Oral Medications Being developed for MS.

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Oral Medicines Being developed for MS EMSP Data Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim on the off chance that you get MS… you will have an incessant ailment with obscure cause unverifiable visualization inadmissible medications and you are one of ~500,000 Europeans in the event that you get MS…
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Oral Treatments in Development for MS EMSP Information Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim

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in the event that you get MS… you will have an interminable illness with obscure reason dubious anticipation unsuitable medicines and you are one of ~500,000 Europeans M Sandberg 2008-11-13

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in the event that you get MS… you are 20 - 30 years of age have begun on your education… have any desires for a stupendous career… have met the adoration for your life… have started to consider having a family… M Sandberg 2008-11-13

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in the event that you get MS… At this a great time, you would prefer not to hear that you have a ceaseless sickness that the treatment includes every day or week by week infusions but then , your future is questionable M Sandberg 2008-11-13

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So, what is MS ? MS is an immune system illness Our invulnerable framework arrives to shield us against what is ”foreign” for occurrence infection, microorganisms however it must endure ”self” our own particular tissues and organs M Sandberg 2008-11-13

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CNS is under reconnaissance of the insusceptible framework Under ordinary circumstances white platelets course through and review tissues and organs on the off chance that they don\'t experience anything ”foreign”, they come back to the flow Sometimes a white platelet will erroneously perceive a ”self” atom as outside This will prompt an immune system response in the CNS (mind and spinal line) the outcome will be ranges of aggravation - MS M Sandberg 2008-11-13

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Danger Signal or Trigger T enactment, separation, clonal extension T grip T transmigration T B APC T IFN- antibodies neighborhood reactivation APC M  Release of cytokines Recruitment of M  T TNF- NO MS as an Autoimmune T-cell Mediated Process autoreactive T - cells T fringe Blood-cerebrum boundary CNS Demyelination and axon misfortune Courtesy sanofi-aventis

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Why treat MS ahead of schedule with DMTs The sickness is clinically verbose BUT the malady procedure is progressing and degenerative Permanent harm (i.e. loss of axons and neurons) is an early and dynamic occasion Trapp et al, NEJM 1998;338;278-285 Fromann (1878), from the outskirt of a cerebellar injury

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From left to right Normal axon Demyelinated axon Transected axon Neuronal demise MS Forum, 1999 M Sandberg 2008-11-13

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Slowing the early ailment course may adjust long haul result Long Term Follow Up Natural history: half of patients have dynamic MS following 14 years PRISMS-study, IFN β 1a sc: <20% have dynamic MS following 14 years BENEFIT-study, IFN β 1b sc, 5-year postliminary: treatment from first assault contrasted with up to 2 yrs later defers gathering of handicap for year and a half M Sandberg 2008-11-13

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DMTs today First line treatment Interferon β 1b subcutaneous infusions once every other day Interferon β 1a intramuscular infusions once week by week subcutaneous infusions thrice week by week Glatiramer acetic acid derivation subcutaneous infusions once day by day Safety: no issues following 10-15 years M Sandberg 2008-11-13

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IFN β and GA 2-year information Relapse rate/year T2 dynamic injuries/patient/filter p 0.0001 0.04 <0.0001 0.055 (0.007*) *ANCOVA Reduces backslide recurrence by ~30% p < 0.009 ? <0.0001 Reduces MRI movement by up to 90%

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DMTs today Second line treatment natalizumab intravenous infusions once month to month wellbeing issues encephalitis (PML) liver harm M Sandberg 2008-11-13

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Placebo n=315 TYSABRI n=627 Over 3 years Natalizumab Efficacy Reduces danger of movement by 42% (3 month supported 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 backslide rate (95% CI) 0.4 0.3 0.1 TYSABRI 17% 0.2 0.27 0.23 0.1 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 record. Clinical study report. C – 1808. Cambridge, MA: Biogen Idec, Inc.; 2006 . Polman CH, et al. N Engl J Med . 2006;354:899-910 .

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Oral treatments being developed M Sandberg 2008-11-13

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CDP-323 Celltech Group MLN3697 Millennium/sanofi-aventis Dronabinol Unimed Pharma AVE 9897 sanofi-aventis Oral treatments 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

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Immune focuses of existing and future MS treatments Courtesy Merck Serono

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BG12 M Sandberg 2008-11-13

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BG12 Biogen Idec/Fumapharm Second era oral fumarate First era utilized as a part of psoriasis 50 years of involvement in dermatology M Sandbergee 2008-11-13

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BG12 Potential method of activity in MS advances T-cell apoptosis modified cell demise advances Th1  Th2 movement shift from genius provocative to suppressive initiates Nrf2 administrative pathway key for insusceptible homeostasis directs myelin support in CNS, embroiled as a potential neuroprotective system M Sandberg 2008-11-13

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BG12 Phase II study configuration Blinded placebo-controlled treatment stage Blinded wellbeing augmentation stage Screening BG00012 240 mg tid (720 mg/day) Placebo n=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 weeks 24 weeks *Patients got 120 mg tid amid the first week to focus decency Kappos L, et al. Lancet. 2008;372:1463-72. qd=once every day; tid=three times day by day

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BG12 Phase II information: new Gd+ injuries (weeks 12 to 24) Pre-determined essential end point 6 5 4 69% decrease versus placebo Mean number of new Gd+ sores 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 bunch Kappos L, et al. Lancet. 2008;372:1463-72. Gd+=gadolinium-upgrading; qd=once day by day; tid=three times day by day

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BG12: stage II wellbeing Common Adverse Events cerebral pain, GI manifestations, flushing most AEs diminished after some time Serious Adverse Events comparative extents of patients with SAEs in placebo and BG12 bunches Renal capacities/urinalysis tests no clinically noteworthy discoveries Similar low rate of contaminations crosswise over gatherings M Sandberg 2008-11-13

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BG12: Development system DEFINE study Phase III, Rzd, DB, PLC, 2-yr PEP: Proportion backsliding patients at 2 yrs began January 2007 CONFIRM study Phase III, Rzd, DB/rater blinded for GA , 2 yrs PEP: Relapse rate at 2 yrs began June 2007 M Sandberg 2008-11-13

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Laquinimod M Sandberg 2008-11-13

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Laquinimod Active Biotech/TEVA Laquinimod has been tried in two stage II studies Crosses blood –brain boundary M Sandberg 2008-11-13

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CI OH O N CH 2 O N CH 3 CH 3 Laquinimod Potential method of activity a quinoline-3-carboxamide subsidiary immunomodulatory by changing dendritic cell reaction advances shift towards Th2 invulnerability not immunosuppressive no impact on T and B cell numbers (mice) no impact on cytokine emission (mice) M Sandberg 2008-11-13

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Laquinimod May influence a vital pathway of aggravation Rheumatoid joint pain (CIA) Type I diabetes (NOD mice) Guillain Barrã© Syndrome (EAN) Inflammatory b owel sickness (DSS) Lupus (NZB/W) Modulates Th1/Th2 ailment particular professional incendiary resistant reactions Does not influence the capacity to mount cell and humoral insusceptible reactions M Sandberg 2008-11-13

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Effects of laquinimod on Gd-improving T1 injuries 60% lessening in middle aggregate number of Gd-T1 sores (12–36 wks) 51% decrease in mean aggregate number of Gd-T1 sores (12-36wks; p<0.0001) 40 30 20 10 0 Mean ± SE Median

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Laquinimod: stage IIb security Liver proteins lifted (ALT) reversible most standardized while on study medicate no indication of liver disappointment/harm Laboratory markers of irritation fibrinogen raised in dynamic treatment assembles all cases reversible while on study drug Mild reversible arthralgia, joint inflammation, oedema Single instance of reversible Budd-Chiari disorder M Sandberg 2008-11-13

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Laquinimod: improvement program ALLEGRO study Phase III, Rzd, DB, PLC, 2-yr 1,000 RRMS patients overall began September 2007 BRAVO study Phase III, Rzd, DB/rater blinded, 2-yr, against Avonex ® 1,200 RRMS patients overall began April 2008 M Sandberg 2008-11-13

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Fingolimod (FTY720) M Sandberg 2008-11-13

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Fingolimod/FTY720 Novartis S1P (sphingosine-1-phosphate) receptor agonist Original sign renal allograft dismissal Crosses blood–brain obstruction M Sandberg 2008-11-13

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HO FTY720 NH 2 Fingolimod Potentional method of activity in MS pieces lymphocyte departure from auxiliary lymphoid organs has no impact on inherent insusceptibility (NK cells, monocytes) is vasoprotective improves myelination and axonal insurance , expands oligode

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