A phase 2, multicenter, randomized, placebo-controlled, double-blind study to investigate the safety, pharmacodynamics, and preliminary efficacy of S-606001 as an add-on to enzyme replacement therapy in patients with late-onset Pompe disease.

The primary objective of this study is to evaluate the preliminary effect of S-606001 as an add-on to enzyme replacement therapy (ERT) on lung function in participants with late-onset Pompe disease (LOPD). This objective is clinically relevant as respiratory impairment represents a major cause of morbidity and mortality in LOPD, and current ERT alone may not adequately address progressive pulmonary decline in all patients.

The secondary objectives include:

• To evaluate the safety and tolerability profile of S-606001 as an add-on to ERT in participants with LOPD.

• To evaluate the pharmacokinetics of S-606001 as an add-on to ERT in participants with LOPD.

• To evaluate the pharmacodynamics of S-606001 as an add-on to ERT in participants with LOPD.

• To evaluate the effect of S-606001 as an add-on to ERT on motor function in participants with LOPD.

• To assess the exploratory clinical effects including physical functions and patient-reported outcomes of S-606001 as an add-on to ERT in participants with LOPD.

The clinical trial enrolled a total of **26 participants** diagnosed with **late-onset Pompe disease**. The study population consisted of both **male and female participants** aged between **18 and 65 years**, with a minimum body weight of **40 kg**. All participants were required to have an established diagnosis of late-onset Pompe disease confirmed through documented deficiency of **acid alpha-glucosidase enzyme** or **GAA genotype** analysis. The trial population was selected based on specific pulmonary function parameters, including a **forced vital capacity** between 30% and 80% in an upright position without mechanical ventilation, or a decrease of at least 10% in forced vital capacity from upright to supine position with a minimum of 20% forced vital capacity in supine position. Participants were also required to demonstrate functional mobility by completing a **6-minute walk test** with a distance of at least 75 meters but not exceeding 90% of the predicted value for healthy adults. A key selection criterion was that all participants had prior experience with **enzyme replacement therapy**. The study included a **vulnerable population**. Participants of childbearing potential were required to adhere to specific contraceptive measures throughout the intervention period and for a defined period following the last dose of the investigational intervention.

This is a Phase 2, multicenter, **randomized**, **placebo-controlled**, **double-blind** clinical trial investigating S-606001 as an add-on therapy to **enzyme replacement therapy** in participants with **late-onset Pompe disease**. The investigational medicinal product S-606001 is administered as a **film-coated tablet** via **oral use**, with a maximum daily dose of 600 mg and a maximum total dose of 223,200 mg over a treatment period of up to 53 weeks. The matching **placebo** is also administered orally with a maximum daily dose of 300 mg and a maximum total dose of 218,400 mg over 52 weeks. The study aims to evaluate the preliminary effect of S-606001 on lung function in participants receiving enzyme replacement therapy.

The primary endpoint is the change from baseline in **%FVC** (percent **forced vital capacity**) at 52 weeks. Secondary endpoints include assessment of **adverse events** and **treatment-emergent adverse events**, physical examinations, vital sign measurements, clinical laboratory evaluations including biochemistry, hematology, and urinalysis, and **electrocardiograms**. Additional secondary endpoints comprise plasma concentration of S-606001, changes from baseline in the **6-minute walk test**, pulmonary function parameters including **maximal inspiratory pressure** and **maximal expiratory pressure**, motor function parameters such as the **GSGC score** (Gait, Stair, Gower's Maneuver, Chair), and various patient-reported outcome measures including PROMIS-Fatigue-8a, PROMIS-PF20, PROMIS-Dyspnea, PROMIS v2.0 PAIN, SF-36, and PGI-S.

Eligible participants must be between 18 and 65 years of age, weigh at least 40 kg, and have a confirmed diagnosis of late-onset Pompe disease based on documented deficiency of **acid alpha-glucosidase** enzyme or GAA genotype. Participants must have %FVC between 30% and 80% in an upright position without mechanical ventilation at screening, or demonstrate at least 10% %FVC drop from upright to supine position with %FVC at least 20% in supine position. The **6-minute walk distance** at screening must be at least 75 meters but not exceed 90% of the predicted value for healthy adults. All participants must be experienced with enzyme replacement therapy prior to enrollment.

The estimated recruitment start date is December 1, 2025, with an estimated study completion date of June 29, 2027. The total duration of participant involvement is approximately 52 to 53 weeks, corresponding to the maximum treatment period. The study includes a screening visit for eligibility assessment, followed by regular follow-up visits throughout the treatment period to monitor safety, efficacy, and pharmacodynamic parameters, and an end-of-study visit at week 52. Conditions that may lead to early termination from the study are not specified in the available protocol information.

The experimental medication **S-606001** is administered as a **film-coated tablet** for **oral use**. The active substance S-606001 is of chemical origin and is also known by the synonyms MZ1449348 and MZE001. The maximum daily dose is 600 mg, with a maximum total dose of 223,200 mg administered over a maximum treatment period of 53 weeks. S-606001 is classified as a **new chemical entity** and is provided by SHIONOGI B.V. The investigational product is administered as an **add-on therapy** to **enzyme replacement therapy** in participants with **late-onset Pompe disease**.

The comparator treatment consists of **S-606001 matching placebo**, which is administered via **oral use**. The maximum daily dose of placebo is 300 mg, with a maximum total dose of 218,400 mg over a maximum treatment period of 52 weeks. The placebo is formulated to match the experimental medication to maintain **blinding** in this **double-blind, placebo-controlled study**. The pharmaceutical form of the placebo is not specified in the available data.

Both treatments are administered in the context of ongoing enzyme replacement therapy, which serves as the background standard-of-care treatment for all participants enrolled in this **phase 2, multicenter, randomized** clinical trial. The study design ensures that participants continue to receive their established enzyme replacement therapy while receiving either the experimental medication or placebo as an adjunctive treatment.

Efficacy will be assessed using forced vital capacity as the primary endpoint, measured as the change from baseline in percent predicted FVC at 52 weeks. Secondary efficacy endpoints include changes from baseline in the 6-minute walk test and pulmonary function parameters such as maximal inspiratory pressure and maximal expiratory pressure. Motor function will be evaluated through changes from baseline in the Gait, Stair, Gower's Maneuver, Chair score and Daily Living Activity Levels. Patient-reported outcomes will be assessed using validated instruments including PROMIS-Fatigue-8a, PROMIS-PF20, PROMIS-Dyspnea, PROMIS v2.0 PAIN, SF-36, and PGI-S, with changes from baseline recorded. Additional efficacy parameters as specified in the protocol will also be evaluated for changes from baseline throughout the treatment period.