Integrating Current and Emerging MS Therapies into Practice

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Integrating Current and Emerging MS Therapies

into Practice


Goals of MSDisease-Modifying Therapy

Delay disability progression Reduce the frequency of relapses Improve MRI measures of disease


StudyARR by Treatment Arm

GA IFN PBOALLEGRO1 – – 0.39BEYOND2 0.34 0.36 –CLARITY3 – – 0.33FORTE4 0.33 – –FREEDOMS5 – – 0.40REGARD6 0.29 0.30 –TEMSO7 – – 0.54TRANSFORMS8 – 0.33 –

Modern-Day Goals—Relapse RateAnnualized relapse rates (ARRs) in recently completed RRMS trials

with glatiramer acetate (GA), interferon (IFN), and placebo (PBO) arms

1. Comi G, et al. Paper presented at: 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract P07.194. 2. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 3. Giovannoni G, et al. N Engl J Med. 2010;362:416-426. 4. Comi G, et al. Ann Neurol. 2011;69:75-82. 5. Kappos L, et al. N Engl J Med. 2010;362:387-401. 6. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 7. O’Connor P, et al. Paper presented at: ECTRIMS; October 13 –16, 2010; Gothenburg, Sweden. Abstract 79. 8. Cohen JA, et al. N Engl J Med. 2010;362:402-415.


Parameter Study GA IFNRelapse-free at 2 years BEYOND1 59% 58%

Disability progression-free at 2 years

BEYOND1 79% 73%REGARD2

(96 weeks) 91% 88%

Disability progression-free at 3 years CAMMS2233 – 59%

Disability progression-free 5 years after CIS BENEFIT4 – 75%

Reduction in MRI T2 lesions at 3 years CAMMS2233 – 13%

Modern-Day Goals—OtherPatients treated with IFN or GA in recent CIS and

RRMS studies

Abbreviations: CIS, clinically isolated syndrome; GA, glatiramer acetate; IFN, interferon; RRMS, relapsing-remitting MS.1. O'Connor P, et al. Lancet Neurol. 2009;8:889-897. 2. Mikol DD, et al. Lancet Neurol. 2008;7:903-914. 3. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801. 4. Kappos L, et al. Lancet Neurol. 2009;8:987-997.


5

Timeline of Approved and Emerging MS Therapies

Phase III Completed In Phase IIIApproved Therapies

2009 2010 201120051995 2000

Fingolimod

Teriflunomide

IFN β-1b SC

NatalizumabIFN β-1b SC

Glatiramer acetate

IFN β-1a IM

IFN β-1a SC

Mitoxantrone Laquinimod*

Approval Date Estimated Launch Date2012

Daclizumab

Ocrelizumab

Fumarate (BG12)

Alemtuzumab

Abbreviations: NDA, new drug application; RRMS, relapsing-remitting MS.1. TEVA Pharmaceutical Industries Ltd. Form 20-F. February 17, 2012. Accessed 3/1/12 at http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-sec. Graphic courtesy of Dr. Mark J. Tullman.

*In 20-F report filed 2/17/12: Teva will not file an NDA with the FDA for laquinimod for RRMS at this time; development continues, however.1


What’s New?Interferon Beta

BEYOND trial data analysis shows negative impact of neutralizing antibodies on MRI measures, but no negative impact on clinical measures1

21-year follow-up from start of phase III enrollment shows significant survival benefit vs placebo2

Meta-analysis finds limited benefits in secondary-progressive MS3

5-year follow-up shows modest beneficial effect on clinical variables and brain atrophy in primary-progressive MS4

1. Goodin DS, et al. Mult Scler. 2012;18:181-195. 2. Goodin D, et al. Paper presented at ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P940. 3. La Mantia L, et al. Cochrane Database Syst Rev. 2012;1:CD005181. 4. Tur C, et al. Arch Neurol. 2011;68:1421-1427.


What’s New?Glatiramer Acetate

Long-term follow-up of patients with mean MS duration of 22 years receiving continuous glatiramer acetate for up to 15 years shows long-term efficacy and safety1

– Reduced relapse rates, decreased disability progression, decreased transition to secondary-progressive MS

– No long-term safety issues 5-year brain MRI study showed less progression of brain

atrophy with glatiramer vs interferon2

Preliminary analysis of Coptimize study shows significant reduction in annualized relapse rate after switching to glatiramer acetate3

Induces in vivo expansion of immunosuppressive CD4+ T-cells4

1. Ford C, et al. Mult Scler. 2010;16:342-350. 2. Khan O, et al. J Neurol Sci. 2012;312:7-12. 3. Ziemssen T, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P510. 4. Ryzhkova A, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P799.


What’s New?Fingolimod

TRANSFORMS subgroup analysis: brain volume reduction with fingolimod not accounted for by inflammatory lesion activity or new disease activity during 1st year of treatment1

Data from safety study extension shows sustained low level of disease activity over 5 years2

July 2011, fingolimod label expanded to include reduction in MRI gadolinium-enhancing lesions3

December 2011, FDA announced safety evaluation of a patient who died within 24 hours of taking first dose; exact cause of death has not been established4

January 2012, Novartis announced a total of 31 deaths worldwide are being investigated: 11 "deaths of potential interest" plus 20 other deaths in 30,000+ patients treated since 20035

1. Barkhof F, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P907. 2. Montalbán S, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P978. 3. FDA letter. July 20, 2011. Accessed 3/5/12 at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022527s002ltr.pdf.

4. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at: http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 5. Novartis webcast, January 25, 2012. Accessed 3/8/12 at: http://www.novartis.com/investors/event-calendar/index.shtml#2012-01-25_full-year-results.


What’s New?Natalizumab

Long-term outcomes from AFFIRM in patients free of disease activity after 2 years presented at ECTRIMS1

Patients treated with natalizumab had higher magnetization transfer ratio volume in normal-appearing brain tissue compared with patients treated with IFN or healthy controls at years 1 and 22

FDA approves STRATIFY JCV antibody ELISA test3 Pathologic and radiologic characteristics of immune

reconstitution inflammatory syndrome described4

1. Rudick R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P513. 2. Zivadinov R, et al. Mult Scler. 2011 Dec 22. [Epub ahead of print]. 3. FDA. News release. 1/20/12. Accessed 3/20/12 at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm288471.htm. 4. Metz I, et al. Acta Neuropathol. 2012;123:235-245.


What’s New?Mitoxantrone

Mitoxantrone found to exert cytotoxic and immunomodulatory effects on central nervous system (CNS) microglia, major CNS antigen-presenting cells that play a key role in MS pathogenesis1

5-year prospective safety study from French cohort (N = 802) reported2

– 0.1% acute congestive heart failure– 4.9% asymptomatic left ventricular ejection fraction

reduction under 50% – 0.25% therapy-related leukemia– 17.3% persistent age-dependent amenorrhea in women

treated before age 45 years

1. Li JM, et al. Immunopharmacol Immunotoxicol. 2012;34:36-41. 2. Le Page E, et al. Mult Scler. 2011;17:867-875.

Electronic Image Safe (Remove for final output)11Gold R, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 95.

Fumarate (BG-12)–DEFINE, Phase III

BG-12 240 mg BID and TID vs placebo for 2 years(N = 1234 RRMS)

All primary and secondary endpoints met Compared with placebo, BG-12 BID and TID

– Reduced the relapse rate by 49% and 50%, respectively (P <.0001)

– Reduced annualized relapse rate by 53% and 48%, respectively (P <.001)

– Reduced 12-week disability progression by 38% (P <.01) and 34%, respectively (P <.05)


Laquinimod–ALLEGRO, Phase III

Comi G, et al. N Engl J Med. 2012;366:1000-1009.

Laquinimod 0.6 mg/d vs placebo for 24 months (N = 1106 RRMS)

Achieved primary end point showing annualized relapse rate significantly reduced by 23% (P = .002)

Achieved secondary endpoints– Expanded Disability Status Scale progression of disability

significantly reduced by 36% (P = .01)– Mean cumulative number Gad-enhancing lesions

significantly reduced by 37% (P <.001) – Mean cumulative number new or enlarging T2 lesions

significantly reduced by 30% (P <.001)


Laquinimod–BRAVO, Phase III

Laquinimod 0.6 mg/d vs placebo vs IFN β-1a for 24 months (N = 1331 RRMS)

Compared with placebo, laquinimod Did not statistically reduce unadjusted annualized relapse

rate (ARR) (P = .075)– Reduced adjusted ARR by 22% (P = .026)– Reduced disability progression by 33.5% (P = .044) – Reduced brain atrophy by 27.5% (P <.0001)

Compared with placebo, interferon β-1a– Significantly reduced ARR by 29% (P = .002) – Did not significantly reduce disability progression or brain

atrophy

Vollmer TL, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 148.


Teriflunomide–Phase III TEMSO Data

Teriflunomide 7 mg/d or 14 mg/d vs placebo for 2 years (N = 1088 RRMS)

Achieved primary endpoint showing ARR significantly reduced by 31.2% at 7 mg and by 31.5% at 14 mg (P <.001 for both)

Achieved key secondary endpoint showing 12-week disability progression significantly reduced by 24% (P = .08) at 7 mg and by 30% (P = .03) for 14 mg

Was superior for a range of MRI endpoints– Significantly reduced total lesion volume by 39.4% at 7 mg

and by 67.4% at 14 mg (P = .03)– Significantly reduced number of Gad-enhancing lesions by

57% at 7 mg and by 80% at 14 mg (P <.001)

O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.


Alemtuzumab 12 mg or 24 mg vs IFN β-1a for 3 years (N = 334 early RRMS)1

Achieved primary endpoints (both doses combined)1

– Significantly reduced relapse rate by 74% (P <.001)– Significantly reduced risk of sustained disability by 71%

(P <.001) Achieved secondary MRI endpoints (both doses combined)1

– Significantly reduced lesion burden (P = .005)– Significantly reduced reduction in brain volume (P = .05)

Treatment effect durable through 5 years2

Alemtuzumab–CAMMS223 Phase II Trial

1. Coles, AJ. N Engl J Med. 2008;359:1786-1801. 2. Twyman C, et al. 63rd AAN; April 9-16, 2011;Honolulu, Hawaii. Abstract PD6.003.


Alemtuzumab vs IFN β-1a for 2 years (N = 581 treatment-naive RRMS)1

Compared with IFN β-1a, alemtuzumab (primary endpoints)1,2 – Significantly reduced ARR by 54% (P <.0001)– Did not significantly reduce sustained accumulation of disability

(11% vs 8%; P = .22) Other outcomes1,2

– Percentage relapse-free: 78% alemtuzumab, 59% IFN (P <.0001)– Percentage with new/enlarging T2 lesions: 49% alemtuzumab, 58% IFN

(P = .035)– Mean change in Expanded Disability Status Scale disability score: 0.14 for both

alemtuzumab and IFN– Percentage with new T1 hypointense lesions: 24% alemtuzumab, 31% IFN

(P = .05)– Brain atrophy: -0.87% alemtuzumab, -1.49% IFN (P <.0001)

Safety1,2

– 0.8% immune thrombocytopenia, 18% thyroiditis

Alemtuzumab–CARE-MS I Phase III Trial

1. Coles A, et al. Paper presented at: ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 151. 2. Gever J. MedPage Today. October 22, 2011. Accessed 3/12/12 at: http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/29173.


• CHOICE phase II trial1

— 3 arms: 2 doses of daclizumab and placebo added to IFN (N = 230 RRMS)— No significant difference in relapse rate — Decrease in new MRI lesions with higher dose vs IFN alone— 5% serious infections with daclizumab, all resolved with standard therapy

• SELECT phase IIb trial2

— Daclizumab monotherapy 150 mg vs 300 mg vs placebo (N = 600 RRMS)

— Compared with placebo, daclizumab Significantly reduced ARR Significantly reduced proportion of patients who relapsed Reduced new or enlarging Gad+ lesions between weeks 8 and 24

— Adverse effects included increase in serious infections (2%)

Daclizumab–CHOICE and SELECT Phase II

1. Wynn D, et al. Lancet Neurol. 2010;9:381-390. 2. Giovannoni G, et al. ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract 149.


Ocrelizumab–Phase II Data

Ocrelizumab (OCR) 600 mg and 2000 mg vs IFN β-1a vs placebo (N = 220 RRMS)1

At week 24, Gad-enhancing lesions reduced by 89% and 96% with OCR 600 mg and 2000 mg, respectively, compared with placebo1

At week 24, ARR reduced by 80% and 73% with OCR 600 mg and 2000 mg1, respectively, compared with placebo

Adverse effects1

– Serious infection rates were similar across groups– 41-year-old woman treated with ocrelizumab 2000 mg died

at week 14 of systemic inflammatory response syndrome Deaths in rheumatoid arthritis and systemic lupus

erythematosus trials suspends development in those settings2

1. Kappos L, et al. Lancet. 2011;378:1779-1787. 2. Reid, K. Reuters. March 8, 2010. Accessed 3/12/12 at: http://www.reuters.com/article/2010/03/08/roche-idUSLDE62705720100308.


Risk Stratification by Baseline Brain MRI

20-Year Clinical Status

Abbreviations: CDMS, clinically definite MS; EDSS, Expanded Disability Status Scale.Fisniku LK et al. Brain. 2008;131:808-817. Graphics courtesy of Dr. Mark J. Tullman.

0 1–3 4–9 ≥100

20

40

60

80

100

21

82 85 81

Number of T2 Brain Lesions at Baseline

% C

onve

rsio

n to

CDM

S

0 1–3 4–9 ≥100

20

40

60

80

100

2636

50

65

6

18

3545

EDSS >3EDSS ≥6

Number of T2 Brain Lesions at Baseline

% P

atie

nts


Factors in Selecting a Disease-Modifying Therapy

Efficacy Safety/tolerance Convenience Patient preference Cost Escalation vs induction Window of opportunity Risk mitigation


Risk Mitigation–Estimated Incidence of PML in Natalizumab-Treated Patients by Risk Factors

Anti-JCV antibody status1,2

Negative Positive

Prior immunosuppressive use

≤0.10/100095% CI: 0–0.593

No Yes

NatalizumabExposure No Prior IS Use Prior IS Use

1–24 mo <1/1000 2/1000

25–48 mo 4/1000 11/1000Abbreviations: JCV, JC virus; IS, immunosuppressant; PML, progressive multifocal leukoencephalopathy.1. Tysabri. [package insert]. South San Francisco, CA: Biogen Idec Inc; 2012. 2. FDA Drug Safety Communication. January 20, 2012. Accessed 2/23/12 at http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm. 3. Bloomgren G, ECTRIMS/ACTRIMS 2011; October 19–20, 2011; Amsterdam, Netherlands. Abstract P995. Graphics courtesy of Dr. Mark J. Tullman.


Monitoring Category

Monitoring Activity

Routine labs • Complete blood count, with differential and platelets1-4

• Blood chemistries with liver function tests1-4

Special tests • Thyroid tests, as indicated1-4

Other

• Monitor for depression, suicidal ideation, and/or psychosis1-4

• Monitor for cardiac symptoms in patients with pre-existing cardiac disease1,2

• Monitor for seizures in patients with pre-existing seizure disorders1-3,4

Monitoring for Interferon-β–Specific Safety Issues

See prescribing information for complete details.1. Avonex [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2010. 3. Extavia [PI]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2009. 4. Rebif [PI]. Rockland, MA: EMD Serono, Inc.; 2011.


Monitoring Category

Monitoring Activity

Routine labs • No routine monitoring for safety required

Special tests ––

Other• No known safety issue with immediate

postinjection hypersensitivity reactions (tolerability issue)

Monitoring for Glatiramer Acetate-Specific Safety Issues

See prescribing information for complete details.

Copaxone [PI]. Kansas City, MO: Teva Neuroscience, Inc.; 2009.


Monitoring Category

Monitoring Activity

Routine labs

• Complete blood count with differential and platelets, baseline and periodic1

— Lymphocyte subsets (optional)2 • Liver function tests, baseline and as indicated1

• IgG antivaricella zoster antibody test, baseline1

• Hepatitis panel screen, baseline and as indicated1,2

• HIV (especially if there are risk factors)2

Special tests

• Baseline ECG and after first 6 hours to check for bradycardia; serial ECG monitoring during 6 hours may be useful2,3; EMA recommends continuous ECG monitoring during the 6 hours4

• Chest X-ray2 • Pulmonary function tests, as indicated1

• Ophthalmologic exam, baseline and periodic1

Other1 • Monitor blood pressure• Monitor for infection

Monitoring for Fingolimod-Specific Safety Issues

See prescribing information for complete details.Abbreviations: ECG, electrocardiogram; EMEA, European Medicines Agency; HIV, human immunodeficiency virus.1. Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. 2. Robert P. Lisak, MD. Written communication. 3/6/12. 3. FDA. Safety announcement. December 20, 2011. Accessed 3/6/12 at: http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm. 4. EMA. Press release. January 12, 2012. Accessed 3/15/12 at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/01/WC500120703.pdf.


Monitoring Category

Monitoring Activity

Routine labs• Complete blood count, with differential and

platelets• Liver function tests

Special tests • JC virus antibody testing

Other

• Monitor for symptoms of hypersensitivity (ie, hives, urticaria)

• Monitor for infection• Monitor for symptoms of progressive multifocal

leukoencephalopathy (PML); if question of PML, additional action and testing required

Monitoring for Natalizumab-Specific Safety Issues

See prescribing information for complete details.Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.


Monitoring Category

Monitoring Activity

Routine labs• Complete blood count with differential and platelets

prior to each infusion• Liver function tests prior to each infusion

Special tests

• Baseline ECG and quantitative LVEF evaluation (eg, MUGA scan); repeat before each infusion plus yearly after discontinuation

• Pregnancy test prior to each infusion for women biologically capable of becoming pregnant

Other • Monitor for infection• Nausea and vomiting (can become safety issue)

Monitoring for Mitoxantrone-Specific Safety Issues

See prescribing information for complete details.Abbreviations: ECG, electrocardiogram; LVEF, left ventricular ejection fraction; MUGA, multiple gate acquisition scan. Mitoxantrone [PI]. Irvine, CA: Teva Parenteral Medicines, Inc.; 2011.


Making Switching Decisions

Decide whether to switch

Decide when to switch

Decide how to switch

Monitoring outcomes

Agent-specific factors

Patient-specific factors

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Integrating Current and Emerging MS Therapies into Practice