A Study to Assess the Safety, Tolerability, and Pharmacology of Darifenacin in Patients With ALS

Overview

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterized by selective death of upper and lower motor neurons, which leads to severe disability and fatal outcomes. One of the major hallmarks of ALS is the denervation of neuromuscular junctions (NMJs), which is one of the earliest events seen in ALS patients and mouse models of ALS. Under healthy conditions, glial cells called Perisynaptic Schwann Cells (PSCs) have a key role in regulating the stability and maintenance of NMJs, but they only participate in NMJ repair once denervation occurs. Denervation and the subsequent decline in synaptic activity triggers a loss of muscarinic acetylcholine receptors (mAChRs) in the PSC, and the resulting decrease in mAChR-mediated gene expression drives the "repair mode" of the PSC. In assessing the NMJ under conditions of ALS, a scarcity of process extensions in PSCs was observed for months prior to disease onset in the superoxide dismutase 1 (SOD1) mouse model of ALS, indicating inadequate glial repair. Collectively, these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated "repair" response of PSCs in the NMJ. Hence, the use of a selective M3 muscarinic receptor antagonist, Darifenacin, as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function, resulting in a beneficial impact on the autonomy and quality of life of ALS patients. The purpose of the current Phase 2 trial is therefore to test the safety, tolerability, and pharmacology of Darifenacin in patients with ALS. Specifically, 30 eligible subjects between 18 and 85 years of age will take 7.5 mg of darifenacin or placebo daily (by mouth) for two weeks followed by an increased dose of 15 mg for the next 22 weeks. The trial will evaluate the effects of this medication on several outcome measures including patient safety, physical and neurological function, muscle strength, depression levels, and NMJ innervation of patients with ALS. Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives.

ALS is a rapidly progressive neurodegenerative disorder caused by the selective death of motor neurons within the brain, brainstem, and spinal cord, leading to paralysis and death within 2-5 years after diagnosis. A limited number of disease-modifying treatments are available for patients with ALS, namely Riluzole (Rilutek), Edaravone (Radicava), and AMX0035 (Relyvrio in the USA and Albrioza in Canada), and novel therapeutic approaches are being investigated to tackle several aspects of ALS pathological features. One of the major hallmarks of ALS is the denervation of neuromuscular junctions (NMJs), which is one of the earliest events seen in ALS patients and murine models that recapitulate ALS-like aspects of the disease due to ALS-causing mutations in the SOD1, TDP-43, and FUS genes. It has been shown that an extensive and extended period of NMJ denervation-reinnervation cycles occurs months prior to disease onset in SOD1 ALS mice. To be specific, scarce Perisynaptic Schwann Cell (PSC) process extensions were observed, which indicates inadequate glial repair. Therefore, while PSCs are responsive to NMJ alterations in ALS, their response does not support NMJ repair. PSCs have a key role in regulating the stability and maintenance of NMJs. They actively participate in NMJ repair once denervation and loss of muscarinic acetylcholine receptors (mAChRs) occur. Additionally, regulation of PSC gene expression, governed by mAChR activation, drives the dynamic adaptation of the PSC in a synaptic activity-dependent manner. PSCs will switch to a repair mode when mAChR activation is reduced, such as following a sciatic nerve crush injury and during synapse formation. Collectively, these preclinical findings support the hypothesis that dampening glial mAChRs will restore the anticipated "repair" response of PSCs in the NMJ. Hence, the use of a selective M3 muscarinic receptor antagonist, Darifenacin, as a disease-modifying therapeutic in familial and sporadic ALS could improve NMJ function, resulting in a beneficial impact on the autonomy and quality of life of ALS patients. The purpose of the current Phase 2 trial is therefore to test the safety, tolerability, and pharmacology of Darifenacin in patients with ALS. APO-DARIFENACIN (Darifenacin Extended Release Tablets), darifenacin as darifenacin hydrobromide, is a known active substance with the chemical name: (S)-2-{1-\[2-(2,3-Dihydrobenzofuran-5-yl)ethyl\]-3-pyrrolidnyl}-2,2-diphenylacetamide hydrobromide. For the purposes of this trial, darifenacin has been formulated by Apotex Inc. as an extended release tablet. Darifenacin will be produced and formulated into 7.5 mg coated tablets (extended-release) and a placebo film-coated tablet will be manufactured without the active substance. Patient enrollment for this trial will consist of 30 eligible ALS patients between 18 and 85 years of age. During the first two weeks (titration period), patients will receive a daily dose of either a placebo or a 7.5 mg darifenacin extended-release tablet. After the titration period, the dose will be increased to 15 mg once daily, which consists of two 7.5 mg tablets together. Depending on the patient's response to the medication, they may be asked to temporarily or permanently stop taking the drug or reduce their dose from 15 mg to 7.5 mg for safety reasons. This treatment period has been selected as a standard for phase 2 trials to study the endpoints and observe significant differences in the outcome measures. The trial will evaluate the effects of this medication and dosing regimen on several outcome measures including patient safety, physical and neurological function, muscle strength, depression levels, and NMJ innervation of patients with ALS. Detailed clinical assessments will be conducted at regular intervals throughout the study in order to achieve these objectives.