title: 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.
authors.affiliation: Knopp Biosciences LLC , Pittsburgh, Pennsylvania , USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bozik
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Brooks
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Rudnicki
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Albert
authors.initials: A
authors.lastname: Ludolph
authors.forename: Merit E
authors.initials: ME
authors.lastname: Cudkowicz
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: James
authors.initials: J
authors.lastname: Mather
authors.forename: Thomas
authors.initials: T
authors.lastname: Petzinger
authors.forename: Donald
authors.initials: D
authors.lastname: Archibald
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D003404:Creatinine / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011433:Propranolol / Q000627:therapeutic use*; D019782:Riluzole / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D018696:Neuroprotective Agents; D019782:Riluzole; D011433:Propranolol; D003404:Creatinine
keywords: Clinical trials; biomarker; mitochondria; risk; therapy