Reduction in the Annualized Relapse Rate
Future therapies
Jerry S. Wolinsky, MD Bartels Family and Opal C. Rankin Professor of Neurology University of Texas Health Science Center at Houston Course of Relapsing MS
SPMS
atrophy
Failure of Repair, disability Compensation and Concomitant Pathologies T2 burden Late RR black holes Inflammatory Phase Early RR CIS Subclinical (RIS)
Gd Occurrence, or Severity Occurrence, Extent, Time Schoonheim et al. Neurology 74:1246, 2010 Current Disease Modifying Drugs: US Registration
CDA po
FTY po qd Annualized Relapse Rates: Proportional Treatment Effects 1.4 1992 – 2001 2002 - 2008
1.2 43.3% ▼ 57% ▼ 1.0 0.8 0.6 0.4 0.2
0.0 Annualized Relapse Rate Relapse Annualized
Relative Risk: Current Disease Modifying Drugs
MTZ NTZ
FTY Warning – Not approved for CME
semi-evidence based – with multipleIFN βcaveats GA hd IFNβ
ld Increased Relative Efficacy Relapses Efficacy Relative Increased
Increased Relative Safety Teriflunomide [Z]-2-cyano-3-hydroxy-but-2-enoic acid – [4’-trifluoromethyl-phenyl]-amide an inhibitor of pyrimidine synthesis primary metabolite of leflunomide
Teriflunomide - MOA o Teriflunomide selectively and reversibly inhibits the mitochondrial enzyme DHO-DH, required for de novo pyrimidine synthesis o Teriflunomide blocks the activation and proliferation of stimulated lymphocytes which require de novo synthesis of pyrimidine to expand o Slowly dividing or resting cells which rely on the salvage pathway for pyrimidine synthesis are DHODH = dihydroorotate dehydrogenase relatively unaffected by teriflunomide
Gold and Wolinsky, Acta Neurol Scand 124:75, 2011 Teriflunomide: Phase 3 - placebo controlled
O’Connor et al. NEJM 365:1293, 2011
Teriflunomide: Phase 3 - placebo controlled
O’Connor et al. NEJM 365:1293, 2011
Teriflunomide: Phase 2 – adjunct trials 6 month Safety Pilot
Freedman et al. MS 15:S273, 2009 Teriflunomide: Phase 2 – adjuncts 6 month Safety Pilots
IFNβ base GA base
Freedman et al. MS 15:S273, 2009; Neurology 74(S2):A293, 2010 Teriflunomide - Risks
nasopharyngitis upper respiratory tract infections alopecia liver enzyme increases pregnancy category D contraception controls for females and males Teriflunomide – in progress
Monotherapy
Extension Phase II POCa
TEMSO: RMS / placebo study Extension of TEMSO
TOWER: RMS / placebo studyb 2012 TENERE: RMS / vs IFN-βb 2011 TOPIC: CIS study vs placebo 2015
Phase II IFN Adjunctive TERACLES with IFNs 2014 therapy in RMS Phase II GA
Phase II extension September 2011 Fumarate (BG00012) dimethyl fumarate activates the nuclear-factor-E2-related factor-2 (Nrf2) transcriptional pathway that controls phase-2 detoxifying enzyme gene expression inhibits cytokines and adhesion molecule expression and neuroprotective effects
Fumarate: Phase 2 – 24 weeks with extension November 2004 – May 2006
Kappos et al. Lancet 372:1463, 2008 Fumarate: Phase 2 – 24 weeks with extension November 2004 – May 2006
MacManus et al, J Neurol 258:449, 2011 Fumarate: Some experimental insight
Linker et al. Brain 134:678, 2011 Fumarate: Phase 3 – 24 weeks with extension BOSTON (Reuters) - Biogen Idec Inc (BIIB.O: Quote, Profile, Research, Stock Buzz) released surprisingly strong results from a clinical trial of its experimental multiple sclerosis drug BG-12 on Thursday (4/21/11), sending its shares up as much as 24 percent to an all-time high.
The Weston, Massachusetts-based biotechnology company said the drug, when given twice a day, cut the annualized relapse rate by 53 percent at two years compared with placebo, and cut the rate of disability progression by 38 percent.
Shares of Teva fell more than 6 percent as BG-12 appears, at least based on initial data, to be more effective than laquinimod. BG-12 cut the annualized relapse rate by 53 percent. Laquinimod cut that rate by 23 percent in its most recently released data. Laquinimod reduced disability progression by 36 percent, less than the 38 percent seen with BG-12.
No direct comparison can be made between the oral drugs since no head-to-head trials have been completed and the full data set for BG-12 has not been compiled. Data from another late-stage trial of the drug is due to be released later this year. Still, if data from the most recent BG-12 trial can be replicated, BG-12 could pose a strong threat to fingolimod, which showed a reduction in annualized relapse rate of about 54 percent.
Fumarate – In progress
NCT00451451: Efficacy and safety study of oral BG00012 with active reference [GA] in RRMS (CONFIRM) - September 2011 NCT01156311: BG00012 phase 2 combination study in patients with multiple sclerosis (EXPLORE) – October 2011 NCT00835770: Long-term safety and efficacy study of oral BG00012 monotherapy in RRMS - June 2013 Laquinimod
linomide related molecule T-lymphocyte regulation (NFB antagonist)
Laquinimod: Phase 2b – placebo controlled March 2005 – July 2006
Comi et al. Lancet 371: 2085, 2008
Laquinimod: Phase 3 – placebo controlled December 2007 – November 2010
0.5 PBO
0.395 0.4 Laq 0.6 mg
0.304 0.3
0.2 23% reduction p = 0.002
0.1 Annualized Relapse Rate Relapse Annualized
0
Comi et al. AAN, 2011
Laquinimod: Phase 3 – placebo controlled December 2007 – November 2010
36% reduction p = 0.012
Placebo
Laquinimod 0.6 mg
Comi et al. AAN, 2011
Laquinimod: Some experimental insight
Hayardeny et al. ECTRIMS, 2010 Laquinimod: Phase 3 – placebo controlled, with active comparator
BioWorld Today AUGUST 2, 2011 Active Biotech AB stock plunged 53.5 percent and partner Teva pharmaceutical Industries Ltd.’s shares took a 6.2 percent hit Monday following their announcement that oral multiple sclerosis (MS) drug laquinimod did not achieve its primary endpoint of reducing the annualized relapse rate (ARR) in the Phase III Bravo trial. Teva explained that results from the Bravo study, the second of two pivotal Phase III laquinimod studies, did not achieve the primary endpoint of reducing the annualized relapse rate (p = 0.075). The company said that while the randomization process for Bravo was adequate, placebo and treatment study groups showed dissimilarity in two baseline magnetic resonance imaging characteristics. Teva added that when the imbalance was corrected “according to a standard and pre- specified sensitivity analysis included within the original statistical analysis plan,” laquinimod did better and demonstrated a significant reduction in the annualized relapse rate (21 .3%, p = 0.026), in the risk of disability progression as measured by Expanded Disability Status Scale (EDSS) (33.5 percent, p = 0.044) and in brain volume loss (27.5 percent, p < 0.0001). Teva said that those Bravo findings are in line with the results of the first laquinimod Phase III trial, Allegro.
Laquinimod – Still in progress
NCT00745615: An open label extension of the LAQ/5062 and LAQ/5063 studies to assess the long term safety and tolerability of laquinimod 0.6mg in RRMS patients - December 2011 NCT00988052: A study to evaluate the long-term safety, tolerability and effect on disease course - November 2012 NCT01047319: A study to evaluate the long-term safety, tolerability and effect of daily oral laquinimod 0.6 mg on disease course in subjects with RRMS - June 2013 Alemtuzumab Anti-CD52 T- and B-lymphocyte depletion
Alemtuzumab: Phase 1- open label April 2002 – March 2007
39 subject ‘aggressive’ relapsing remitting MS cohort
alemtuzumab
Hirst et al. J Neurol 255:231, 2008 Alemtuzumab: Phase 2 - active comparator December 2002 – (September 2005) July 2007
Coles et al. NEJM 359:1786, 2008
Alemtuzumab: Phase 2 - active comparator December 2002 – (September 2005) January 2010
46 (41%) of sq IFNβ-1a and 149 (67%) Alz subjects with 4 to 5 year data
69% relative reduction p < 0.001 50% relative reduction p < 0.001
Coles et al. ECTRIMS, 2011
Alemtuzumab - Risks
Graves’ disease autoimmune hypoythyroidism idiopathic thrombocytopenia purpura Goodpasture’s syndrome antinuclear antibody induction Pityriasis lichenoides chronicus Alemtuzumab: Phase 3 - active comparator July 11, 2011 01:46 AM Eastern Daylight
PARIS--(BUSINESS WIRE)--Sanofi (EURONEXT: SAN and NYSE: SNY) and its subsidiary Genzyme announced today positive top-line results from CARE-MS I, the first of two randomized, Phase 3 clinical trials comparing the investigational drug alemtuzumab to the approved multiple sclerosis therapy high dose subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). Genzyme is developing alemtuzumab in MS in collaboration with Bayer HealthCare. In the CARE-MS I trial, 2 annual cycles of alemtuzumab treatment resulted in a 55 percent reduction in relapse rate compared to interferon beta-1a over the two years of the study (p<0.0001), hence satisfying the first primary endpoint, and therefore meeting the predefined protocol criteria for declaring the study a success. Statistical significance was not achieved for the second primary endpoint, time to six month sustained accumulation of disability, as compared to interferon beta-1a. At the two year time point, 8 percent of alemtuzumab treated patients had a sustained increase in their Expanded Disability Status Scale (EDSS) score (or worsening) as compared to 11 percent of those who received interferon beta-1a (Hazard Ratio=0.70, p=0.22). The patients will have the option to be evaluated over the next 3 years as part of a separate protocol. Alemtuzumab – Still in progress
NCT00548405: Comparison of alemtuzumab and IFNβ-1a sq efficacy in MS, Study Two (CARE-MS II) - September 2011 NCT00930553: An extension protocol for MS Patients who participated in Genzyme-sponsored studies of alemtuzumab - September 2014 Third Wave Disease Modifying Drugs: US Registration Teri po
ALZ iv
BG-12 po
FTY720 po qd
LAQ po Relative Risk:
Increased Relative Efficacy Relapses MTZ
ALZ ThirdWave DiseaseDrugs Modifying
FTY
Increased RelativeSafety NTZ
Teri IFN
hd β
BG IFN 12 l d LAQ
-
β
GA
Relative Risk:
Increased Relative Efficacy Disability MTZ
ALZ ThirdWave DiseaseDrugs Modifying
FTY
Increased RelativeSafety NTZ
Teri IFN
hd β
IFN
BG 12 l d LAQ
β
-
GA
Progressive Disease Fingolimod in PPMS – Fully enrolled Ocrelizumab in PPMS – Enrolling now Mastinib (mast cell tyrosine kinase inhibitor) in PMS – Enrolling now Fumurate in PMS – grapevine Laquinimod in PPMS - grapevine