Emerging Therapies for Multiple Sclerosis Horea Rus MD PhD

Existing Therapies and Emerging Therapies for MS 2005 2006 2007 2010 2011 2012 2013 Orals Injectables BG 12 Oral Fumarate Oral Cladribine Rebif Teriflunomide Betaseron FTY 720 Laquinimod Copaxone Fampridine ambulation indication? SB683699 Avonex IV Novantrone IV Campath Tysabri Rituximab II - RRMS; III - PPMS Generic Mitoxantrone (oncology) (MS) Daclizumab MBP 8298 MLN1202 Filed approved In phase II In phase III

New Oral Therapies

Fingolimod (FTY720) A sphingosine -1-phosphate inhibitor that reversibly sequester lymphocytes to lymph nodes

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

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) Figure 2. 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). P values are for each fingolimod dose as compared with placebo. Kappos L et al. N Engl J Med 2006;355:1124-1140

Fingolimod Clinically asymptomatic elevations of liver enzymes Side effects: Clinically asymptomatic elevations of liver enzymes Initial reduction of the heart rate Modest decrease of forced expiratory volume No serious infections reported

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 1 1275 Novartis has two large-scale, randomised global Phase III studies underway: FREEDOMS and TRANSFORMS. Another study, 2309, has started in the US and is similar in design to FREEDOMS. The purpose of these studies are to evaluate the efficacy and safety of FTY720 in RRMS and permit successful registration and marketing approval throughout the world.

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 From the protocol: Inclusion criteria: Patients who explicitly decline initiation or continuation of treatment with available disease modifying drugs for multiple sclerosis, for whatever reason, after having been informed about their respective benefits and possible adverse events by the investigator.

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

Cladribine It disrupts cellular metabolism, induces DNA damage 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

Cladribine 1290 patients recruited; 10 mg Cladribine vs. placebo for 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

Laquinimod Phase II - 306 patients randomized to either 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.

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

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

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

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.

Phase II Studies of New Oral Multiple Sclerosis Therapies 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 Cladribine (2.1 mg) -90%, P = .001 -51%, NS

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.

MONOCLONAL ANTIBODIES

Monoclonal antibody production. From: The Neurologist 2006;12, 171

Chimeric and humanized monoclonal antibody From: The Neurologist 2006;12, 171

Alemtuzumab -334 patients, -3 year data were reported at ECTRIMS 2007 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

Alemtuzumab in multiple sclerosis Humanized monoclonal antibody against CD 52 From: The Neurologist 2006;12, 171

Alemtuzumab 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

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

T. Ito, H. Rus 2007

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

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.

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

Existing Therapies and Emerging Therapies for MS 2005 2006 2007 2010 2011 2012 2013 Orals Injectables BG 12 Oral Fumarate Oral Cladribine Rebif Teriflunomide Betaseron FTY 720 Laquinimod Copaxone Fampridine ambulation indication? SB683699 Avonex IV Novantrone IV Campath Tysabri Rituximab II - RRMS; III - PPMS Generic Mitoxantrone (oncology) (MS) Daclizumab MBP 8298 MLN1202 Filed approved In phase II In phase III