Efficacy and Safety Evaluation of Utreloxastat in Adult Patients with Amyotrophic Lateral Sclerosis: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of PTC857 in reducing disease progression in subjects with **amyotrophic lateral sclerosis** (ALS). This is clinically relevant as ALS is a progressive neurodegenerative disease with limited treatment options, and slowing disease progression could significantly impact patient outcomes.

Secondary objectives include: - Assessing the **safety** and tolerability of PTC857. - Evaluating **respiratory function** in subjects randomized to PTC857 versus placebo. - Assessing **motor/limb and bulbar function** in subjects randomized to PTC857 versus placebo. - Evaluating **survival** in subjects randomized to PTC857 versus placebo. - Assessing **quality of life** via the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) in subjects randomized to PTC857 versus placebo. - Investigating the **pharmacokinetics** (PK) of PTC857. - Evaluating the efficacy of PTC857 in reducing disease progression in subjects with ALS with any baseline rate of functional decline. - Assessing effects on **plasma neurofilament light chain** (NfL) activity in subjects randomized to PTC857 versus placebo.

The clinical trial involves a total of **94 participants** diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**. The study population comprises both male and female subjects, aged between 18 and 80 years, who are in generally good health with preserved function and no significant respiratory compromise. Participants were selected based on specific criteria, including a total ALSFRS-R score of at least 34 and stable chronic concomitant medications. The trial includes individuals who are willing and able to comply with all protocol procedures. Lifestyle considerations such as diet and physical activity are not specified, but participants must maintain stable standard-of-care therapy for ALS throughout the study. The trial population includes a vulnerable group, and both genders are represented, with females required to adhere to specific reproductive health guidelines. The selection process ensures that participants have a recent onset of ALS symptoms, defined as within 24 months, and meet the Revised El Escorial criteria for clinically definite or probable ALS.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, parallel study designed to evaluate the efficacy, safety, tolerability, pharmacokinetics, and biomarker effects of **PTC857** in adult subjects with **Amyotrophic Lateral Sclerosis** (ALS). The trial aims to assess the ability of PTC857 to reduce disease progression in ALS patients. The study will involve a total treatment period of 24 weeks, with an estimated end date in June 2027. Participants will be randomly assigned to receive either PTC857 or a placebo, both administered as an oral solution.

The trial will commence with a screening visit to determine eligibility based on specific inclusion criteria, such as age, ALS diagnosis, and respiratory function. Participants must be between 18 and 80 years old and have a total ALS Functional Rating Scale-Revised (ALSFRS-R) score of at least 34. The screening visit will also ensure that all chronic concomitant medications are stable. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will involve assessments such as clinical laboratory tests, physical examinations, and pulmonary function tests.

The primary endpoint of the study is the subject ranks based on the combined assessment of ALSFRS-R and survival after 24 weeks of treatment. Secondary endpoints include changes from baseline in ALSFRS-R, safety and tolerability as measured by the severity and number of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), and changes in slow vital capacity and motor/limb and bulbar function. The study will also evaluate the quality of life using the ALSAQ-40 and changes in plasma neurofilament light chain (NfL) activity.

Participants are expected to be involved in the study for approximately 24 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The end-of-study visit will conclude the trial, where final assessments will be conducted to gather comprehensive data on the study's outcomes. The trial is not categorized as low intervention and is conducted under strict adherence to protocol procedures to ensure the integrity and reliability of the results.

The clinical trial involves the administration of **PTC857**, an experimental medication formulated as an **oral solution**. The active substance in PTC857 is **utreloxastat**, a chemical compound also known by synonyms such as EPI 857 and 2,3,5-trimethyl-6-nonyl-2,5-cyclohexadiene-1,4-dione. The medication is provided by PTC Therapeutics, Inc. The maximum daily dose of PTC857 is 500 mg, and the treatment period extends up to 160 days. The route of administration is oral, and the medication is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to PTC857, the study includes a **placebo** designed to match the 60 mg/mL oral solution of PTC857. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo. The placebo does not contain any active substance and is administered in the same manner as PTC857 to ensure consistency in the study protocol.

Another formulation of the active substance, **Utreloxastat 62.5**, is also included in the trial. Like PTC857, it is an oral solution provided by PTC Therapeutics, Inc. The maximum daily dose and treatment period for Utreloxastat 62.5 are identical to those of PTC857, with a maximum of 500 mg per day over a period of 160 days. The administration route is oral, and the formulation is not intended for pediatric use. Compliance with the dosing regimen will be closely monitored to ensure adherence to the study protocol.

The efficacy of PTC857 in the treatment of **Amyotrophic Lateral Sclerosis (ALS)** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves subject ranks based on the combined assessment of the ALS Functional Rating Scale-Revised (ALSFRS-R) and survival after 24 weeks of treatment in the Intent-to-Treat 1 (ITT1) Analysis Set. Secondary endpoints include changes from baseline in ALSFRS-R scores, safety and tolerability as measured by the severity and number of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), and changes in clinical laboratory tests, physical examination, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), and 12-lead electrocardiograms (ECGs) during the treatment period.

Additional secondary endpoints include changes from baseline in slow vital capacity as assessed by pulmonary function tests (PFTs), changes in motor/limb and bulbar function as assessed by the Modified Norris Scale, and subject ranks based on the combined assessment of ALSFRS-R and survival in the Intent-to-Treat 2 (ITT2) Analysis Set. Other measures include survival rates, quality of life as assessed by ALSAQ-40, changes in plasma neurofilament light chain (NfL) activity, and plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) exposure of PTC857. These assessments will be conducted after 24 weeks of treatment to evaluate the efficacy of the investigational product in reducing disease progression in subjects with ALS.