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

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.

ENABLEX (Darifenacin Extended Release Tablets), or 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. Darifenacin will be produced and formulated into 7.5 mg coated tablets (extended-release) by Searchlight Pharma and a placebo film-coated tablet will be manufactured without the active substance by Apotex Inc.

Patient enrollment for this trial will consist of 60 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.