A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Assess the Efficacy, Safety, Tolerability, PK, and Biomarker Effects of PTC857 in Adult Subjects With Amyotrophic Lateral Sclerosis (CARDINALS)

Prior treatment

• History of alcohol or drug abuse within the last 6 months prior to the start of the Screening Period or current evidence of substance dependence
• Any surgery within 30 days prior to the start of the Screening Period that may affect the subject’s ability to complete all study procedures
• 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 longe
• Subject has previously received PTC857

Other illness

• For female subjects, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer
• History of allergies or adverse reactions to any of the excipients in the study drug formulation
• Subjects 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 subject 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 subject’s ability to participate in the study or increase the risk of participation for that subject

Lab values

• Hepatic insufficiency, defined as liver function tests (LFTs) (ie, AST and/or ALT) ≥3× the upper limit of normal (ULN), or bilirubin ≥1.5× the ULN (except in the case of Gilbert’s disease)
• Subject is taking a non-approved form of sodium phenylbutyrate and/or taurursodiol for the treatment of ALS
• Moderate or worse renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min
• Subject is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 (-3) days prior to the start of the Screening Period

Other

• Females who are pregnant or nursing or plan to become pregnant during the study

• Males or females aged between 18 and 80 years at the time of the initial Screening Visit
• Females must refrain from ova (egg cell) donation from the start of the Screening Period through 90 days after the last dose of study drug
• Males, if not surgically sterilized, with female partners of childbearing potential must agree to use barrier contraceptive (ie, condom) and their female partners must use a highly effective method of contraception from the start of the Screening Period through 90 days after the last dose of study drug
• Males must refrain from sperm donations from the start of the Screening Period through 90 days after the last dose of the study drug
• Willing and able to comply with all protocol procedures
• ALS with preserved function, defined as: a. Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit b. 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 (refer to the laboratory manual for specific requirements)
• All chronic concomitant medications (both prescription and over the counter [OTC]) and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol (refer to inclusion criterion 13) 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 subjects 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. Note: should a subject be discontinued from standard-of-care therapy due to removal of the therapy from the market, this will not be considered a protocol deviation.
• Subjects or their designee (ie, legal authorized representative or caregiver) must understand the nature of the study and must provide signed and dated written informed consent prior to conducting any study-related procedures
• Females must be either postmenopausal for ≥1 year (cessation of menses for 12 consecutive months) or surgically sterile (having undergone tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use a highly effective method of contraception from the start of the Screening Period through 90 days after the last dose of study drug. Females who are abstinent will not be required to use a contraceptive method unless they become sexually active