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

The primary objective of this study is to evaluate the efficacy of **INZ-701** in increasing inorganic pyrophosphate (PPi) levels and overall survival in infants diagnosed with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. This is clinically relevant as ENPP1 Deficiency is associated with severe complications, including vascular calcification and cardiac dysfunction, which can significantly impact survival and quality of life.

Secondary objectives include:

• To determine if INZ-701 prevents decline in cardiac ejection fraction.
• To determine if INZ-701 prevents heart failure.
• To determine if INZ-701 attenuates progression of arterial calcification.
• To determine if INZ-701 increases physical growth, specifically body length and weight.
• To determine if INZ-701 prevents respiratory dysfunction.
• To characterize the pharmacokinetics (PK) and ENPP1 activity of INZ-701.

The clinical trial involves a total of **6 participants** diagnosed with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. The study population includes both male and female subjects from birth to less than 1 year of age. Participants were selected based on a confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency with biallelic mutations, and clinical evidence of Generalized Arterial Calcification of Infancy (GACI). The trial population is considered vulnerable due to the young age of the participants. Key lifestyle considerations such as diet and physical activity are not specified, as the focus is on the medical condition and age of the participants. The selection criteria ensure that participants have a plasma inorganic pyrophosphate (PPi) concentration of less than 1400 nM and a body weight of at least 0.5 kg at the time of the first dose of the investigational product, INZ-701.

The clinical trial is designed to evaluate the efficacy and safety of **INZ-701** in infants diagnosed with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**. This is an open-label, Phase III study, which will involve a randomized, controlled trial design. The trial aims to assess whether INZ-701 can increase inorganic pyrophosphate (PPi) levels and improve overall survival in the target population. The study is expected to last until February 2028, with recruitment starting in October 2024. Participants will be involved in the study for a maximum treatment period of 104 weeks.

The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency and clinical evidence of generalized arterial calcification of infancy (GACI). Following the screening, participants will undergo regular follow-up visits to monitor changes in plasma PPi concentration, left ventricular ejection fraction, and vascular calcification, among other parameters. The primary endpoints include changes from baseline in plasma PPi concentration through Week 52 and overall survival. Secondary endpoints will assess changes in cardiac function, growth metrics, and the incidence of heart failure.

The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience adverse events that compromise their safety or if they fail to comply with the study protocol. The trial will utilize a subcutaneous injection route for administering INZ-701, with a maximum daily dose of 2.4 mg/kg. The study is not categorized as low intervention, given its Phase III status and the evaluation of an unapproved drug. The trial is conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, ensuring the integrity and reliability of the data collected.

The clinical trial involves the administration of **INZ-701**, a recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of immunoglobulin G1. This experimental medication is provided in two pharmaceutical forms: a lyophilized powder for preparation for injection and a powder for injection. Both forms are intended for subcutaneous injection. The dosing regimen for INZ-701 is set at a maximum daily dose of 2.4 mg/kg, with the treatment period extending up to 104 weeks. The medication is not formulated specifically for pediatric use, and it has been designated as an orphan drug under the designation number EU/3/18/2049.

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 infants with **ENPP1 deficiency**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the potential of INZ-701 to increase inorganic pyrophosphate (PPi) levels and improve overall survival in the target population.

Efficacy in the clinical trial titled "The ENERGY 2 Study: An Open-Label Phase 3 Study to Evaluate the Efficacy and Safety of INZ-701 in Infants with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency**" will be assessed using both primary and secondary endpoints. The primary endpoints include the change from baseline over time in plasma inorganic pyrophosphate (PPi) concentration through Week 52 and overall survival based on the time from the date of birth to the event of all-cause mortality. Secondary endpoints will evaluate changes from baseline in left ventricular ejection fraction via echocardiography, incidence of heart failure, changes in vascular calcification in the coronary arteries and aorta via CT scan, changes in growth Z-score (body length and weight), growth velocity, the number of days of mechanical ventilation, and measurement of INZ-701 plasma concentration and specific activity, all through Week 52.