Project Overview

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, primarily affecting motor neurons, for which there are currently no adequately effective therapies. It is therefore imperative that clinical trials investigating the safety and efficacy of potential therapies be well designed and provide as much critical information as possible to the field. With this in mind, in October we will begin recruiting patients with ALS for a phase Ib/IIa investigator-initiated clinical trial to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral enoxacin, an antibiotic that was previously approved by the FDA. Enoxacin is a small molecule antagonist of DICER, a regulator of miRNAs; previous preclinical work by Dr. Eran Hornstein’s group has shown that enoxacin has the potential to reverse the global downregulation of miRNAs in motor neurons that is observed in patients with ALS. In our trial, patients will be treated with three doses of enoxacin and assessed for safety measures, and the pharmacokinetics and pharmacodynamics of enoxacin will be measured in blood and cerebrospinal fluid samples. Patients currently receiving riluzole are eligible and do not require dose adjustment of riluzole. CYP1A2 is the principal enzyme involved in the mechanism of riluzole, and since enoxacin is a potent inhibitor of CYP1A2, co-administration of both compounds could decrease the rate of riluzole elimination. Given that previous studies of tirasemtiv, a drug that also inhibits CYP1A2, was found to increase riluzole levels when administered to patients on riluzole, prompting a reduction of riluzole dose in subsequent trials, it is critical to determine if enoxacin affects riluzole levels. Furthermore, there is an opportunity for additional exploratory analyses of potential biomarkers in patient samples from the trial that can offer a more comprehensive pharmacodynamic profile of enoxacin. While our trial itself is fully funded, we are lacking funds to complete these additional analyses, which are necessary to fully understand the effects of enoxacin in patients with ALS and to inform the dosing considerations for future trials. Thus, the proposed project aims to (1) determine Riluzole pharmacokinetics in patients with ALS treated with enoxacin, with an emphasis on potential Enoxacin-Riluzole drug-drug interactions, and (2) further evaluate Enoxacin pharmacodynamics with respect to regulation of miRNA levels in patients with ALS in order to provide critical information required for the clinical development of Enoxacin for ALS. The results of these analyses will not only provide evidence around a potential therapy for patients with ALS for the field but will also leverage the existing funding for this trial and lend added value to the study data, by bridging the gap to a possible registrational trial as the next critical step in the clinical development of enoxacin.

Principal Investigator

Angela Genge , McGill University

Team Members

Eran Hornstein, Weizmann Institute of Science

Iddo Magen, Weizmann Institute of Science

Partners and Donors

ALS Canada