A phase 2, randomized, double-blind study of S-606001 as an add-on to enzyme replacement therapy in patients with late-onset Pompe disease.

Prior treatment

• Presence of hepatitis B surface antigen or hepatitis B virus core antibody at screening or within 3 months prior to the first dose of investigational intervention.
• Positive hepatitis C virus antibody test result at screening or within 3 months prior to the first dose of investigational intervention. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative hepatitis C virus RNA test is obtained.
• Has received any investigational therapy or pharmacological treatment for Pompe disease, within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before day 1 or is anticipated to do so during the study.
• Has received gene therapy or small interfering RNA therapy for Pompe disease.
• Is taking any of the prohibited medications listed in the study protocol.
• Is currently enrolled or past participation in another investigational study in which an investigational intervention (eg, drug, vaccine, invasive device) was administered within 30 days before the planned first dose of investigational intervention in this clinical study.

Other illness

• Has a medical condition or any other extenuating circumstance that may, in the opinion of the investigator or medical monitor, pose an undue safety risk to the participant or may compromise his/her ability to comply with or adversely impact protocol requirements.
• Positive HIV antibody test.
• Has active infections at screening, including but not limited to viral hepatitis, HIV infection, or pulmonary tuberculosis. If the infection is acute and resolved before day 1, the participant may be enrolled.
• Malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Has bleeding disorders or clinically significant abnormal values in prothrombin or activated partial thromboplastin time (in the investigator's opinion).
• Is unable to discontinue drugs or substrates identified as substrates of CYP2B6, CYP2C8, CYP2C9, CYP3A with narrow therapeutic window, breast cancer resistance protein (BCRP), as well as inducers or inhibitors of CYP3A at day 1
• Has a known hypersensitivity to any component of the S-606001 drug product
• Has chronic obstructive pulmonary disease or any other chronic pulmonary disorders including active or latent lung tuberculosis.

Lab values

• Total bilirubin > 1.5 × upper limit of normal (ULN; participants with Gilbert’s syndrome can be included with total bilirubin > 1.5 × ULN if direct bilirubin is ≤ 1.0 × ULN).
• Current or chronic history of liver disease, including, but not limited to: hepatitis virus infections; drug- or alcohol-related liver disease; non-alcoholic steatohepatitis; autoimmune hepatitis; hemochromatosis; Wilson’s disease; α-1 antitrypsin deficiency; primary biliary cholangitis; primary sclerosing cholangitis; or any other liver disease considered clinically significant by the investigator (eg, higher abnormal alanine aminotransferase [ALT] value with relatively lower aspartate aminotransferase [AST] value, or abnormal gamma-glutamyl transaminase value).
• QT interval corrected for heart rate according to Fridericia’s formula (QTcF) > 450 msec for male participants, QTcF > 470 msec for female participants, or QTcF > 480 msec in participants with bundle branch block. NOTE: The QTcF is either machine-read or manually over-read.
• Has poorly controlled glycemia (ie glycated hemoglobin, [HbA1c] > 7%).
• 25. Has moderate to severe renal impairment, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula), will be excluded from participation in this study.
• Has any known significant cardiac malfunction including but not limited to, heart failure (ie, < 40% ejection fraction), severe cardiomyopathy, and arrythmias with possible QT prolongation, a history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) and the use of concomitant medications that prolong the QT/QTc interval.

Other

• Requires the use of invasive or noninvasive ventilation support while awake.
• Participant, if female, is pregnant or breastfeeding at screening.
• Participant, whether male or female, is planning to conceive a child during the study.
• Known biallelic loss of function mutations whether in glycogenin 1 gene or in glycogen phosphorylase muscle-associated gene (PYGM).
• Is currently enrolled in any other clinical study involving an investigational study or any other type of medical research.

• Participant must be ≥ 18 years and ≤ 65 years of age and ≥ 40 kg of body weight at the time of signing the informed consent.
• Participant must have a diagnosis of LOPD based on documentation of 1 of the previous results of the following: a. Deficiency of acid alpha-glucosidase (GAA) enzyme b. GAA genotype.
• Participant has a %Forced Vital Capacity (FVC) ≥ 30% and ≤ 80% in an upright position without mechanical ventilation at screening; or Participant has > 80% FVC in upright position and ≥ 10% %FVC drop from upright position to supine position and %FVC ≥ 20% in a supine position.
• Participant performs the 6MWT at screening, as determined by the clinical evaluator, and meets all of the following criteria: a. Screening values of 6-minute walk distance (6MWD) are ≥ 75 meters b. Screening values of 6MWD are ≤ 90% of the predicted value for healthy adults.
• a. Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 weeks after the last dose of investigational intervention: Refrain from donating fresh unwashed semen PLUS either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed in the protocol. b. Female participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) as defined in the protocol OR is a WOCBP and using a contraceptive method that is highly effective preferably with low user dependency, as described in the protocol during the intervention period and for at least 184 days after the last dose of investigational intervention, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of investigational intervention.
• Capable of giving signed informed consent prior to any study-related procedures being performed that includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Participants must be ERT-experienced.