Study to Assess the Effects of PTC857 Treatment in Participants With Amyotrophic Lateral Sclerosis ALS

Phase 2

Terminated

Conditions: Amyotrophic Lateral Sclerosis

Interventions: Drug: Placebo
Drug: PTC857

Registration Number: NCT05349721

Lead Sponsor: PTC Therapeutics

Brief Summary: This study will assess the efficacy and safety of PTC857 treatment in participants diagnosed with ALS.

Detailed Description: Participants will be randomized to 1 of the 2 treatment groups: PTC857 or matching placebo. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 336

Inclusion Criteria

ALS with preserved function, defined as:
1. Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit
2. Revised EL Escorial criteria of either:
(i) Clinically definite ALS (ii) Clinically probable ALS
A total ALSFRS-R score of at least 34 at the start of the Screening Period
No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period
All chronic concomitant medications (both prescription and over the counter), and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, should be stable and unchanged from 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study
Female participants must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit, or during the Screening Period.
Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study.

Key

Exclusion Criteria

Females who are pregnant or nursing or plan to become pregnant during the study
Participants with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator would jeopardize the safety of the participant or impact the validity of the study results
Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant
Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer
Participant has previously received PTC857
Participant is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 days prior to the start of the Screening Period
For female participants, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants will receive matching placebo during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.
PTC857	PTC857	Participants will receive PTC857 during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who enter the Long-term Extension (LTE) Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.

Primary Outcome Measures

Name	Time	Method
Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population)	Week 24	The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 306 (ITT1 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. Multiple imputation was used to impute participants with missing ALSFRS-R score at Week 24. A higher rank was considered a better outcome. Least square (LS) means and standard error (SE) were calculated using analysis of covariance (ANCOVA) model.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Modified Norris Scale Total Score at Week 24	Baseline, Week 24	Modified Norris scale is used to assess the motor/limb and bulbar function. The Modified Norris Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris Scale and the Norris Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity function, and the Norris Bulbar Scale has 13 items to evaluate bulbar function. Each item was rated in 4 ordinal categories, corresponding to the following values and ratings or functional scores: normal (3 points), somewhat impaired (2 points), inadequate (1 point), and "cannot do at all" (0 points). The total score was calculated by summing all the scales, ranging from 0 (worst) to 102 (best) where higher scores indicated better functional abilities. LS mean and SE were calculated using MMRM.
Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24	Baseline, Week 24	The ALSAQ-40 is a disease-specific measure of health-related quality of life (QOL) for ALS. The ALSAQ-40 is comprised of 40 questions measuring 5 discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of 5 options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score ranging from 0 (no impairment) to 160 (severe impairment) was calculated by adding the 5 domain scores. A lower score indicates a better health state. LS mean and SE were calculated using MMRM.
Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24	Baseline, Week 24	The NfL is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions.
Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma	Day 1 and Day 29
Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population)	Week 24	The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 334 (ITT2 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. A higher rank was considered a better outcome. LS mean and SE were calculated using ANCOVA model.
Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population)	Baseline, Week 24	The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using mixed model repeated measures (MMRM).
Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population)	Baseline, Week 24	The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using MMRM.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Day 1 through Week 24	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that began after the first administration of study drug or any existing AEs that worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24	Baseline, Week 24	The SVC is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent of predicted SVC is reported. LS mean and SE were calculated using MMRM.
Overall Survival Rate	Baseline to Week 24	Overall survival rate was defined as percentage of participants who were alive at given timepoint. Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die.
Overall Survival	Baseline to Week 24	Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die.
Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma	Day 1 and Day 29
Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF)	Day 1 and Day 29

Trial Locations

Locations (55): UC Irvine Health ALS and Neuromuscular Center
🇺🇸
Orange, California, United States
Forbes Norris MDA/ALS Research Center at California Pacific Medical Center
🇺🇸
San Francisco, California, United States
Holy Cross Hospital, Phil Smith Neuroscience Institute
🇺🇸
Fort Lauderdale, Florida, United States
University of South Florida - Carol and Frank Morsani Center for Advanced Healthcare
🇺🇸
Tampa, Florida, United States
Augusta University
🇺🇸
Augusta, Georgia, United States
University of Kansas Medical Center (KUMC) - Landon Center on Aging
🇺🇸
Kansas City, Kansas, United States
Henry Ford Health System Department of Neurology
🇺🇸
Detroit, Michigan, United States
Neurology Associates, P.C. / Somnos Clinical Research
🇺🇸
Lincoln, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Providence Brain and Spine Institute
🇺🇸
Portland, Oregon, United States
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UC Irvine Health ALS and Neuromuscular Center
🇺🇸Orange, California, United States