Phase 3 Evaluation of INZ-701 Efficacy and Safety in Pediatric Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Deficiency

The primary objective of the study is to evaluate the efficacy of **INZ-701** in increasing inorganic pyrophosphate (PPi) levels and improving skeletal abnormalities in children with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. This is clinically relevant as ENPP1 Deficiency is associated with low PPi levels, leading to pathological calcification and skeletal abnormalities. By potentially increasing PPi levels and improving skeletal conditions, INZ-701 could address the underlying pathophysiology of the disease and improve patient outcomes.

Secondary objectives include:

• To determine if INZ-701 improves rickets as measured by the Rickets Severity Score (RSS).
• To determine if INZ-701 increases height/body length and weight.
• To characterize the pharmacokinetics (PK) and ENPP1 activity of INZ-701.

The clinical trial involves a total of **26 participants** diagnosed with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. The study population includes both male and female subjects, aged between **1 and 12 years** at the start of the study. Participants were selected based on a confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency with biallelic mutations. The trial includes individuals with open growth plates of the distal femur and proximal tibia in both legs, and a plasma PPi concentration of less than 1400 nM at screening. Participants are required to have 25-hydroxyvitamin D levels of at least 12 ng/mL and radiographic evidence of skeletal abnormalities. The study population is considered vulnerable, and the selection process ensures that participants are able to complete all aspects of the study. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of INZ-701 in children with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. This is a randomized, controlled, open-label, Phase 3 study. The trial aims to determine if INZ-701 increases plasma inorganic pyrophosphate (PPi) levels and improves skeletal abnormalities as measured by the Radiographic Global Impression of Change (RGI-C). The study is expected to last until February 2027, with recruitment starting in April 2024. Participants will be involved for a maximum treatment period of 52 weeks.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency and specific age and health conditions. The primary endpoints include changes from baseline in plasma PPi concentration and RGI-C global score through Week 52. Secondary endpoints involve changes in RSS total score, growth Z-score, and measurement of INZ-701 serum concentration and specific activity.

Participants will receive INZ-701 as a **lyophilized powder for preparation for injection**, administered via subcutaneous use. The maximum daily dose is 2.4 mg/kg. Study visits will include regular follow-up assessments to monitor safety and efficacy, with the end-of-study visit marking the conclusion of the participant's involvement. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of adverse events that, in the investigator's opinion, warrant discontinuation. The study is conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **INZ-701**, an experimental medication developed by Inozyme Pharma, Inc. **INZ-701** is a **lyophilized powder for preparation for injection**, specifically designed for subcutaneous use. The active substance in **INZ-701** is **recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of IgG1**, classified as a protein of other origin. The medication is administered at a maximum daily dose of 2.4 mg/kg, with the treatment period extending up to 52 weeks. The dosing schedule is determined based on the participant's body weight, and the medication is reconstituted prior to administration.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy and safety of **INZ-701** in children with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the prescribed treatment protocol. The trial aims to assess the impact of **INZ-701** on increasing pyrophosphate (PPi) levels and improving skeletal abnormalities, as measured by the Radiographic Global Impression of Change (RGI-C).

The efficacy of INZ-701 in children with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency** will be assessed through a series of primary and secondary endpoints over a 52-week period. The primary endpoints include the change from baseline in plasma inorganic pyrophosphate (PPi) concentration and the change in the Radiographic Global Impression of Change (RGI-C) global score, both measured through Week 52. These endpoints will provide insights into the biochemical and skeletal improvements associated with the treatment.

Secondary endpoints will further evaluate the efficacy by assessing changes from baseline in the Radiographic Severity Score (RSS) total score and growth Z-scores, including height/body length and weight, through Week 52. Additionally, the serum concentration and specific activity of INZ-701 will be measured to understand the pharmacokinetics and pharmacodynamics of the treatment. These assessments will be conducted using validated scales and laboratory tests at specified timepoints throughout the study duration.