A Long-Term follow-up Study to evaluate safety and tolerability of olipudase alfa in patients who completed the DFI12712 or the LTS13632 Study in France - PTA17397

The primary objective of this study is to assess the **safety** and **tolerability** of **olipudase alfa** in patients with **acid sphingomyelinase deficiency** (ASMD), also known as **Niemann-Pick disease**, who have completed prior clinical trials DFI12712 or LTS13632 in France. This long-term follow-up evaluation is clinically relevant to monitor the ongoing adverse event profile and tolerability of enzyme replacement therapy in both pediatric and adult populations with ASMD until reimbursement is granted in France or for a maximum duration of 5 years. The study addresses the need for continued safety surveillance of olipudase alfa, a recombinant human acid sphingomyelinase administered intravenously, in patients transitioning from completed clinical trials to potential commercial availability.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes both **male** and **female** patients diagnosed with **Niemann-Pick disease** (specifically **acid sphingomyelinase deficiency**, ASMD). The trial is designed for **adults** and **elderly** participants. Eligible participants must have completed a previous clinical study (DFI12712 or LTS13632) conducted in France. Female participants of **childbearing potential** are required to demonstrate negative **pregnancy test** results at enrollment. All sexually active participants of childbearing potential must practice **contraception** using two acceptable effective methods throughout the treatment period and for at least 28 days following the last dose of study drug. The trial population represents a **vulnerable population** and participants must demonstrate willingness to comply with the clinical protocol requirements.

This clinical trial is designed as a **Phase 4**, **long-term follow-up study** to evaluate the **safety** and **tolerability** of **olipudase alfa** in patients with **Acid sphingomyelinase deficiency** (ASMD), also known as **Niemann-Pick disease**, who have completed previous studies DFI12712 or LTS13632 in France. The study employs an **open-label**, **single-arm** design without randomization or blinding, as all eligible participants receive the investigational medicinal product. The investigational product, Xenpozyme, is administered as a **powder for concentrate for solution for infusion** via **intravenous use**, containing olipudase alfa as the active substance. The maximum daily dose is 3 mg/kg, with a maximum total dose of 360 mg/kg administered over a treatment period of up to 60 months. The estimated recruitment start date is November 18, 2021, with an estimated study completion date of May 5, 2025. The overall trial duration is designed to continue until olipudase alfa reimbursement is granted in France or until 5 years, whichever occurs first.

The study population consists of pediatric and adult participants who have successfully completed the DFI12712 (ASCEND) or LTS13632 studies in France. Principal inclusion criteria require that patients must have completed one of these prior studies, provide signed informed consent, and demonstrate willingness to comply with the clinical protocol. Female patients of childbearing potential must have a negative pregnancy test result (urine beta-human chorionic gonadotropin) at enrollment. Sexually active female patients of childbearing potential and male patients are required to practice true abstinence in accordance with their preferred lifestyle or use two acceptable effective methods of contraception throughout the treatment period and for at least 28 days after receiving the last study drug dose. The primary endpoint is the number of **adverse events** (AEs) and **serious adverse events** (SAEs) observed during the study period. No secondary endpoints are specified for this trial.

Participant involvement begins with an enrollment visit following completion of the previous studies, during which eligibility is confirmed through review of inclusion criteria and pregnancy testing for applicable participants. Study visits are scheduled regularly throughout the treatment period to monitor safety parameters, assess tolerability, and document any adverse events or serious adverse events. The frequency and timing of follow-up visits are determined by the ongoing treatment schedule and safety monitoring requirements. The end-of-study visit occurs when the participant completes the planned treatment duration, when olipudase alfa reimbursement is granted in France, after 5 years of participation, or upon early termination from the study. Conditions that may lead to early termination include withdrawal of informed consent, pregnancy, non-compliance with the clinical protocol, occurrence of unacceptable adverse events or safety concerns, or administrative decisions by the investigator or sponsor. The expected length of participant involvement extends up to 5 years or until reimbursement approval, with each participant receiving continuous treatment with olipudase alfa throughout their enrollment period.

The experimental treatment in this clinical trial is **Xenpozyme**, which contains the active substance **olipudase alfa** (also known as GZ-402665 or recombinant human acid sphingomyelinase). The medicinal product is supplied as a **powder for concentrate for solution for infusion**. The active substance is classified as a protein of non-human origin. Olipudase alfa is administered via the **intravenous route**. The maximum daily dose is **3 mg/kg** body weight. The maximum total dose administered is **360 mg/kg** over a maximum treatment period of **60 months**. Xenpozyme has been designated as an **orphan drug** under the designation number EU/3/01/056 for the treatment of **acid sphingomyelinase deficiency** (ASMD). The study protocol includes monitoring of participant compliance throughout the treatment period to ensure adherence to the prescribed dosing schedule.

This long-term follow-up study is designed to evaluate the safety and tolerability of olipudase alfa in patients who have previously completed either the DFI12712 or LTS13632 study in France. The treatment will continue until reimbursement is granted in France or for a maximum duration of 5 years, whichever occurs first. The manufacturer of the medicinal product is Genzyme Corporation.

Efficacy will be assessed through the evaluation of the number of adverse events (AEs) and serious adverse events (SAEs) occurring during the study. This primary endpoint will serve to evaluate the safety and tolerability profile of olipudase alfa in patients with acid sphingomyelinase deficiency (ASMD) who have completed prior clinical studies.