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, 60 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.
Able to comprehend and willing to sign an Informed Consent Form (ICF).
Male or female, ≥ 18 years old and ≤85 years old, at the time of signing the ICF.
Confirmed diagnosis of familial or sporadic ALS, defined as meeting the probable, laboratory-supported probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology Modified El Escorial criteria (1).
ALS duration of less than 36 months from the symptom onset.
Untreated or uncontrolled narrow-angle glaucoma;
Gastric retention
Urinary retention
Liver disease
Parallel
Darifenacin 7.5 MG Extended Release Oral Tablet
DrugDuring the first \~two weeks (titration period), patients in the treatment arm will receive a daily dose of 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 for a period of 22 weeks.
Placebo
DrugDuring the first two weeks (titration period), patients in the placebo arm will receive a daily dose of 1 placebo tablet. After the titration period, the dose will be increased to two placebo tablets taken together, for a period of 22 weeks.
Safety and tolerability of oral doses of 15 mg darifenacin
The incidence of adverse events and any abnormal clinical assessments will be monitored.
Pharmacokinetics of oral doses of darifenacin
The pharmacokinetic profile of darifenacin in ALS patients will be visualized at Day 1, 14, and 28.
Electrical Impedance Myography (EIM)
EIM is a non-invasive technique that measures the electrical impedance characteristics of specific muscles or muscle groups as a readout of muscle health.
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score
The ALSFRS-R will be used to measure activities of daily living (ADL) and global function across four domains (respiratory, bulbar function, gross motor skills, and fine motor skills) and consists of 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function.
Forced Vital Capacity (FVC)
The FVC test examines lung capacity and overall respiratory function.
Depression and depressive symptoms
The self-administered Patient Health Questionnaire (PHQ-9) will be used to assess depressive symptoms.
Physical function and daily activities
The self-administered the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) questionnaire will assess levels of overall disability in patients.
Neuromuscular junction innervation
Neuromuscular junctions (NMJs) will be functionally and visually examined to monitor the effect of darifenacin.
Pharmacodynamics of oral doses of 15 mg darifenacin
Blood-based biomarkers will be examined on Day 1, 14, 28, and 168 to determine the pharmacodynamic profile of darifenacin in ALS patients.
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