Oral MS therapies. Ralf Gold Neurologische Klinik St. Josef Hospital, Klinikum der Ruhr-Universität Bochum

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1 Oral M therapies Ralf Gold Neurologische Klinik t. Josef Hospital, Klinikum der Ruhr-Universität Bochum

2 Fumaric acid (BG-) Natalizumab Cladribine eriflunomide Oral fingolimod Alemtuzumab Laquinimod Oral fingolimod Daclizumab Rituximab APC, antigen presenting cell; BBB, blood brain barrier; IFN, interferon; NF, tumour necrosis factor; CN, central nervous system; 1P-R, sphingosine-1-phosphate receptor Linker/Gold, rends Pharmacol ci 0

3 Novel ideas/risks s s on the therapeutic horizon? promises and drawbacks the ysabri story recent data on novel oral therapeutics and how they can be interpreted

4 a) b) c) d) e) f)

5 Natalizumab PML Incidence Estimates by reatment Duration per 0 00 patie ents Inc cidence 3,0 2, 2,0 1, 1,0 0, 00 0,0 Clinical rials* 0 2,0 2 2, 2,43 2, 2,0 1,0 1, 1, 1,3 1, 1,42 1,40 1, 1, 1, 0 1,00 1,0 0 1,00 0,0 0,0 0,0 0,4 0, Post Marketing >= Infusions >= Infusions >= Infusions >=30 Infusions >=3 Infusions >= 42 Infusions 1,34 *Yousry A, et al. N Engl J Med. 0;34:-33. Observed clinical trial rate in patients who received a mean of. monthly doses of natalizumab Incidence estimates by treatment duration are calculated based on YABRI exposure through August 31, and confirmed cases as of eptember 2,. he incidence for each time period is calculated as the number of PML cases divided by the number of patients exposed to YABRI (e.g. for infusions all PML cases diagnosed with exposure of infusions or more divided by the total number of patients exposed to at least infusions).

6 Confidential, not for distribution

7 Novel ideas/risks s s on the therapeutic horizon? promises and drawbacks the ysabri story recent data on novel therapeutics and how they can be interpreted

8 Cladribine takes advantage of lymphocyte- specific enzyme repertoire features Cl ADA Cl ADA highest activity in lymphoid cells (proliferation, maturation, function) -N deoxynucleotidase ('-nucleotidase), high expression in most tissues, low expression in lymphocytes

9 herapy regimen: annual short cycles total dosage 3. mg/kg (. mg/kg) e.g. patient kg, tablets/ cycle Erstes Jahr (4 W.): 2 herapiezyklen ( ) Zweites Jahr (4 W.): für Hochdosis weitere 2 ( ) 2 ( ) herapiezyklen herapiezyklen in den Folgemonaten M W 2 M 2 M 2 M F M W F W W 2 W F M W F M 2 M W F M W F M W F W F M W F M W F M W F M W F F 3 M W F M W F M W F M W F M W F F M W F M W F M W F M W F M W F Jeder Zyklus = 0. mg/kg, 1 oder 2 abletten ( mg), 1 mal täglich, für 4 oder Folgetage im Jahr

10 Cladribine in RRM CLARIY extension CLARIY study (43) Extension to CLARIY study () Placebo wo courses of cladribine per year Placebo creening Patients with RRM randomized (1:1:1) (n=2) wo courses of cladribine per year wo courses of cladribine per year Placebo Four courses (then two courses) of cladribine wo courses of cladribine per year 4 tudy Day Weeks wo courses X X X X X X X X X X Four courses (then two courses) X X X X X X X X X X X Placebo X Cladribine Giovannoni G et al. AAN 0. (LB001)

11 CLARIY Primary endpoint Rate Annualized Relapse p< p< ide effects: increase of cancer cases (pancreas, 0.2 ovarian..in several patients of Clad group register?) 0 0. % % Low High Placebo

12 Confidential, not for distribution ignificant reduction of MRI lesion load (sec. endpoint, I) 1 Gd+ lesions active 2 lesions Combined active lesions(cu).%*.%*.%* 2.0.%* %* %* *p< *p< *p<0.001 Lesions/P Patient/can n Placebo mg/kg mg/kg Placebo Placebo mg/kg mg/kg mg/kg mg/kg Giovannoni G et al. AAN 0. (LB001)

13 Mechanism of action of oral fingolimod Oral fingolimod is the lead compound in a novel class of drugs for the treatment e t of M It targets the disease via actions in both the immune system and CN, modulating sphingosine-1-phosphate receptors on lymphocytes and neural cells CN, central nervous system; M, multiple sclerosis

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15 ide effects: 2 patients in 1. mg group with herpes encephalitis or zoster sepsis. Melanoma?

16 RANFORM M-activity in MRI Number of new/enlarged 2- lesions after months Number of Gd+ 1-lesions after months t Mittelwert 2, p=0, p=0,01 01 vs. IFN -1a vs. IFN -1a 2,0 1, 1,0 0, 0 2,1 1, 1,4 Mittelwert 0 0, p<0,0004 p<0, , vs. IFN -1a vs. IFN -1a 0,4 0,3 0,2 0,1 Approval UA at..: Baseline and escalation! IFN -1a i.m. (n=3) Fingolimod Fingolimod 0. 0, mg mg (n (n=30) = 30) Fingolimod Fingolimod 1. 1, mg mg (n (n=3) = 3) 0,1 0 IFN -1a i.m. (n=34) 0, Fingolimod Fingolimod 0. mg 0, mg (n = 34) (n=34) 0, Fingolimod 1, mg (n=32) Analyse von eilnehmern mit verwertbaren MR-cans; Cohen et al. N Engl J Med ;./NEJMoa003.

17 Fumarate = BG000 Basic Facts O O O O DMF (BG000) OH O O O MMF OH O O OH Fumarate C CONFIDENIAL. NO O BE DIEMINAED, COPIED OR MODIFIED.

18 Nrf2 signalling mediates cellular protection RO, Electrophiles, etc. Keap1 Nrf2 Keap1 Nrf2 Nrf2 - Detox Enzymes - Antioxidant Enzymes - NADPH Generating Enzymes - GH Biosynthesis Enzymes - Chaperones - Ubiquitination/Proteasome Maf ide effects: flushing, rare Jun gastrointestinal side effects; AF4 More than patient years in psoriasis Keap1 ARE Nucleus - Detoxification - Normalization of energy metabolism - Repair/degradation of damaged proteins

19 Fumarates protect against oxidative cell death AROCYE LIVING DEAD R. Linker, D. Lee..R.Gold In revision ZN-level: 3µM

20 Laquinimod Laquinimod is a new oral available substance for the treatment of Relapsing- Remitting Multiple clerosis (RRM). In Phase Iia study (n=) in RRM patients: Laquinimod 0.1 mg/day vs. Laquinimod 0.3 mg/day vs. Placebo or Phase IIb study (n=30) in RRM : Laquinimod 0.3 mg/day vs. Laquinimod 0. mg/day vs. Placebo, over 3 weeks, over weeks.: about 4% reduction of Gd-enhancement he exact mechanisms of action of laquinimod are yet not fully elucidated.

21 Phase IIb and Extension results: Laquinimod reduces 1 Gd positive M lesions Primary end point weeks mg vs. Placebo p < Laquinimod 0.3 mg Laquinimod 0. mg Placebo Comi et al. Lancet 0, Multiple clerosis

22 Phase IIb sera: Laquinimod increases BDNF (hoene Linker Gold AAN, Paper in prep)

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24 see late breakers session on aturday for phase III trials

25 Multiple l clerosis - there is no cure for this heterogeneous syndrome on the horizon - novel oral immunotherapies with novel risks: here is no free lunch - recent progress: - neuroprotection and antioxidative mechanisms CONFIDENIAL. NO O BE DIEMINAED, COPIED OR MODIFIED.