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  1. 1. Emerging Therapies for Multiple Sclerosis Horea Rus MD PhD
  2. 2. Existing Therapies and Emerging Therapies for MS 2005 2011 Injectables IV TeriflunomideTeriflunomide LaquinimodLaquinimodFTY 720FTY 720 Oral Cladribine Oral Cladribine DaclizumabDaclizumab Generic Mitoxantrone (oncology) (MS) Generic Mitoxantrone (oncology) (MS) Orals TysabriTysabri IV 2006 2007 Copaxone Betaseron Avonex Novantrone Rituximab II - RRMS; III - PPMS Rituximab II - RRMS; III - PPMS Rebif 2010 2012 MLN1202MLN1202 BG 12 Oral Fumarate BG 12 Oral Fumarate Fampridine ambulation indication? Fampridine ambulation indication? MBP 8298MBP 8298 Filed approved In phase II In phase III SB683699SB683699 2013 Campath
  3. 3. New Oral Therapies
  4. 4. Fingolimod (FTY720) A sphingosine -1-phosphate inhibitor that reversibly sequester lymphocytes to lymph nodes
  5. 5. Fingolimod (FTY720) • Phase II studies: •281 patients received FTY 720 1.25 or 5 mg or placebo once daily • Primary end point : number of gadolinium enhancing lesions • Reduced the number of gadolinium enhancing lesions detected on the brain MRI and clinical disease activity • Both measures decreased in patients who switched from placebo to fingoloimod
  6. 6. Kappos L et al. N Engl J Med 2006;355:1124-1140 Proportions of Patients Who Were Free of Gadolinium-Enhanced Lesions on T1-Weighted MRI at 0 to 6 Months (Panel A) and the Estimated Time to a First Confirmed Relapse (Panel B)
  7. 7. Fingolimod • Side effects: - Clinically asymptomatic elevations of liver enzymes - Initial reduction of the heart rate - Modest decrease of forced expiratory volume - No serious infections reported
  8. 8. Fingolimod (FTY720) Phase III Studies have begun and patients can be referred Study Treatment Indication Duration FREEDOMS II (2309) Oral FTY720 0.5 & 1.25 mg once daily vs placebo RRMS 2 960 TRANSFORMS (2302) Oral FTY720 0.5 & 1.25 mg once daily vs interferon β-1a (Avonex® ) once weekly RRMS 1 1275
  9. 9. FREEDOMS II: Inclusion Criteria • Oral FTY720 0.5 & 1.25 mg once daily vs. placebo • Male and Females18 through 55 years of age with a diagnosis of multiple sclerosis by 2005 McDonald criteria • EDSS score 0−5.5 inclusive • One documented relapse in the last year or two documented relapses in the last 2 years
  10. 10. TRANSFORMS: Inclusion Criteria • Oral FTY720 0.5 & 1.25 mg once daily vs. i.m. interferon β-1a (Avonex®) once weekly • Treatment naïve patients or patients already treated with MS drugs can be screened. • 18 - 55 years of age with a diagnosis of MS by 2005 McDonald criteria • A relapsing-remitting course with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years • Expanded Disability Status Scale (EDSS) score of 0-5.5 inclusive
  11. 11. Cladribine • Purine nucleoside with lymphocyte depleting properties • It disrupts cellular metabolism, induces DNA damage and subsequent cell death. • Was shown to suppress Gd-enhancing lesions in patients which received iv Cladribine for 12 months • Reduced the frequency of relapses
  12. 12. Cladribine • Phase III study with oral Cladribine is ongoing. • 1290 patients recruited; • 10 mg Cladribine vs. placebo for 5 days a month, 2-4 cycles a year. • End points: Relapse rate, EDSS, MRI activity Side effects: • Lymphopenia , but risk of opportunistic infections is low, limited to segmental Herpes Zoster, one case of fulminant hepatitis B • Long term safety of tablets use not established
  13. 13. Laquinimod • Oral immunomodulator • Phase II - 306 patients randomized to either Laquinimod 0.3 or 0.6 mg/day or placebo; • Significant reduction in cumulative number of enhancing lesions on brain MRI for 36 weeks with 0.6 mg/day; • Positive trends on annual relapse rates, relapse free subjects and time to first relapse; • Phase III trials to begin soon.
  14. 14. Fumaric acid derivate BG00012 • Medication is used in treatment of psoriasis • Cytoprotective and anti-inflammatory effects • Phase II study: 235 patients were randomized to 120, 360 or 720 mg/ day • Reduced the number of new gadolinium –enhancing lesions by 69% versus placebo • Relapse rate in all treatment groups decreased as compared with placebo
  15. 15. Fumaric acid derivate BG00012 • When patients on placebo were switched to BG00012 720 mg/day for the extension phase the relapse rate was reduced by 52% •Side effects: • Favorable safety profile • Reported: flushing,increased liver enzymes, no infections •Phase III in progress
  16. 16. TERIFLUNOMIDE •Analogue of Leflunomide used in the therapy of Rheumatoid Arthritis • Inhibits a mitochondrial enzyme and proliferation of T and B Cells Phase II study: Two different regimens: 7 and 14 mg/day vs. Placebo for 36 weeks in 179 patients. Patients on Teriflunomide when compared with placebo had : • Significantly reduced number of active and new lesions On the brain MRI • A lower annualized relapse rate
  17. 17. TERIFLUNOMIDE Side effects: • Generally well tolerated • Most common side effects: upper respiratory tract infections and headache • In RA patients- toxic liver necrosis and pancytopenia have been described.
  18. 18. Cumulative Number of Gd-Positive Lesions Annualized Relapse Rate Fingolimod (1.25 mg) -43%, P < .001 -55%, P = . 009 Teriflunomide (7 mg) -61%, P < .03 -32%, NS Laquinimod (0.3 mg) -44%, P = .05 No difference BG00012 (720 mg) -69%, P < .001 -32%, NS Cladribine (2.1 mg) -90%, P = .001 -51%, NS Phase II Studies of New Oral Multiple Sclerosis Therapies
  19. 19. Conclusions – Oral therapies • Potential benefits of oral treatments for modifying the course of RRMS are significant. • They will expand the options available while improving the ease of administration • Will reduce the cost of therapy (?). • Might facilitate new combinations of agents • Could lead to increase adherence.
  20. 20. MONOCLONAL ANTIBODIES
  21. 21. Monoclonal antibody production. From: The Neurologist 2006;12, 171
  22. 22. Chimeric and humanized monoclonal antibody From: The Neurologist 2006;12, 171
  23. 23. Alemtuzumab Phase II study: -334 patients, -3 year data were reported at ECTRIMS 2007 • 73% reduction in the risk for relapse after 3 years follow-up when compared to patients treated with interferon beta 1a • 70% reduction in the risk for progression of clinically significant disability when compared to patients treated with Interferon beta 1a
  24. 24. Alemtuzumab in multiple sclerosis Humanized monoclonal antibody against CD 52 From: The Neurologist 2006;12, 171
  25. 25. Alemtuzumab • Side effects: •Six patients developed ITP • Infusion related side effects • Severe Infections were infrequent • Thyroid related events were less then expected Two phase III studies to start: • CARE-MS I - Alemtuzumab as a first line therapy • CARE-MS II – Alemtuzumab in patients which continued to experience relapses
  26. 26. RITUXIMAB IN MS Chimeric Monoclonal antibody anti CD20 Stem Pro-B Pre-B Immature Transitional Activated Memory Plasma Cell CD20 T. Ito, H. Rus 2007
  27. 27. T. Ito, H. Rus 2007
  28. 28. RITUXIMAB IN MS Phase II Study: -104 patients - 1000 mg iv x 2 -91% relative reduction in number of cumulative number of Gd-enhancing lesions -58% Reduction in clinical relapses Decision on starting phase III trial is pending
  29. 29. DACLIZUMAB IN MS Phase II CHOICE study: • At 24 weeks, 75 patients in the 2 mg/kg group experienced 72% fewer new or enlarged Gd+ on average compared to the 77 patients who received a placebo (p=0.004). • The 78 patients in the 1 mg/kg group experienced a 25% reduction in new or enlarged lesions: did not achieve statistical significance. • Both daclizumab regimens revealed a trend in reducing the annualized relapse rate compared to placebo (35%); did not reach statistical significance.
  30. 30. MBP8298 in secondary progressive MS Synthetic peptide aa 82-98 of myelin basic protein • Immunodominant target for both B- and T-cells in MS patients with HLA haplotype DR2. • Administration of the peptide results in long term suppression of anti-MBP autoantibodies; • Phase II study: • 32 patients, followed for 24 months • 500mg of MBP8298 every 6 months. • the HLADR2 positive responder group showed a median time to progression of 78 months as compared with 18 months for placebo Phase III study - recruiting patients
  31. 31. Existing Therapies and Emerging Therapies for MS 2005 2011 Injectables IV TeriflunomideTeriflunomide LaquinimodLaquinimodFTY 720FTY 720 Oral Cladribine Oral Cladribine DaclizumabDaclizumab Generic Mitoxantrone (oncology) (MS) Generic Mitoxantrone (oncology) (MS) Orals TysabriTysabri IV 2006 2007 Copaxone Betaseron Avonex Novantrone Rituximab II - RRMS; III - PPMS Rituximab II - RRMS; III - PPMS Rebif 2010 2012 MLN1202MLN1202 BG 12 Oral Fumarate BG 12 Oral Fumarate Fampridine ambulation indication? Fampridine ambulation indication? MBP 8298MBP 8298 Filed approved In phase II In phase III SB683699SB683699 2013 Campath

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