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anne h cross md professor of neurology washington university school of medicine st louis missouri n.
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New and Emerging Therapies in MS: Is It Time to Change the Status Quo? PowerPoint Presentation
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New and Emerging Therapies in MS: Is It Time to Change the Status Quo?

New and Emerging Therapies in MS: Is It Time to Change the Status Quo?

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New and Emerging Therapies in MS: Is It Time to Change the Status Quo?

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  1. Anne H. Cross, MD Professor of NeurologyWashington University School of MedicineSt. Louis, Missouri New and Emerging Therapies in MS: Is It Time to Change the Status Quo?

  2. Outline • How have our goals been altered by the new MS therapies? • Balancing efficacy with safety • The “old guard” medications vs newer agents • 3 newest FDA-approved disease-modifying therapies • Natalizumab • Fingolimod • Teriflunomide • Drugs in late-phase trials • Dimethylfumarate, alemtuzumab, daclizumab, laquinimod, and ocrelizumab • Combination therapies: teriflunomide + IFN-β, CombiRx trial • Individualizing therapy • The role of MRI and other biomarkers in guiding therapies

  3. 9 FDA-Approved MS Disease-Modifying Therapies Abbreviations: CIS, clinically isolated syndrome; MS, multiple sclerosis; RRMS, relapsing-remitting MS; SPMS, secondary-progressive MS. Graphic courtesy of Anne H. Cross, MD.

  4. More Treatments Are Good, But It Makes Treatment Choices More Difficult! ? No Switch treatments? Treatment A Maybe Treatment C Treatment B Yes Graphic courtesy of Anne H. Cross, MD.

  5. Impact Disease course Disability outcomes Tolerance Convenience Treatment Decisions—A Balancing Act Benefits Risks Short-term safety Long-term safety Pregnancy Financial costs Graphic courtesy of Anne H. Cross, MD.

  6. Role of MRI in Guiding Initial Medication Decisions • Improves diagnostic certainty • Spinal cord MRI • Helps to gauge the aggressiveness of the MS • Number and extent of T2 lesions on early MRI • Infratentorial lesions • Degree of cerebral atrophy − requires careful measurement • Helps to gauge MS activity • Number of contrast-enhancing lesions • Although correlation of Gd+ lesions with future disability not clear

  7. Advantages of The “Old Guard” Interferon-βs and Glatiramer Acetate • Highly efficacious in a sizeable proportion of relapsing-remitting MS patients • Known safety profiles – years, decades • No immunosuppression • Glatiramer acetate (GA) is Pregnancy Category B • No blood monitoring needed for GA

  8. Disadvantages of The “Old Guard” IFN-βs and GA • Partial efficacy against relapses • Effect on long-term disability less clear • Immediate IM IFN β-1a at time of clinically isolated syndrome reduced relapse rate over 10 years but did not improve disability outcomes1 • Neutralizing antibody formation with IFNs • Injections: site reactions, lipoatrophy, infections • “Flu-like” illness with IFN-βs • Nonadherence in up to 40%−50%2,3 • Blood monitoring needed for IFN-βs • IFN-βs are Pregnancy Category C 1. Kinkel RP, et al. Arch Neurol. 2012;69:183-190. 2. Klauer T, et al. J Neurol. 2008;255:87-92. 3. Wong J, et al. Can J Neurol Sci. 2011;38:429-433.

  9. Long-Term Outcome Considerations • Age of patient and expected lifespan? • How aggressive does the disease appear? • How long can the patient be on the medication? • Future and present childbearing potential? • Concomitant illnesses? • Does the medication increase risk of future neoplasm?

  10. Newer Drugs

  11. Natalizumab

  12. Transmigration of Inflammatory Cells Blood Lymphocyte VLA-4,LFA-1, Mac-1, (integrins) Chemokine R Lectins Chemokine ICAM-1, VCAM-1 (Igsuperfamily) MMPs Addressins Step 1 (“rolling”) Step 2 Step 3 Inside the CNS Chemokines Graphic courtesy of Anne H. Cross, MD.

  13. Natalizumab for Relapsing MS • Humanized monoclonal antibody to α4-integrins (part of VLA-4)1 • Blocks interactions of α4β1 and α4β7 on leukocyte surface with VCAM-1 on endothelium and fibronectin in extracellular matrix1 • Suppressing cell transmigration through the blood–brain barrier and trafficking into tissues • Initially approved 2004, “generally recommended for patients who have had an inadequate response to, or unable to tolerate, an alternate MS therapy”2 • Available only through the TOUCH program2 1. Engelhardt B, et al. Neurodegener Dis. 2008;5:16-22. 2. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012.

  14. Natalizumab—Boxed Warning • “[Natalizumab] increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability”1 • As of October 3, 2012, 298 cases of PML with 104,300 exposures to natalizumab worldwide2 • 3 risk factors for PML1 • Longer treatment duration, particularly >2 years • Prior immunosuppressant treatment • Presence of anti-JCV antibodies 1. Tysabri [PI]. Cambridge, MA: Biogen Idec Inc.; 2012. 2. Biogen Idec. Tysabri Update. October 18, 2012.

  15. PML—Biomarkers to Stratify Risks with Natalizumab • Antibodies to JCV indicate prior JCV exposure and risk of PML • Absence of anti-JCV antibodies indicates low, but not 0, risk • Examples of prior immunosuppressants include mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolatemofetil FDA. Drug Safety Communication. Accessed 12/21 at: http://www.fda.gov/drugs/drugsafety/ucm288186.htm.

  16. AFFIRM Trial—Natalizumabvs Placebo • Annualized Relapse Rate, Primary Endpoint at 1 Year Placebo (n = 315) Natalizumab (n = 627) Adjusted Annualized Relapse Rate P<.001 Polman CH, et al. N Engl J Med. 2006;354:899-910.

  17. AFFIRM Trial—Natalizumabvs Placebo • Sustained Progression of Disability, Primary Endpoint at 2 Years Placebo (n = 315) P<.001 Natalizumab (n = 627) Risk of Sustained Progression of Disability (%) Polman CH, et al. N Engl J Med. 2006;354:899-910.

  18. AFFIRM—Natalizumab Compared with PlaceboSecondary Imaging Endpoints 83% • New or enlarging T2 lesions at year 2 92% • Gd+ lesions at years 1 and 2 Polman CH, et al. N Engl J Med. 2006;354:899-910.

  19. AFFIRM—Proportion of Patients Without Disease Activity at 2 Years Post-Hoc Analysis Placebo (n = 304) Natalizumab (n = 600) Patients Free of Clinical and Radiologic Disease Activity* (%) P<.0001 *No relapses, sustained disability progression, Gd+ lesions, or new or enlarging T2-hyperintense lesions. Havrdova E, et al. Lancet Neurol. 2009;8:254-260.

  20. It’s Time to Move The Goalposts Toward Disease Activity-Free Status! ++++ Graphic courtesy of Anne H. Cross, MD.

  21. MRI Can Be Used to Monitor Treatment • MRI can detect “breakthrough” disease • New lesion or enhancing lesion • Enhancing lesion or new T2 lesion >12 months on IFN-β suggests future nonresponsiveness to IFN-βs1,2 • Equivalent studies not done with glatiramer acetate, natalizumab, fingolimod, or teriflunomide • But progression of MRI lesions on any of these medications raises the question of efficacy for individual patient • Timing of baseline MRI is a question • Consider waiting until 1–2 months on new therapy to ensure that next MRI truly reflects the new medication effects 1. Tomassini V, et al. J Neurol. 2006;253:287-293. 2. Rudick RA, et al. Ann Neurol. 2004;56:548-555.

  22. Case 1—Mr. R History and Presentation • 44-year-old male architect • 1-year history of personality changes • Lost job 6 months prior to presentation • Around same time, he developed weakness and tingling when taking showers • Abnormal gait noticed by wife

  23. Case 1—Initial MRI Findings • >20 Gd+ lesions • Many T1-weighted hypointensities (“black holes”) • Significant brain volume loss Graphic courtesy of Anne H. Cross, MD.

  24. Case 1—CSF and Neurocognitive Findings • Cerebrospinal fluid (CSF) analysis • 9 oligoclonal bands restricted to CSF • IgG Index 0.85 • 10 mononuclear cells • Formal neurocognitive testing • Severe deficits in learning, memory, and reasoning

  25. Case 1—First-Line Treatment Decision • Initial laboratory tests and baseline evaluations normal • Dermatology, ophthalmology • Negative for anti-JC virus antibodies • Began natalizumab 300 mg IV every 4 weeks

  26. Case 1—Follow-Up at 4 and 6 Months • MRI after 4 months • All enhanced lesions disappeared • No new MS lesions • Cerebral volume loss remained, along with sizeable burden of disease on T2 and T1 weighted MR imaging • Neurocognitive testing after 6 months • Minimal improvement • Failed driving test • Unable to return to work Graphic courtesy of Anne H. Cross, MD.

  27. Case 1—Ongoing Management • Continues to take natalizumab • Monitoring plans • Liver function tests and complete blood count every 3 months • Anti-JC virus antibodies every 6 months • MRI yearly • Dermatology and ophthalmology exams yearly

  28. Fingolimod

  29. Fingolimod—Mechanism of Action Blood Efferent lymph • Down-modulates sphingosine-1-phosphate receptors1 • Leaves T- and B-cells unable to migrate along a sphingosine-1-phosphate gradient between lymph tissue and blood1 • Retains otherwise healthy lymphocytes in lymph nodes1 • No effect on lymphocyte induction, proliferation, memory1,2 Lymph node S1P gradient = lymphocyte 1. Brinkmann V, et al. Am J Transplant. 2004;4:1019-1025. 2. Pinschewer DD, et al. J Immunol. 2000;164:5761-5770. Graphic courtesy of Anne H. Cross, MD.

  30. Fingolimod Crosses the Blood-Brain Barrier—May Have Beneficial CNS Effects • Fingolimod may be phosphorylated in the CNS1 • Fingolimod modulates sphingosine-1-phosphate (SIP) receptors: 1, 3, 4, and 5 (all but SIP2) 2 • S1P receptors throughout body, including on glia and neurons in the CNS3 • S1P5 agonists enhance blood-brain barrier function of cultured human endothelial cells4 • Increased brain-derived neurotrophic factor production by neurons in mouse model5 1. Foster CA, et al. J Pharmacol Exp Ther. 2007;323:469-475. 2. Brown BA, et al. Ann Pharmacother. 2007;41:1660-1668. 3. Aktas O, et al. Nat Rev Neurol. 2010;6:373-382. 4. van Doorn R, et al.J Neuroinflamm. 2012;9:133. 5. Deogracias R, et al. Proc NatlAcadSci USA. 2012;109:14230-14235.

  31. FREEDOMS—Fingolimodvs Placebo for 2 YearsAnnualized Relapse Rate, Primary Endpoint P <.001 for both Annualized Relapse Rate N = 1272mean age 36–37 y, mean EDSS 2.3–2.5 *FDA-approved dose. Abbreviations: EDSS, Expanded Disability Status Scale; FNG, fingolimod. Kappos L, et al. N Engl J Med. 2010;362:387-401.

  32. FREEDOMS—Fingolimod 0.5 mg* Compared with Placebo, 2 YearsSecondary Endpoints 30% • Sustained disability progression (3 months) 30% • Reduction in rate of decrease in MRI brain volumes 89.7%vs 65.1% • Free of Gd+ lesions *FDA-approved dose. Kappos L, et al. N Engl J Med. 2010;362:387-401.

  33. TRANSFORMS—FingolimodvsIFN β-1a IM for 1 YearAnnualized Relapse Rate, Primary Endpoint P <.001 for both N = 1280 mean age 35–36 y, mean EDSS 2.2–2.4 Annualized Relapse Rate *FDA-approved dose. Abbreviations: EDSS, Expanded Disability Status Scale; FNG, fingolimod. Cohen JA, et al. N Engl J Med. 2010;362:402-415.

  34. TRANSFORMS—Fingolimod 0.5 mg* Compared with IFN β-1a, 1 YearSecondary Endpoints No Difference • Sustained disability progression (3 months) 35% • Mean new or enlarged T2 lesions 55% • Mean Gd+ lesions In 1.25-mg arm, 2 deaths from herpes infections (encephalitis, disseminated varicella zoster). *FDA-approved dose. Cohen JA, et al. N Engl J Med. 2010;362:402-415.

  35. FREEDOMS II—Fingolimodvs Placebo for 2 YearsAnnualized Relapse Rate, Primary Endpoint P <.001 N = 1083 Mean age 40–41 y, mean EDSS 2.4–2.5, higher BMI than FREEDOMS Annualized Relapse Rate Note: Showing only the 0.5 mg dose. *FDA-approved dose. Abbreviations: BMI, body mass index; EDSS, Expanded Disability Status Scale; FNG, fingolimod. Calabresi PA, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Poster P491.

  36. FREEDOMS II—Fingolimod 0.5 mg* Compared with Placebo, 2 YearsSecondary Endpoints 17% (NS) • Disability progression (3 months) 33% • Proportion of brain volume loss Adverse effects, FNG 0.5 mg vs placebo: herpes zoster: 2.5% vs 0.8%; basal cell skin cancer: 2.8% vs 0.6%; hypertension 8.9% vs 3.1%. No deaths. *FDA-approved dose. Abbreviations: FNG, fingolimod; NS, nonsignificant. Calabresi PA, et al. ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract P491.

  37. Fingolimod—Contraindications • Within past 6 months: myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure • History or presence of Mobitz Type II 2nd- or 3rd-degree atrioventricular block or sick sinus syndrome, unless patient has a functioning pacemaker • Baseline QTc interval ≥500 ms • Treatment with Class Ia or Class III antiarrhythmic drugs Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  38. Fingolimod—Other Precautions • Monitor pulse and blood pressure after 1st dose >6 hours • If heart rate has not reached nadir after 6 hours, continue monitoring • Patients on drugs that prolong QT or that cause bradycardia should be monitored with EKG overnight • Obtain EKG prior to and at end of dosing • Monitor for signs/symptoms of infections • Avoid live vaccines • Perform ophthalmologic exam at baseline and at 3–4 months (macular edema) • Obtain pulmonary function tests, if indicated • Contraception during and for 2 months after stopping Gilenya [PI]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.

  39. Case 2—Mrs. M History and Presentation • 54-year-old female real estate agent • Works full time, right-handed • MS began at age 40 with optic neuritis • Initially took glatiramer acetate for 5 years • Single mild relapse and lipoatrophy • Switched to an interferon-β

  40. Case 2—History and Presentation • Developed fatigue • Timed 25-Foot Walking (T25FW) worsened • 7 seconds, 2010 • 8.4 seconds, 2011 • 9 seconds, early 2012 • Neutralizing antibodies, negative • No history of heart disease, lung disease, or hypertension

  41. Case 2—MRI Findings • Brain MRI showed findings compatible with MS • Patient had a mild to moderate burden of disease • A few “black holes” • No enhancing lesions Graphic courtesy of Anne H. Cross, MD.

  42. Case 2—Evaluation and Switching Therapy • Laboratory tests • Complete metabolic profile (CMP), including liver function tests – normal • CBC – normal • Varicella zoster +IgG • Pregnancy test – negative • Dermatology and ophthalmology evaluations – normal • 12-lead EKG with rhythm strip – normal • Initiated fingolimod at standard 0.5 mg/day dose • 1st dose observation March 2012 (after approximately 4-week wash-out period)

  43. Case 2—Follow-Up • Patient tolerating fingolimod well • Fatigue improved • Monitoring plans • Ophthalmology exam at 3–4 months, then yearly • Lab tests monthly for first 3 months, then every 3 months • Her total lymphocyte count 3 months after starting fingolimod was 400/mL • Yearly MRI • Yearly dermatology evaluation

  44. Teriflunomide

  45. Teriflunomide—Overview • Approved fall 2012 for relapsing MS • 1st-line agent • Oral – 7 mg or 14 mg daily • Antiproliferative and anti-inflammatory1 • Not considered “immunosuppressive”1 • Active metabolite of leflunomide, approved for rheumatoid arthritis in 19981 1. Claussen MC, et al. ClinImmunol. 2012;142:49-56.

  46. Teriflunomide—Mechanism of Action • Inhibits the pyrimidine synthesis enzyme, dihydro-orotatedehydrogenase (DHODH) • 2 pathways of pyrimidine synthesis • de novo synthesis used in activated lymphocytes • Salvage pathway used by resting lymphocytes • 8-fold increase in pyrimidine synthesis required for proliferation of activated lymphocytes • Without DHODH, sufficient pyrimidine cannot be synthesized to support proliferation • Does not eliminate resting lymphocytes Claussen MC, et al. ClinImmunol. 2012;142:49-56.

  47. TEMSO—Teriflunomidevs Placebo for 2 YearsAnnualized Relapse Rate, Primary Endpoint P <.001 for both N = 1086 Mean EDSS 2.68 Annualized Relapse Rate Abbreviations: EDSS, Expanded Disability Status Scale; TFN, teriflunomide. O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.

  48. TEMSO—Teriflunomide Compared with Placebo, 2 YearsSecondary Endpoints 23.7% (7 mg) and 29.8% (14 mg) • Sustained disability progression (3 months) 48% (7 mg) and 69% (14 mg) • Combined unique and active MRI lesions O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.

  49. TOWER—Teriflunomidevs Placebo for 2 YearsAnnualized Relapse Rate, Primary Endpoint P = .0183 P = .0001 N = 1165 Mean EDSS 2.7 Annualized Relapse Rate Abbreviations: EDSS, Expanded Disability Status Scale; TFN, teriflunomide. Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.

  50. TOWER—TeriflunomideCompared with Placebo, 2 YearsSecondary Endpoints 31.5% (14 mg)* • Sustained disability progression (3 months) 52% (14 mg) and 38% (placebo) • Relapse-free at study end *7 mg, nonsignificant. Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.