A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS

Abstract

Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

Key words::

• Clinical trials
• biomarker
• mitochondria
• therapy
• risk

Acknowledgements

The phase II and phase III dexpramipexole studies were sponsored by Knopp Biosciences and Biogen Idec, respectively. Knopp Biosciences was involved in the design and conduct (collection/analysis of data) of the phase II dexpramipexole trial and Biogen Idec and Knopp Biosciences were involved in the design and conduct (collection/analysis of data) of the EMPOWER trial.

Declaration of interest: MEB, TVP, JM and DA are employees of Knopp Biosciences. HM was a phase II and EMPOWER study investigator and received grants from Avanir, Knopp Biosciences, Biogen Idec, and Cytokinetics for clinical trials and honoraria for participating in advisory board meetings from Avanir, Sanofi-Aventis, Shionogi, and Biogen Idec. He is now a member of the Data Safety Monitoring Board for the NeuralStem clinical trial. He received honoraria from Sanofi-Aventis Japan for giving seminars at the annual meetings of the Japanese Neurological Society in 2009 and 2010. He received a conference grant (to Columbia University) for the 2011 International ALS Conference from the National Institute of Neurological Disorders and Stroke, the National Institutes of Health's Office of Rare Diseases Research, Muscular Dystrophy Association, ALS Association, ALS Society of Canada, Adams Foundation, Ride for Life, ALS Hope Foundation, Les Turner Foundation, Sanofi-Aventis, Biogen Idec, Knopp Biosciences, and Avania.

BB was a phase II and EMPOWER study investigator and a consultant to Knopp Biosciences. SAR was a phase II and EMPOWER study investigator and a consultant to Knopp Biosciences. DHM has been a consultant to Knopp Biosciences. BZ is an employee of MacroStat. AL was an EMPOWER investigator and received consulting fees and travel support from Biogen Idec and Teva Pharmaceuticals, consulting fees from Lundbeck, Knopp Biosciences, GlaxoSmithKline, and Boehringer Ingelheim, and speaker honoraria from Biogen Idec and Merz. MEC was the principal investigator of this study and has received a grant from Biogen Idec for this role. In the past five years she has served as a consultant for Teva Pharmaceuticals, GlaxoSmithKline, Millenium, Synapse (DSMB), Ono (DSMB), Link Medicine, and Trophos (DSMB) and has served on an advisory board for Biogen Idec. LHvdB was a study investigator and has served on an advisory board for Biogen Idec and Cytokinetics and as a consultant for Baxter.

The authors alone are responsible for the content and writing of the paper.