Achieving Therapeutic Goals with Current Treatments

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

ARS Polling

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-ApprovedDisease-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

Pantich H, et al. Neurology. 2002;59:1496-1506.

Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week.per week.

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%

Head-to-Head StudyEVIDENCE (IFN beta-1a) Trial,

48 Weeks

Durelli L, et al. Lancet. 2002;359:1453-1460.

Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.

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%

Head-to-Head StudyINCOMIN (IFN beta-1b vs beta-1a)

Trial, 104 Weeks

Mikol DD, et al. Lancet Neurol. 2008;7:903-914.

Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per weekAbbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week ..

Patients Relapse-Free

Difference P Value

Glatiramer acetate 20 mg QD

62%

No difference <.96

IFN beta-1a 44 mcg SC TIW

62%

Head-to-Head StudyREGARD (Glatiramer Acetate vs

IFN beta-1a), 96 weeks

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)

GA 20 mg QD 59% 1% in favor of IFN 500

mcg

NS

IFN beta-1b 250 mcg SC QOD

58%

IFN beta-1b 500 mcg SC QOD

60%

1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897.

Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other day; NS, not significant.other day; NS, not significant.

Head-to-Head StudiesBECOME and BEYOND

(Glatiramer Acetate vs IFN beta-1b)

Head-to-Head StudiesBottom 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

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.

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

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

1. Goodin DS, et al. Neurology. 2007;68:977-984.

45

3124

50

20

40

60

80

100

IFN beta-1b 250 mcg SC QODIFN beta-1a 22 mcg SC TIWIFN beta-1a 44 mcg SC TIWIFN beta-1a 30 mcg IM QW

Pro

babi

lity

of N

Abs

(%

)

Data from prescribing information.

Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009.

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

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 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

Side Effect Management Tips

Timing of Therapy May Be Key to Preventing Disability

First Clinical AttackFirst Clinical Attack

Time (years)

Clinical thresholdClinical threshold

Axonal lossAxonal loss

DemyelinationDemyelination

Time Time window window

for early for early treatmenttreatment

Relapsing-RemittingRelapsing-Remitting TransitionalTransitionalSecondarySecondaryProgressiveProgressive

First First Demyelinating Demyelinating

EventEventPre-Pre-

clinicalclinical

InflammationInflammation

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

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 2 y 28% 45% <.0001

PreCISe4 Glatiramer acetate 20 mg/d

481 3 y 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 TherapiesNatalizumab

• 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 TherapiesNatalizumab

• 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.

Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 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 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

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

Year 122%

Year 320%

Year 413%

Year 58%

Year 65%

Year 73%

Year 83%

Year 227%

Assess Adherence!Most Patients Who Discontinue

Do So in First 2 Years

Rio J, et al. Mult Scler. 2005;11:306-309.

Cohort of patients who stopped therapy

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

ResourcesMS 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

ResourcesMS Centers in Washington State

Cascadia Multiple Sclerosis Center11 Bellwether Way, Suite 210, Bellingham, WA 98225360-752-9919

Evergreen Neuroscience Institute MS Center12040 NE 128th St, MS #118, Kirkland, WA 98034425-899-5350

Rockwood Multiple Sclerosis Center400 East Fifth Ave, Spokane, WA 99202509-838-2531

Swedish Neuroscience Institute550 17th Ave, Suite 540, Seattle, WA 98122206-386-3880

ResourcesMS Centers in Washington State

VA MS Center of Excellence–West (VAMC Seattle)1660 S Columbian Way, Seattle, WA 98108206-277-4688

Virginia Mason Multiple Sclerosis Center1100 9th Ave, Seattle, WA 98101206-223-6600

Western MS Center at University of Washington Medical Center/MSRRTC

1959 NE Pacific St, Seattle, WA 98195206-598-3344

ResourcesMS Center in Idaho

Idaho Falls Multiple Sclerosis Center2353 Coronado, Idaho Falls, ID 83404208-552-4823Stephen G. Vincent, MD, and Bradford L. Talcott, MD, PhD

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

ARS Polling

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