Evaluation of INZ-701 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Infants with ENPP1 or ABCC6 Deficiency

The primary objective of the study is to assess the **safety** and **tolerability** of INZ-701 in infants diagnosed with Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency or ATP-binding Cassette Sub-family C Member 6 (ABCC6) Deficiency. This evaluation is clinically significant as it aims to determine the potential adverse effects and overall acceptability of INZ-701, which is crucial for ensuring patient safety and guiding future therapeutic use.

Secondary objectives include:

• To study the **pharmacokinetics** (PK) and **pharmacodynamics** (PD) activity of INZ-701, which will provide insights into the drug's absorption, distribution, metabolism, and excretion, as well as its biological effects and mechanism of action.

The clinical trial involves a total of **14 participants** diagnosed with either **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency** or **ATP-binding Cassette Sub-family C Member 6 (ABCC6) Deficiency**. The study population includes both male and female subjects from birth to less than one year of age. Participants were selected based on a confirmed post-natal molecular genetic diagnosis of ENPP1 or ABCC6 Deficiency with biallelic mutations, verified through a CE-marked assay or a CAP/CLIA certified laboratory. The trial population is considered vulnerable due to the young age of the participants. All participants must weigh at least 0.5 kg at the time of the first dose of the investigational product, INZ-701. The study does not specify any particular lifestyle considerations such as diet or physical activity, given the age of the participants. The selection criteria ensure that participants have clinical manifestations of Generalized Arterial Calcification of Infancy (GACI) or GACI-2, which may include symptoms like pathologic ectopic calcification, heart failure, respiratory distress, edema, cyanosis, hypertension, and cardiomegaly.

The clinical trial is designed to evaluate the **safety** and tolerability of INZ-701 in infants diagnosed with Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency or ATP-binding Cassette Sub-family C Member 6 (ABCC6) Deficiency. This is an open-label, Phase 3 trial, which will involve the administration of INZ-701 as a **lyophilized powder for preparation for injection** via subcutaneous use. The trial is expected to commence on May 6, 2024, and conclude by October 30, 2026. Participants will be involved in the study from birth to less than one year of age, with a requirement to weigh at least 0.5 kg at the time of the first dose.

The trial will include several key visits: an initial screening visit to confirm eligibility, followed by a baseline visit on Day 1 where the first dose of INZ-701 will be administered. Subsequent follow-up visits will be scheduled to monitor the participants' health and response to the treatment, with assessments including adverse events, vital signs, laboratory tests, and immunogenicity. The primary endpoints focus on the incidence and severity of adverse events, while secondary endpoints include pharmacokinetic parameters and changes in PPi levels over time. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. Such conditions may include significant adverse reactions or the inability to comply with study procedures. The trial will adhere to the International Council for Harmonisation Good Clinical Practice guidelines, ensuring that all procedures are conducted ethically and with the utmost care for participant safety.

The clinical trial involves the administration of **INZ-701**, a recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of IgG1. 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 use**. The lyophilized powder requires reconstitution prior to administration. The dosing schedule and frequency of administration are determined by the study protocol, which aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of INZ-701 in infants with ENPP1 deficiency or ABCC6 deficiency. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The focus remains solely on the administration of INZ-701 to assess its effects in the target population. The trial is designed to gather comprehensive data on the investigational product's impact on the specified conditions, with all procedures conducted in accordance with regulatory and ethical standards.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of adverse events, vital signs, weight, laboratory tests (including chemistry, hematology, and urine tests if feasible), immunogenicity, concomitant medications, left ventricular ejection fraction via echocardiogram, and electrocardiogram results. These parameters will provide a comprehensive assessment of the safety and tolerability of the investigational product, INZ-701, in infants with **Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Deficiency** or ATP-binding Cassette Sub-family C Member 6 (ABCC6) Deficiency.

Secondary endpoints focus on pharmacokinetic and pharmacodynamic measures, including the measurement of INZ-701 serum concentration-time profiles and pharmacokinetic parameters. Additionally, changes from baseline in inorganic pyrophosphate (PPi) levels will be monitored through Week 52, along with the measurement of ENPP1 activity. These assessments will be conducted at specified timepoints throughout the study to evaluate the efficacy of INZ-701 in modifying disease-related biomarkers and clinical outcomes. The trial is designed to provide a detailed understanding of the drug's impact on the targeted conditions over the course of the study.