Abstract: 233
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Prior Phase III studies of laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS) show a substantially larger effect of the drug on disability progression than predicted by its effect on relapses, suggesting a potentially different mechanism of action and efficacy profile from other disease-modifying therapies.
Objective: To evaluate the efficacy, safety, and tolerability of laquinimod versus placebo in patients with RRMS.
Methods: A randomized, double-blind, placebo-controlled, Phase III study (CONCERTO) was conducted in patients with RRMS. Key inclusion criteria included age of 18-55 years, Expanded Disability Status Scale score of 0-5.5 at screening and randomization, and ≥1 relapse in the 12 months before randomization. Patients were randomized 1:1:1 to receive oral laquinimod 0.6 mg or 1.2 mg or placebo once daily. The primary endpoint was time to 3-month confirmed disability progression (CDP). The primary and secondary endpoints were evaluated using a predefined, conditional, hierarchical statistical testing procedure. The laquinimod 1.2 mg dose arm was discontinued (1 January 2016) due to findings of cardiovascular events at high doses in CONCERTO and in ARPEGGIO, an ongoing Phase II study of laquinimod in primary progressive MS. Safety was monitored throughout the study.
Results: Patients (N=2199) were randomized to receive laquinimod 0.6 mg (n=727) or 1.2 mg (n=732) or placebo (n=740). CONCERTO did not meet the primary endpoint of significant treatment effect on 3-month CDP (hazard ratio, 0.94; 95% confidence interval, 0.67 to 1.31; P=0.71). Therefore, P values for secondary endpoints were nominal and noninferential. Laquinimod 0.6 mg demonstrated 40% reduction in the percent brain volume change from baseline to Month 15 versus placebo (P< 0.0001). The risk for first relapse was significantly reduced by 28% and annualized relapse rate was significantly reduced by 25% with laquinimod 0.6 mg versus placebo (both P=0.0001). As with the primary endpoint, secondary endpoints of 6- or 9-month CDP did not show treatment effect. The clinical safety profile of laquinimod 0.6 mg, which was previously studied with >12,000 patient-years of exposure, was confirmed in CONCERTO.
Conclusion: While CONCERTO did not meet the primary endpoint of time to 3-month CDP, laquinimod 0.6 mg demonstrated a nominally significant effect on reducing brain volume loss and clinical relapses, and was generally well tolerated in patients with RRMS.
Disclosure: Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Serono Symposia International Foundation, Almirall, Chugai, and Receptos.
Timothy Vollmer has received consulting fees, and his institution has received a grant and consulting fee, for his participation in the BRAVO study. He is the Medical Director for the Rocky Mountain MS Center; he or his institution has received consultancy fees from Biogen Idec, Teva Pharmaceutical Industries, Hoffman-LaRoche, Accelerated Cure Project, Genzyme, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received grants from Teva Pharmaceutical Industries, Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Serono, Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research, Janssen Pharmaceutical, MedImmune, Delta Quest, and Genentech. He is co-holder of a patent with Teva Pharmaceutical Industries.
Alexey Boyko has received compensation for serving on Advisory Boards and participating in clinical trials from Bayer Schering, Merck Serono, Teva Pharmaceutical Industries, Novartis, Biogen, Genzyme, Sanofi Aventis, and Takeda.
Patrick Vermersch received honoraria and consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Teva, Merck-Serono, Roche, Servier, Medday and Almirall; and research support from Biogen, Bayer, Novartis, Sanofi-Genzyme, Roche and Merck-Serono.
Tjalf Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support from: Almirall, Bayer, Biogen, Genzyme,
Merck, Novartis, Roche, Sanofi, and Teva Pharmaceutical Industries.
Xavier Montalban has received honoraria for speaking and travel expenses to scientific meetings and is a steering committee member or has participated in advisory boards for clinical trials or has had consulting agreements with Almirall, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, GeNeuro, Genzyme, GSK, Neurotec, Novartis, Roche, Sanofi-Aventis, and Teva Pharmaceutical Industries.
Fred D. Lublin has received compensation for activities such as consulting, Advisory Boards, and data and safety monitoring boards from Bayer Healthcare, Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Genentech, Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Bristol-Myers Squibb, Xenoport, Receptos, Forward Pharma, Osmotica, NIH, and NMSS, and has received compensation from Elsevier for serving as co-Chief Editor of Multiple Sclerosis and Related Disorders.
Nissim Sasson is an employee of Teva Pharmaceutical Industries and owns stock in Teva Pharmaceutical Industries.
Yuval Dadon is an employee of Teva Pharmaceutical Industries and owns stock in Teva Pharmaceutical Industries.
Joshua R. Steinerman is an employee of Teva Pharmaceutical Industries.
Volker Knappertz is a former employee of Teva Pharmaceutical Industries, owns stock in Teva Pharmaceutical Industries, and is a co-holder of patents with Teva Pharmaceutical Industries.
Abstract: 233
Type: Oral
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: Prior Phase III studies of laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS) show a substantially larger effect of the drug on disability progression than predicted by its effect on relapses, suggesting a potentially different mechanism of action and efficacy profile from other disease-modifying therapies.
Objective: To evaluate the efficacy, safety, and tolerability of laquinimod versus placebo in patients with RRMS.
Methods: A randomized, double-blind, placebo-controlled, Phase III study (CONCERTO) was conducted in patients with RRMS. Key inclusion criteria included age of 18-55 years, Expanded Disability Status Scale score of 0-5.5 at screening and randomization, and ≥1 relapse in the 12 months before randomization. Patients were randomized 1:1:1 to receive oral laquinimod 0.6 mg or 1.2 mg or placebo once daily. The primary endpoint was time to 3-month confirmed disability progression (CDP). The primary and secondary endpoints were evaluated using a predefined, conditional, hierarchical statistical testing procedure. The laquinimod 1.2 mg dose arm was discontinued (1 January 2016) due to findings of cardiovascular events at high doses in CONCERTO and in ARPEGGIO, an ongoing Phase II study of laquinimod in primary progressive MS. Safety was monitored throughout the study.
Results: Patients (N=2199) were randomized to receive laquinimod 0.6 mg (n=727) or 1.2 mg (n=732) or placebo (n=740). CONCERTO did not meet the primary endpoint of significant treatment effect on 3-month CDP (hazard ratio, 0.94; 95% confidence interval, 0.67 to 1.31; P=0.71). Therefore, P values for secondary endpoints were nominal and noninferential. Laquinimod 0.6 mg demonstrated 40% reduction in the percent brain volume change from baseline to Month 15 versus placebo (P< 0.0001). The risk for first relapse was significantly reduced by 28% and annualized relapse rate was significantly reduced by 25% with laquinimod 0.6 mg versus placebo (both P=0.0001). As with the primary endpoint, secondary endpoints of 6- or 9-month CDP did not show treatment effect. The clinical safety profile of laquinimod 0.6 mg, which was previously studied with >12,000 patient-years of exposure, was confirmed in CONCERTO.
Conclusion: While CONCERTO did not meet the primary endpoint of time to 3-month CDP, laquinimod 0.6 mg demonstrated a nominally significant effect on reducing brain volume loss and clinical relapses, and was generally well tolerated in patients with RRMS.
Disclosure: Giancarlo Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries, Sanofi, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Serono Symposia International Foundation, Almirall, Chugai, and Receptos.
Timothy Vollmer has received consulting fees, and his institution has received a grant and consulting fee, for his participation in the BRAVO study. He is the Medical Director for the Rocky Mountain MS Center; he or his institution has received consultancy fees from Biogen Idec, Teva Pharmaceutical Industries, Hoffman-LaRoche, Accelerated Cure Project, Genzyme, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received grants from Teva Pharmaceutical Industries, Biogen Idec, Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Serono, Accelerated Cure Project, Hoffmann-LaRoche, Jensen Research, Janssen Pharmaceutical, MedImmune, Delta Quest, and Genentech. He is co-holder of a patent with Teva Pharmaceutical Industries.
Alexey Boyko has received compensation for serving on Advisory Boards and participating in clinical trials from Bayer Schering, Merck Serono, Teva Pharmaceutical Industries, Novartis, Biogen, Genzyme, Sanofi Aventis, and Takeda.
Patrick Vermersch received honoraria and consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Teva, Merck-Serono, Roche, Servier, Medday and Almirall; and research support from Biogen, Bayer, Novartis, Sanofi-Genzyme, Roche and Merck-Serono.
Tjalf Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support from: Almirall, Bayer, Biogen, Genzyme,
Merck, Novartis, Roche, Sanofi, and Teva Pharmaceutical Industries.
Xavier Montalban has received honoraria for speaking and travel expenses to scientific meetings and is a steering committee member or has participated in advisory boards for clinical trials or has had consulting agreements with Almirall, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, GeNeuro, Genzyme, GSK, Neurotec, Novartis, Roche, Sanofi-Aventis, and Teva Pharmaceutical Industries.
Fred D. Lublin has received compensation for activities such as consulting, Advisory Boards, and data and safety monitoring boards from Bayer Healthcare, Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Genentech, Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Bristol-Myers Squibb, Xenoport, Receptos, Forward Pharma, Osmotica, NIH, and NMSS, and has received compensation from Elsevier for serving as co-Chief Editor of Multiple Sclerosis and Related Disorders.
Nissim Sasson is an employee of Teva Pharmaceutical Industries and owns stock in Teva Pharmaceutical Industries.
Yuval Dadon is an employee of Teva Pharmaceutical Industries and owns stock in Teva Pharmaceutical Industries.
Joshua R. Steinerman is an employee of Teva Pharmaceutical Industries.
Volker Knappertz is a former employee of Teva Pharmaceutical Industries, owns stock in Teva Pharmaceutical Industries, and is a co-holder of patents with Teva Pharmaceutical Industries.