• Current MS therapies can reduce relapse rates and
disability progression
– Interferon beta or glatiramer acetate is first line
• It is best to start treatment as early as possible
• Patient education is essential when starting treatment
– Rationale for treatment, injection technique, side effect
management, importance of adherence
• After starting treatment, monitor for response,
tolerability, and adherence