Download Laquinimod For Relapsing Remitting Multiple Sclerosis

Laquinimod, an Oral Product in Development for
the Treatment of Relapsing Remitting Multiple
Sclerosis
Steve Glenski, PharmD
Medical Affairs
Teva Neuroscience
Teva Pharmaceuticals, Inc.
Introduction to Laquinimod
Unique Features of Laquinimod
 Oral Agent
– Once Daily Dosing
 Product of Rational Drug Design
– A novel oral synthetic compound, licensed from Active Biotech
(Lund, Sweden) in September 2004
– A quinoline-3-carboxamide derivative, structurally related to
roquinimex (Linomide) – laquinimod designed to maximize safety
and efficacy
 Immunomodulator, not a general immunosuppressor
 Reduced disease activity in two phase II clinical trials
 Tolerability and safety profile
– No opportunistic infections
– Transient self-limiting elevations in liver enzymes
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Mechanism of Action
 Lack of immunosuppression
 Down-regulation of antigen presenting,
pro-inflammatory, NK and B cell pathway
genes
 Th2 shift
 Decreased IL-17 in splenocytes
 Reduced T cell infiltration
 Independent of IFN-β mode of action
 Prevents demyelination and axonal loss
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Prevention of Demyelination and Axonal Loss
Effect on Demyelination Area
Wegner C, et al. Presented at the 24th Congress of the European Committee for Treatment and Research in Multiple
Sclerosis September 17-20, 2008 Montreal, Canada.
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LAQ/5062 STUDY (PHASE IIb)
Study Design
 Double-blind study
 Duration – 36 weeks
 Patient population – RRMS, with ≥1 enhancing lesions in
screening MRI scan
– Laquinimod 0.6mg – 106 patients
– Laquinimod 0.3mg – 98 patients
– Placebo – 102 patients
 MRI (Gd/T1/T2) performed at weeks 12, 16, 20, 24, 28, 32
and 36
 Safety assessment performed every 4 weeks
Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
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Mean Number of Cumulative Gd
Enhancing Lesions (week 12-36)
51% Reduction (Week 12-36)
(Mean) p < 0.0001
35
30
25
20
15
10
5
0
Median Number of Cumulative Gd
Enhancing Lesions (week 12-36)
Effect of Laquinimod on T1 Gd
Enhancing Lesions
60% Reduction (Week 12-36)
(Median) p < 0.0001
16
14
12
10
8
6
4
2
0
0.3 mg Laquinimod
0.6 mg Laquinimod
Placebo
Adapted from Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
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Laquinimod’s Effect on Annual Relapse Rate
Annualized Relapse Rate
33%
0.9
0.8
0.775
0.759
0.7
0.6
0.522
0.5
0.4
0.3
 Trend (p=0.0978) toward
reduction of annualized
relapse rate
 Study was not powered
to detect a statistical effect
on relapse rate
0.2
0.1
0
0.3 mg Laquinimod
0.6 mg Laquinimod
Placebo
Adapted from Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
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Safety and Tolerability
Data from both Phase IIb Study and its Extension
 No deaths
 No effect on vital signs or ECGs
 Transient self-limiting elevations in liver enzymes
 No opportunistic or life-threatening infections
 Serious Adverse Events:*
– Budd-Chiari Syndrome (n=1): reversible, in a patient with Factor V
Leiden mutation
– Pituitary Adenoma (n=1): incidental MRI finding. Was present
before initiation of study drug. No signs of adenoma on histology
– Liver enzymes elevation (n=1): reversible, without elevations in
bilirubin. Re-appeared in same magnitude 5 months after
laquinimod was stopped
* Assessed as possibly related to study drug in both placebo-controlled and active extension studies
Comi G, et al (LAQ/5062 Study Group). Lancet. 2008;371:2085-92.
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Conclusions
 In the Phase IIb study, an oral, once-daily dose of
Laquinimod 0.6mg has shown:
– A robust, consistent and early effect on MRI disease
activity in RRMS patients
– A trend in reducing the number of relapses (the study
was powered to detect an effect on MRI disease
activity)
– A trend in slowing the progression of brain atrophy
 The effect of Laquinimod 0.6mg on MRI disease activity
was sustained and reproducible in the 36 wks extension
phase of the study
 Good safety profile
 Excellent tolerability
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Clinical Development Plan
Two Phase III Studies
ORAL LAQUINIMOD 0.6 MG OD; 500 RRMS PATIENTS
24 MONTHS OF DOUBLE-BLIND TREATMENT
ORAL MATCHING PLACEBO; 500 RRMS PATIENTS
ENDPOINTS: CONFIRMED RELAPSES, PROGRESSION OF DISABILITY (EDSS), MRI (T1/T2/BH/ BRAIN VOLUME), MSFC
ORAL LAQUINIMOD 0.6 MG OD; 400 RRMS PATIENTS
AVONEX® 30MCG/WEEK; 400 PATIENTS
ORAL MATCHING PLACEBO; 400 RRMS PATIENTS
24 MONTHS OF TREATMENT; DOUBLE BLIND FOR ORAL, RATER BLINDED FOR AVONEX®
ENDPOINTS: RELAPSES, EDSS, MRI (T1/T2/BLACK HOLES, BRAIN VOLUME), MSFC
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Laquinimod Clinical Development Plan
Two Phase III Studies
Enrollment completed Nov 2008
Results expected early 2011
Enrollment completed June 2009
Results expected late 2011
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