A Study of KB408 for the Treatment of Alpha-1 Antitrypsin Deficiency

Study Overview
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Brief Summary
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The Sponsor is developing KB408, a replication-defective, non-integrating herpes simplex virus type 1 (HSV-1)-derived vector engineered to deliver functional full-length human SERPINA1 to the airways of people with alpha-1 antitrypsin deficiency (AATD) via nebulization. This study is designed to evaluate safety and pharmacodynamics of KB408 in adults with AATD with a PI*ZZ genotype. Three planned dose levels of KB408 will be evaluated in single dose escalation cohorts. Subjects taking intravenous AAT augmentation therapy are not required to wash out from IV AAT in the low and mid dose cohorts. At the high dose, two cohorts will be conducted in parallel to evaluate patients on and off IV augmentation therapy.

Official Title
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A Phase 1 Study of Inhaled KB408 for the Treatment of Alpha-1 Antitrypsin Deficiency

Conditions
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Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
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* Drug: KB408 (Nebulization)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject or legally authorized representative must have read, understood, and signed an Institutional Review Board (IRB) approved Informed Consent Form and must be willing and able to comply with study procedures and instructions. Subject is aged ≥18 to ≤70 years, at the time of informed consent. Subject has a genetically confirmed diagnosis of AATD with a PI*ZZ genotype. Cohort 3b: Subjects receiving AAT augmentation therapy must be willing to washout for at least 6 weeks (42 days) prior to Screening and be willing to remain off augmentation therapy for the duration of the study. Cohort 3b: Serum AAT level <11 μM at Screening. Willing to remain on a stable regimen of treatment during the study. Resting oxygen saturation ≥92% on room air at Screening. Clinically stable and in good general health, except for AATD, as determined by the Investigator. Exclusion Criteria: Pulmonary function test with percent predicted forced expired volume in 1 second (ppFEV1) after inhalation of a bronchodilator is <50% at Screening. Diffusing capacity of the lungs for carbon monoxide (DLCO) <30 percent predicted (historical DLCO within 2 years prior to Screening without any intervening change in clinical status since the measurement was taken, or as measured at Screening). Known ongoing or history of clinically significant pulmonary impairment other than AATD. A pulmonary exacerbation within six weeks of first dose. Initiation of any new chronic therapy or any change in ongoing therapy routine within 28 days of first dose. Participation in another interventional clinical study or treatment with an investigational agent within 30 days or 5 half-lives, whichever is longer, of first dose. Previous treatment with a genetic therapy for AATD, where the investigational product was demonstrated to be non-efficacious, is not exclusionary. History of or listed for solid organ transplantation or has undergone major lung surgery (e.g., lobectomy) within 6 months of first dose. Any clinical condition or illness (including a history or current evidence of substance abuse or dependence) that, in the opinion of the Investigator, would impact a subject's ability to complete all study-related procedures and/or poses an additional risk to the assessment of safety of KB408. An active oral herpes infection 30 days prior to the first dose. Clinically significant hepatic dysfunction defined as any one of the following: AST and ALT ≥3× upper limit of normal (ULN) at Screening Total bilirubin ≥2× ULN at Screening (unless associated with Gilbert's syndrome) Evidence of liver cirrhosis with clinical manifestations of portal hypertension (e.g., ascites, encephalopathy, variceal hemorrhage) History of cigarette smoking or any other tobacco use, or use of e-cigarettes or other recreational inhalant, within 6 months of Screening. Unwilling to refrain from smoking, e-cigarette use, or vaping throughout the duration of the study. A positive urine cotinine result that is consistent with active smoking at Screening. (A positive cotinine test due to nicotine replacement therapy for the purpose of smoking cessation, as attested by the Investigator, is allowed.) Abnormal hematology or chemistry testing at Screening as defined below, or any other clinically significant abnormalities that the Investigator believes may interfere with the assessment of safety of the study treatment. Platelet count <100×10^9/L Hemoglobin <10 g/dL White blood cell count <3 or >15×10^9/L Sodium <130 or >150 mmol/L Potassium <3 or >5.5 mmol/L Bicarbonate <20 or >40 mmol/L Creatine >2 mg/dL Subject is known to be noncompliant or is unlikely to comply with the requirements of the study protocol, in the opinion of the Investigator. Females who are pregnant or nursing. Subject who is unwilling to comply with contraception requirements per protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Low dose KB408<br>Single dose of KB408 (low dose) | Drug: KB408 (Nebulization)<br>* Nebulized solution of KB408, a replication-defective HSV-1 vector expressing full length human SERPINA1<br>|
| Experimental: Cohort 2: Mid dose KB408<br>Single dose of KB408 (mid dose) | Drug: KB408 (Nebulization)<br>* Nebulized solution of KB408, a replication-defective HSV-1 vector expressing full length human SERPINA1<br>|
| Experimental: Cohort 3a/3b: High dose KB408<br>Single dose of KB408 (high dose) | Drug: KB408 (Nebulization)<br>* Nebulized solution of KB408, a replication-defective HSV-1 vector expressing full length human SERPINA1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate safety and tolerability of KB408 based upon assessment of adverse events (frequency, severity, relatedness), and changes from baseline in vital signs, ECG, spirometry, and clinical laboratory test results | Number of subjects with treatment related adverse events as assessed by NCI-CTCAE v5 | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect of KB408 on serum alpha-1 antitrypsin (AAT) concentration | Change from baseline in serum AAT levels | 2 months | 
| To assess the effect of KB408 on plasma neutrophil elastase (NE) concentration | Change from baseline in plasma NE levels | 2 months | 
| To evaluate the effect of KB408 on AAT concentration in the lung | Change from baseline in AAT levels in bronchoalveolar lavage fluid and sputum | 2 months | 
| To evaluate the effect of KB408 on NE concentration in the lung | Change from baseline in NE levels in bronchoalveolar lavage fluid and sputum | 2 months |