A Randomized Placebo-Controlled Phase III Trial of Oral Laquinimod for Multiple Sclerosis Timothy L. Vollmer, MD Professor, Neurology and Neuroscience Co-Director, MS Program University of Colorado Health Science Center Medical Director, Rocky Mountain Multiple Sclerosis Center Aurora, CO Fred D. Lublin, MD Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis The Icahn School of Medicine New York, NY

Laquinimod: Mechanism of Action Specific mechanism of action unknown Anti-inflammatory effects –Modestly inhibits pro-inflammatory T and B cells and promoting Th2 to Th3 switch –Possibly increases number of regulatory T cells –Shifts function of antigen-presenting cells away from an inflammatory response to regulatory response Neuroprotective effects –May increase production brain-derived neurotrophic factor, a neuroprotective cytokine –In mouse model, substantially inhibits cuprizone-induced demyelination by inhibiting activation of pro-inflammatory NF-κB pathway, thereby inhibiting subsequent activation of astrocytes –In autoimmune encephalomyelitis (EAE) models Inhibited progression of disability Preserved myelin and induced remyelination in established disease

BRAVO: Trial Design Phase III trial in relapsing-remitting MS Randomized, parallel-group, placebo-controlled, 24-month trial (N = 1331) 3 study arms (1:1:1) –Laquinimod oral 0.6 mg, once-daily –Matching oral placebo –Interferon β-1a IM 30 µg once-weekly (descriptive comparator) Primary endpoint –Annualized relapse rate at 24 months Secondary endpoints –Percent change in normalized brain volume, baseline to 24 months –3-month sustained disability progression

BRAVO: Key Findings Annualized relapse rate –Laquinimod 0.28; placebo 0.34; interferon β-1a 0.26 –18% reduction with laquinimod vs placebo, P = NS 3-month sustained disability progression –Laquinimod 10%; placebo 13%; interferon β-1a 11% –31.3% reduction with laquinimod vs placebo, P = NS Percent brain volume change –Laquinimod –0.75%; placebo –1.03%; interferon β-1a –1.14% –28% reduction with laquinimod vs placebo, P <.001 Abbreviation: NS, not significant.

BRAVO: Post-Hoc Analyses First post-hoc analysis –To adjust for significantly greater mean T2 lesion volume and higher proportion of patients with gadolinium- enhanced lesions in the laquinimod group vs placebo group –Adjusted annualized relapse rate reduced 21% with laquinimod vs placebo, P =.0264 –Adjusted 3-month sustained disability progression reduced 33.5% with laquinimod vs placebo, P =.044 –Brain volume change consistent with unadjusted analyses Second post-hoc analysis –To adjust for lower-than-anticipated relapse rate in placebo group –Only 48% statistical power to detect a significant laquinimod treatment effect

Laquinimod: Future Outlook in MS Robust effect on brain atrophy –May be more effective in preventing disability progression compared with interferons and glatiramer acetate –Modest effect on focal inflammation-related disease activity Excellent tolerability –Projected simple safety monitoring Probable Class C pregnancy safety rating CONCERTO trial to evaluate higher dose and disability as primary endpoint Attractive candidate for combination therapy with an anti- inflammatory disease-modifying agent –To achieve dual outcome of neuroprotective effect + anti- inflammatory effect –No combination trials pending, however