Phase 1 Study to Assess the Safety, PK and PD of INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency

Study Overview
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Brief Summary
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This is an open-label, 2-part, dose-escalating, Phase 1 study of INBRX-101 (rhAAT-Fc). Part 1 will consist of single ascending dose (SAD) administration of INBRX-101 and Part 2 will consist of multiple ascending dose (MAD) administrations of INBRX-101. The planned dosing schedule is IV every 3 to 4 weeks.

Official Title
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An Open-Label, Multicenter, Phase 1 Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Intravenous Doses of Inhibrx rhAAT-Fc (INBRX-101) in Adults With Alpha-1 Antitrypsin Deficiency (AATD)

Conditions
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AATD, Alpha-1 Antitrypsin Deficiency

Intervention / Treatment
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* Drug: INBRX-101/rhAAT-Fc


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented alpha-1 antitrypsin (AAT) serum concentration <11 μM. Diagnosis of alpha-1 antitrypsin deficiency (AATD) with any allelic combination with exception of the null/null genotype. For subjects in Part 2 80 and 120 mg/kg cohorts ONLY: post-bronchodilator FEV1 of at least 40% of predicted normal value. For subjects in Part 2 80 and 120 mg/kg cohorts ONLY: subjects eligible for bronchoscopy per judgment of investigator. Nonsmoker for at least 6 months prior to study and must remain nonsmoking for the entire study duration. Adequate hepatic and renal function as defined per protocol. Willing to undergo current augmentation therapy washout (if applicable) and refrain from initiating augmentation therapy, other investigational drug trials for AATD, therapy with IV immunoglobulins or monoclonal antibodies during the entire study, including follow-up. Exclusion Criteria: Known or suspected allergy to components of INBRX-101 (AAT or human IgG) or pdAAT. Participation in any investigational drug trial within 30 days prior to this trial, or subjects receiving IV immunoglobulins or monoclonal antibodies within 30 days prior to this trial. History of and/or on the waiting list for lung or liver transplant, lobectomy, or lung volume reduction surgery. Acute respiratory tract infection or COPD exacerbation that required antibiotic treatment and/or increase in systemic steroid dosage within the 4 weeks prior to screening. Subjects are permitted to continue to receive steroids if the investigator judges the subject to have a history of stable dosing. Subjects with ongoing or history of unstable cor pulmonale. Infection with hepatitis A, B, or C or human immunodeficiency virus (HIV). Active autoimmune disease or documented history of autoimmune disease that 1) required systemic steroids or immune-suppressive medications and 2) tested positive for auto-antibodies. Exception: Endocrinopathies managed with hormone replacement therapy (HRT). Current substance and/or alcohol abuse with protocol defined exceptions. Current narcotics abuse with protocol defined exceptions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Single Ascending Dose<br>INBRX-101 will be escalated in subjects with alpha-1 antitrypsin deficiency (AATD). | Drug: INBRX-101/rhAAT-Fc<br>* INBRX-101 is a recombinant human alpha-1 antitrypsin (AAT) Fc fusion protein (rhAAT-Fc).<br>|
| Experimental: Part 2 Multiple Ascending Dose<br>INBRX-101 will be escalated in subjects with alpha-1 antitrypsin deficiency (AATD). | Drug: INBRX-101/rhAAT-Fc<br>* INBRX-101 is a recombinant human alpha-1 antitrypsin (AAT) Fc fusion protein (rhAAT-Fc).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events of INBRX-101 | Adverse events will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. | Up to 7 months | 
| Severity of adverse events of INBRX-101 | Severity of adverse events will be assessed and assigned by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. | Up to 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration time curve (AUC) of INBRX-101 | Area under the serum concentration time curve (AUC) of INBRX-101 will be determined. | Up to 7 months | 
| Maximum observed serum concentration (Cmax) of INBRX-101 | Maximum observed serum concentration (Cmax) of INBRX-101 will be determined. | Up to 7 months | 
| Trough observed serum concentration (Ctrough) of INBRX-101 | Trough observed serum concentration (Cmax) of INBRX-101 will be determined. | Up to 7 months | 
| Time to Cmax (Tmax) of INBRX-101 | Time to Cmax (Tmax) of INBRX-101 will be determined. | Up to 7 months | 
| Half-life (T1/2) of INBRX-101 | Half-life of INBRX-101 will be determined. | Up to 7 months | 
| Immunogenicity of INBRX-101 | Frequency and consequences of anti-drug antibodies (ADA) against INBRX-101 will be determined. | Up to 7 months | 
| Distribution of INBRX-101 in Bronchoalveolar Lavage Fluid (BALF) | The concentration of INBRX-101 in bronchoalveolar lavage fluid (BALF) be determined. | Up to 7 months | 
| Functional concentration of INBRX-101 in serum and BALF | The functional concentration of INBRX-101 in serum and BALF will be determined. | Up to 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alpha-1 antitrypsin deficiency, AATD, alpha-1 disease, AAT