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Oral Treatments in Development for MS

Oral Treatments in Development for MS EMSP Information Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim if you get MS… you will have a chronic disease with unknown cause uncertain prognosis unsatisfactory treatments and you are one of ~500,000 Europeans if you get MS…

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Oral Treatments in Development for MS

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  1. Oral Treatments in Development for MS EMSP Information Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim

  2. if you get MS… • you will have a chronic disease with • unknown cause • uncertain prognosis • unsatisfactory treatments • and you are one of ~500,000 Europeans M Sandberg 2008-11-13

  3. if you get MS… • you are 20 - 30 years old • have started on your education… • have hopes of a spectacular career… • have met the love of your life… • have begun to think of having a family… M Sandberg 2008-11-13

  4. if you get MS… • At this time of your life, you do not want to hear • that you have a chronic disease • that the treatment involves daily or weekly injections • and yet, your future is uncertain M Sandberg 2008-11-13

  5. So, what is MS ? • MS is an autoimmune disease • Our immune system is there to defend us against what is ”foreign” • for instance virus, bacteria • but it must tolerate ”self” • our own tissues and organs M Sandberg 2008-11-13

  6. CNS is under surveillance of the immune system • Under normal circumstances white bloodcells circulate through and survey tissues and organs • if they do not encounter anything ”foreign”, they return to the circulation • Sometimes a white blood cell will mistakenly recognize a ”self” molecule as foreign • This will lead to an autoimmune reaction • in the CNS (brain and spinal cord) the result will be areas of inflammation -- MS M Sandberg 2008-11-13

  7. Danger Signal or Trigger T T activation, differentiation,clonal expansion T adhesion T transmigration T B APC T IFN- antibodies local reactivation APC M Release of cytokines Recruitment of M T TNF- NO MS as an Autoimmune T-cell Mediated Process autoreactive T - cells T T periphery Blood-brain-barrier CNS Demyelination and axon loss Courtesy sanofi-aventis

  8. Why treat MS early with DMTs • The disease is clinically episodic • BUT the disease process is ongoing and degenerative • Permanent damage (i.e. loss of axons and neurons) is an early and progressive event Trapp et al, NEJM 1998;338;278-285 Fromann (1878), from the border of a cerebellar lesion

  9. From left to right • Normal axon • Demyelinated axon • Transected axon • Neuronal death MS Forum, 1999 M Sandberg 2008-11-13

  10. Slowing the early disease course may alter long-term outcome • Long Term Follow Up • Natural history: • 50% of patients have progressive MS after 14 years • PRISMS-study, IFNβ 1a sc: • <20% have progressive MS after 14 years • BENEFIT-study, IFNβ 1b sc, 5-year follow up: • treatment from first attack compared to up to 2 yrs later delays accumulation of disability for 18 months M Sandberg 2008-11-13

  11. DMTs today • First line therapy • Interferon β 1b • subcutaneous injections once every other day • Interferon β 1a • intramuscular injections once weekly • subcutaneous injections thrice weekly • Glatiramer acetate • subcutaneous injections once daily • Safety: no issues after 10-15 years M Sandberg 2008-11-13

  12. IFN β and GA2-year data Relapse rate / year T2 active lesions/patient/scan p 0.0001 0.04 <0.0001 0.055 (0.007*) *ANCOVA Reduces relapse frequency by ~30% p <0.009 ? <0.0001 Reduces MRI activity by up to 90%

  13. DMTs today • Second line therapy • natalizumab • intravenous injections once monthly • safety issues • encephalitis (PML) • liver damage M Sandberg 2008-11-13

  14. Placebo n=315 TYSABRI n=627 Over 3 years Natalizumab Efficacy Reduces risk of progression by 42% (3 month sustained EDSS change) Reduces Relapse Rate by 68% P<0.001 1.0 P<0.001 HR=0.58 P<0.001 0.4 0.9 0.8 Placebo 29% 68% 0.3 68% 0.7 0.6 Proportion with Sustained Progression 0.5 0.81 0.73 0.2 Annualized relapse rate (95% CI) 0.4 0.3 0.1 TYSABRI 17% 0.2 0.27 0.23 0.23 0.1 0.0 0.0 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120 Over 1 year Over 2 years Polman CH, et al. N Engl J Med. 2006;354:899-910; Data on file. Clinical study report. C–1808. Cambridge, MA: Biogen Idec, Inc.; 2006. Polman CH, et al. N Engl J Med. 2006;354:899-910.

  15. Oral therapies in development M Sandberg 2008-11-13

  16. CDP-323 Celltech Group MLN3697 Millennium/sanofi-aventis Dronabinol Unimed Pharma AVE 9897 sanofi-aventis Oral therapies in MS: the pipeline Laquinimod Teva Cladribine Merck Serono GSK-683699 GSK NBI-5788 Neurocrine BioSci Inc. BG-12 Fumapharm /Biogen ZK-117137 Schering AG IFN beta 1A Biopartners Cpn 10 Cbio Ltd Rituximab Biogen ATL-1102 Antisense Daclizumab, Biogen Idec ISIS-107248 Antisense Teriflunomide sanofi aventis Abatacept Bristol-Myers ABT-874 Abbots Lab IFN beta 1A Synovex IFN beta 1A Vakzine Phase III TV-5010 Teva MBP8298 Lilly/BioMS Phase II Interferon t, Pepgen C-6448 Merck & Co Fampridine Accorda/Elan BX-471 Berlex Biosciences/ Schering AG EMZ 701 Transition E-2007 Eisai Co. Ltd Fingolimod Novartis/ Mitsubishi CNTO1275 Centocor CCI-779 Wyeth Tovaxin, Opexa PharmaFrontiers Alemtuzumab ILEX Pharma Phase I Biosimilars Injectables Orals Other Courtesy Merck Serono

  17. Immune targets of existing and future MS therapies Courtesy Merck Serono

  18. BG12 M Sandberg 2008-11-13

  19. BG12 • Biogen Idec / Fumapharm • Second generation oral fumarate • First generation used in psoriasis • 50 years of experience in dermatology M Sandbergee 2008-11-13

  20. BG12 • Potential mode of action in MS • promotes T-cell apoptosis • programmed cell death • promotes Th1  Th2 shift • shift from pro-inflammatory to suppressive • activates Nrf2 regulatory pathway • essential for immune homeostasis • regulates myelin maintenance in CNS, implicated as a potential neuroprotective mechanism M Sandberg 2008-11-13

  21. BG12 Phase II study design Blinded placebo-controlled treatment phase Blinded safety-extension phase Screening BG00012 240 mg tid (720 mg/day) Placebon=54 BG00012 120 mg qd (120 mg/day) n=59 Randomization BG00012 120 mg tid (360 mg/day) n=56 n=257 BG00012 240 mg tid (720 mg/day)* n=54 4 8 12 16 20 24 24 weeks 24 weeks *Patients received 120 mg tid during the first week to determine tolerability Kappos L, et al. Lancet. 2008;372:1463-72. qd=once daily; tid=three times daily

  22. BG12 Phase II data: new Gd+ lesions (weeks 12 to 24) Pre-specified primary end point 6 5 4 69%reduction vs. placebo Mean number of new Gd+ lesions 3 P < 0.001 2 1 n=54 n=59 n=56 n=54 0 Placebo 120 mg qd 120 mg tid 240 mg tid Treatment group Kappos L, et al. Lancet. 2008;372:1463-72. Gd+=gadolinium-enhancing; qd=once daily; tid=three times daily

  23. BG12: phase II safety • Common Adverse Events • headache, GI symptoms, flushing • most AEs decreased over time • Serious Adverse Events • similar proportions of patients with SAEs in placebo and BG12 groups • Renal functions/urinalysis tests • no clinically significant findings • Similar low incidence of infections across groups M Sandberg 2008-11-13

  24. BG12:Development programme • DEFINE study • Phase III, Rzd, DB, PLC, 2-yr • PEP: Proportion relapsing patients at 2 yrs • started January 2007 • CONFIRM study • Phase III, Rzd, DB/rater blinded for GA, 2 yrs • PEP: Relapse rate at 2 yrs • started June 2007 M Sandberg 2008-11-13

  25. Laquinimod M Sandberg 2008-11-13

  26. Laquinimod • Active Biotech / TEVA • Laquinimod has been tested in two phase II studies • Crosses blood–brain barrier M Sandberg 2008-11-13

  27. CI OH O N CH2 O N CH3 CH3 Laquinimod • Potential mode of action • a quinoline-3-carboxamide derivative • immunomodulatory by changing dendritic cell response • promotes shift towards Th2 immunity • not immunosuppressive • no effect on T and B cell numbers (mice) • no effect on cytokine secretion (mice) M Sandberg 2008-11-13

  28. Laquinimod • May affect a pivotal pathway of inflammation • Rheumatoid arthritis (CIA) • Type I diabetes (NOD mice) • GuillainBarré Syndrome (EAN) • Inflammatory bowel disease (DSS) • Lupus (NZB/W) • Modulates Th1/Th2 disease specific pro-inflammatory immune responses • Does not affect the ability to mount cellular and humoral immune responses M Sandberg 2008-11-13

  29. Effects of laquinimod on Gd-enhancing T1 lesions 60% reduction in median total number of Gd-T1 lesions (12–36 wks) 51% reduction in mean total number of Gd-T1 lesions (12-36wks; p<0.0001) 40 40 30 30 20 20 10 10 0 0 Mean ± SE Median

  30. Laquinimod: phase IIb safety • Liver enzymes elevated (ALT) • reversible • most normalized while on study drug • no sign of liver failure/damage • Laboratory markers of inflammation • fibrinogen elevated in active treatment groups • all cases reversible while on study drug • Mild reversible arthralgia, arthritis, oedema • Single case of reversible Budd-Chiari syndrome M Sandberg 2008-11-13

  31. Laquinimod: development programme • ALLEGRO study • Phase III, Rzd, DB, PLC, 2-yr • 1,000 RRMS patients worldwide • started September 2007 • BRAVO study • Phase III, Rzd, DB/rater blinded, 2-yr, against Avonex® • 1,200 RRMS patients worldwide • started April 2008 M Sandberg 2008-11-13

  32. Fingolimod (FTY720) M Sandberg 2008-11-13

  33. Fingolimod / FTY720 • Novartis • S1P (sphingosine-1-phosphate) receptor agonist • Original indication • renal allograft rejection • Crosses blood–brain barrier M Sandberg 2008-11-13

  34. HO FTY720 NH2 Fingolimod • Potentional mode of action in MS • blocks lymphocyte egress from secondary lymphoid organs • has no effect on innate immunity (NK cells, monocytes) • is vasoprotective • enhances myelination and axonal protection, increases oligodendrocyte numbers, activates S1P receptors on astrocytes, stimulates astrocyte migration M Sandberg 2008-11-13

  35. Fingolimod: phase II study • Phase II, Rzd, DB, PLC, 6-month trial • placebo, 1.25 mg, 5 mg • At 6 mths, plc group was randomized • to 1.25 mg or 5 mg • and followed for 24 mths M Sandberg 2008-11-13

  36. Total cumulative number of Gd+ lesions over 6 monthsprimary end point p=0.212 1.25mg vs 5.0mg ECTRIMS 2006

  37. Mean annualized relapse ratemonths 0-6 ECTRIMS 2006

  38. Fingolimod: safety • In phase II most common side effects • nasopharyngitis, dyspnoea, headache, diarrhoea, nausea • Other side effects • bradycardia, deteriorating lung function • retinopathy, macular oedema • skin cancer • In phase III: two fatal infections • one case of Herpes simplex encephalitis • one case of disseminated Varicella zoster M Sandberg 2008-11-13

  39. Fingolimod: development programme • FREEDOMS I • Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg,1.25 mg, plc) • 1250 patients worldwide (not USA) • started January 2006 • FREEDOMS II • Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg, 1.25 mg, plc) • 960 patients in USA • started June 2006 • TRANSFORMS • Phase III, Rzd, Avonex®-controlled, 12 months (0.5 mg, 1.25 mg, Avonex®) • 1275 patients worldwide • started May 2006 M Sandberg 2008-11-13

  40. Cladribine M Sandberg 2008-11-13

  41. Cladribine • Merck Serono • Synthetic purine nucleoside analogue • 2-chloro-2’-deoxyadenosine (2-CdA) • Original indication • lymphocyte malignancies • Crosses the blood–brain barrier M Sandberg 2008-11-13

  42. Cladribine C10H12CIN5O3 MWt = 285.69 • Mode of action • preferential depletion of CD4+ rather than CD8+ T cells • relative sparing of other haematological and immune cells • reduction of pro-inflammatory chemokinesCCL5 and CXCL8 • Differs from other agents affecting purine metabolism • cytotoxic to both actively dividing and resting cells M Sandberg 2008-11-13

  43. Cladribine: trials • Early studies in MS: parenteral • few patients • relatively short trials • Ongoing studies in MS: oral • many patients • longer trials • Registry for long-term follow up in place M Sandberg 2008-11-13

  44. Cladribine: safety • Ongoing studies – no safety signals to date • Possible risks • severe infections • due to lymphocyte depletion • malignancies • due to agent being mutagenic • myelodysplasia • due to effect on haematologic parameters M Sandberg 2008-11-13

  45. Cladribine: development programme • CLARITY study • Phase III, Rzd, DB, PLC, 2-yr, monotherapy in RRMS, 1327 patients • LastPatientLastVisit in November 2008 • extension study is underway • ONWARD study • Phase IIb, Rzd, DB, 2-yr, cladribine add-on in ‘active’ RRMS • ORACLE study • Phase III, Rzd, DB, 2-yr, disease modification study in CIS • approx 650 patients M Sandberg 2008-11-13

  46. Teriflunomide M Sandberg 2008-11-13

  47. Teriflunomide • sanofi aventis • Active metabolite of leflunomide (ARAVA) • ARAVA indicated for rheumatoid arthritis since 1998 M Sandberg 2008-11-13

  48. O CF3 N C C C N H C HO CH3 Teriflunomide • Potential mode of action in MS • inhibits DHODH, a key enzyme needed for de novo pyrimidine synthesis • mediates a cytostatic effect on B and T cells, but B cells are more sensitive than T cells • both anti-proliferative and anti-inflammatory • Vital salvage pathways are preserved allowing for generalized immune surveillance M Sandberg 2008-11-13

  49. (n=61) Placebo Teriflunomide 7 mg (n=61) Teriflunomide 14 mg (n=57) W - 4 Phase II study: Schematic design Randomization (n=179) Screening Observation (n=207) (n=160) W 0 W 36 W 42 * * * * * * * * * * *MRI scans were performed at screening (x2), every 6 weeks throughout treatment and at follow-up Courtesy sanofi-aventis

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