1. Achieving Therapeutic Goals with Current Treatments

2. ARS Polling
Which of the following is not recommended as a first-line treatment for a patient with relapsing-remitting MS?
Interferon beta-1b 250 mcg SC QOD
Natalizumab 300 mg IV monthly infusion
Glatiramer acetate 20 mg SC QD
Interferon beta-1a 44 mcg SC TIW or 30 mcg IM weekly

3. 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

4. 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

5. Therapeutic Targets in MS

6. 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

7. 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

8. 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

9. 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

10. Head-to-Head Study EVIDENCE (IFN beta-1a) Trial, 48 Weeks
Patients Relapse-Free
Difference
P Value
IFN beta-1a 30 mcg IM QW
52%
19% in favor of IFN beta-1a 44 mcg SC TIW
<.009
IFN beta-1a 44 mcg SC TIW
62%
Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week.
Pantich H, et al. Neurology. 2002;59:

11. Head-to-Head Study INCOMIN (IFN beta-1b vs beta-1a) Trial, 104 Weeks
Patients Relapse-Free
Difference
P Value
IFN beta-1b 250 mcg SC EOD
51%
42% in favor of IFN beta-1b
<.036
IFN beta-1a 30 mcg IM QW
36%
Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.
Durelli L, et al. Lancet. 2002;359:

12. Patients Relapse-Free
Head-to-Head Study REGARD (Glatiramer Acetate vs IFN beta-1a), 96 weeks
Patients Relapse-Free
Difference
P Value
Glatiramer acetate 20 mg QD
62%
No difference
<.96
IFN beta-1a 44 mcg SC TIW
Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week.
Mikol DD, et al. Lancet Neurol. 2008;7:

13. Patients Relapse-Free
Head-to-Head Studies BECOME and BEYOND (Glatiramer Acetate vs IFN beta-1b)
Patients Relapse-Free
Difference
P Value
BECOME1
(18 mo)
GA 20 mg QD
70%
8% in favor of GA NS
IFN beta-1b 250 mcg SC QOD
62%
BEYOND2
(2 years)
59%
1% in favor of IFN 500 mcg
58%
IFN beta-1b 500 mcg SC QOD
60%
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: O’Connor P, et al. Lancet Neurol. 2009;8:

14. 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

15. 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; Betaseron [package insert] Montville, NJ: Bayer HealthCare Pharmaceuticals; Extavia [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; Rebif [package insert]. Rockland, MA: EMD Serono; 2009.

16. Neutralizing Antibodies
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
Probability of NAbs (%)
Data from prescribing information.
1. Goodin DS, et al. Neurology. 2007;68:

17. 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.

18. Side Effect Management Tips
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 self-injecting
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

19. Timing of Therapy May Be Key to Preventing Disability
First Demyelinating Event
Secondary
Progressive
Pre- clinical
Relapsing-Remitting
Transitional
Time window for early treatment
First Clinical Attack
Axonal loss
Clinical threshold
1841 CMSC Slide
Demyelination
Inflammation
Time (years)

20. Rationale for Early Treatment
Time is ticking…
What is lost by delaying early therapy is not regained by starting later
1841 CMSC Slide

21. 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 21

22. Placebo-Controlled Trials of Disease-Modifying Therapy in CIS
Study
Treatment N
Conversion to CDMS
Follow- up
On Tx
Placebo P
CHAMPS1
Interferon beta-1a 30 μg IM qwk
383
3 y
35%
50%
.002
ETOMS2
Interferon beta-1a 22 μg SC once weekly
309
2 y
34%
45%
.047
BENEFIT3
Interferon beta-1b 250 μg SC q48h
468
28%
<.0001
PreCISe4
Glatiramer acetate 20 mg/d
481
61%
77%
.0005
1. Jacobs LD, et al. N Engl J Med. 2000;343: Comi G, et al. Lancet. 2001;357: Kappos L, et al. Neurology. 2006;67: Comi G, et al. Lancet. 2009;374:

23. 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

24. 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:

25. 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.

26. 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 disease-modifying 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.

27. 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

28. 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

29. Assess Adherence! Most Patients Who Discontinue Do So in First 2 Years
Cohort of patients who stopped therapy
Rio J, et al. Mult Scler. 2005;11:

30. 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)

31. 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

32. 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)

33. 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:

34. 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

35. Resources MS Centers in Oregon
OHSU Multiple Sclerosis Center
3181 SW Sam Jackson Park Rd, Portland, OR 97239
Providence Multiple Sclerosis Center
9427 SW Barnes Rd, Suite 595, Portland, OR 97225
VA Medical Center–Portland
3710 SW US Veterans Hospital Rd (153), Portland, OR 97239
x 57260

36. Resources MS Centers in Washington State
Cascadia Multiple Sclerosis Center
11 Bellwether Way, Suite 210, Bellingham, WA 98225
Evergreen Neuroscience Institute MS Center
12040 NE 128th St, MS #118, Kirkland, WA 98034
Rockwood Multiple Sclerosis Center
400 East Fifth Ave, Spokane, WA 99202
Swedish Neuroscience Institute
550 17th Ave, Suite 540, Seattle, WA

37. Resources MS Centers in Washington State
VA MS Center of Excellence–West (VAMC Seattle)
1660 S Columbian Way, Seattle, WA 98108
Virginia Mason Multiple Sclerosis Center
1100 9th Ave, Seattle, WA 98101
Western MS Center at University of Washington Medical Center/MSRRTC
1959 NE Pacific St, Seattle, WA 98195

38. Resources MS Center in Idaho
Idaho Falls Multiple Sclerosis Center
2353 Coronado, Idaho Falls, ID 83404
Stephen G. Vincent, MD, and Bradford L. Talcott, MD, PhD

39. ARS Polling
Which of the following is not recommended as a first-line treatment for a patient with relapsing-remitting MS?
Interferon beta-1b 250 mcg SC QOD
Natalizumab 300 mg IV monthly infusion
Glatiramer acetate 20 mg SC QD
Interferon beta-1a 44 mcg SC TIW or 30 mcg IM weekly

40. 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