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

Safety and tolerability of oral doses of 15 mg darifenacin

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.