Inozyme Pharma Announces Positive Preliminary Data from Phase 1/2 Clinical Trial

Inozyme Pharma, Inc. recently announced positive preliminary biomarker, safety, and pharmacokinetic (PK) data from the first three patients treated in the Phase 1 portion of its ongoing first-in-human Phase 1/2 clinical trial of INZ-701 in adult patients with ENPP1 Deficiency. At the 0.2 mg/kg dose level of INZ-701, all three patients showed rapid, significant, and sustained increases in PPi levels. Preclinical findings demonstrated PPi as a key predictive biomarker of therapeutic benefit in ENPP1 Deficiency.

“ENPP1 Deficiency is a devastating disease, and patients currently have no approved therapies,” said Axel Bolte, MSc, MBA, Inozyme’s Co-founder, President, and Chief Executive Officer. “We are greatly encouraged by the data reported today, as they represent the first clinical evidence supporting the potential of INZ-701 to address an urgent medical need. The data from the lowest dose cohort demonstrated that INZ-701 was able to rapidly and significantly increase PPi levels in these patients, with a potential for therapeutic benefit. We look forward to additional data from patients at the next dose levels in our ongoing clinical trial.”

Summary of Preliminary Data

• The range of PPi levels across three patients at screening was 132-333 nM.
• The range of PPi levels measured at six hours after the first dose was 581-1239 nM, an approximately 4-fold mean increase from screening across the three patients.
• The mean PPi level during the 32-day dose evaluation period across the three patients was 1356 nM, an approximately 5-fold mean increase from screening across the three patients.
• The range of peak PPi levels observed during the 32-day dose evaluation period across the three patients was 1082-2416 nM, and was comparable to data from our study of healthy subjects (n=10), which showed PPi levels between 1002 nM and 2169 nM.

PPi levels observed after dosing of INZ-701 correlated to systemic exposure and activity of INZ-701. PK analysis showed INZ-701 nearing steady-state by Day 29 with an approximately 4-fold accumulation from Day 1, based on AUC_0-72. The half-life of INZ-701 observed in this trial suggests the potential for once-weekly dosing. INZ-701 was generally well-tolerated, with no serious adverse events reported, and otherwise exhibited a favorable initial safety profile.

All three patients from the first cohort enrolled in the open-label Phase 2 48-week extension portion of the trial. At Week 12, low titers of anti-drug antibodies were observed in two out of three patients. The significantly increased PPi levels observed during the 32-day dose evaluation period were sustained in all three patients through Week 12 of the extension portion of the trial.

Following conclusion of the 32-day dose evaluation period, an independent Data Safety Monitoring Board (DSMB) reviewed preliminary data from the ongoing trial. Based on this review, the DSMB recommended the trial continue as planned. Dosing is underway at the 0.6 mg/kg dose level of INZ-701 in the second cohort of the trial. Inozyme plans to report topline data from the ongoing trial in the second half of 2022.

Inozyme conducted a controlled study in healthy subjects to establish a highly sensitive, reproducible PPi assay and to determine factors that may influence PPi measurements. The assay was validated in accordance with the Clinical Laboratory Improvement Amendments (CLIA) and is being used in the ongoing Phase 1/2 trial as a laboratory-developed test (LDT).

Key objectives of the healthy subject study were to determine if and how exercise and timing of meals, respectively, affect PPi levels in each subject. Results demonstrated intra-subject variability of PPi levels during the day with the timing of meals. In addition, exercise was shown to increase PPi levels in all subjects. Samples collected after an overnight fast had consistent PPi measurements with low intra-subject variability.

Data from this study of healthy subjects (n=10), using the same sample processing protocol employed in the ongoing and planned Phase 1/2 clinical trials of INZ-701 in ENPP1 Deficiency and ABCC6 Deficiency, showed PPi levels between 1002 nM and 2169 nM. Additional data from this study is expected to be presented at the European Calcified Tissue Society Congress (ECTS), being held on the 7-10^th of May 2022.

The ongoing Phase 1/2 open-label clinical trial is expected to enroll up to nine adult patients with ENPP1 Deficiency at sites in North America and Europe. The trial will primarily assess the safety and tolerability of INZ-701 in adult patients with ENPP1 Deficiency, as well as characterize the PK and pharmacodynamic (PD) profile of INZ-701, including evaluation of PPi and other biomarker levels. In the Phase 1 dose-escalation portion of the trial, Inozyme is assessing INZ-701 for 32-days at doses of 0.2 mg/kg, 0.6 mg/kg, and 1.8 mg/kg administered via subcutaneous injection twice weekly, with three patients per dose cohort. Doses were selected based on preclinical studies and PK/PD modeling. The Phase 1 dose-escalation portion of the trial seeks to identify a safe, tolerable dose that increases PPi levels, and that can be used for further clinical development. The open-label Phase 2 extension portion of the trial is assessing long-term safety, pharmacokinetics, and pharmacodynamics of continued treatment with INZ-701 for up to 48 weeks, where patients may receive doses of INZ-701 at home depending on site-specific protocols. Exploratory endpoints will include evaluations of skeletal, vascular, physical function and patient-reported outcomes.

ENPP1 Deficiency is a progressive condition that manifests as a spectrum of diseases. Individuals who present in utero or in infancy are typically diagnosed with generalized arterial calcification of infancy (GACI), which is characterized by extensive vascular calcification and neointimal proliferation (overgrowth of smooth muscle cells inside blood vessels), resulting in myocardial infarction, stroke, or cardiac or multiorgan failure. Approximately 45% to 50% of infants with ENPP1 Deficiency die within six months of birth. Children and adults with ENPP1 Deficiency typically experience rickets and osteomalacia (softened bones), a condition also known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2), and they can exhibit a range of signs and symptoms that include hearing loss, arterial calcification, and cardiac and/or neurological involvement. There are no approved therapies for ENPP1 Deficiency.

INZ-701 is a clinical-stage enzyme replacement therapy in development for the treatment of mineralization disorders of the circulatory system, bones, and kidneys. In preclinical studies, the experimental therapy has shown potential to generate PPi and to restore it to appropriate physiological levels, thereby preventing calcification in the vasculature and kidneys, while at the same time normalizing bone mineralization. Inozyme is developing INZ-701 for certain rare, life-threatening, and devastating genetic disorders such as ENPP1 Deficiency and ABCC6 Deficiency in which PPi levels are below the normal physiological levels. INZ-701 is currently in a Phase 1/2 clinical trial for the treatment of ENPP1 Deficiency.

Inozyme Pharma, Inc. is a clinical-stage rare disease biopharmaceutical company developing novel therapeutics for the treatment of diseases of abnormal mineralization impacting the vasculature, soft tissue, and skeleton. Through our in-depth understanding of the biological pathways involved in mineralization, we are pursuing the development of therapeutics to address the underlying causes of these debilitating diseases. It is well established that two genes, ENPP1 and ABCC6, play key roles in a critical mineralization pathway and that defects in these genes lead to abnormal mineralization. We are initially focused on developing a novel therapy, INZ-701, to treat the rare genetic diseases of ENPP1 and ABCC6 Deficiencies. INZ-701 is currently in a Phase 1/2 clinical trial for ENPP1 Deficiency. Inozyme Pharma was founded in 2017 by Joseph Schlessinger, PhD, Demetrios Braddock, MD, PhD, and Axel Bolte, MSc, MBA, with technology developed by Dr. Braddock and licensed from Yale University. For more information, visit www.inozyme.com.