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

NCT06049082 | Recruiting Phase 1 FDA Drug

• 1 other identifier: KB408-01
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

Brief Summary

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 or PI\*ZNull genotype. Three planned dose levels of KB408 will be evaluated in single dose escalation cohorts. Repeat dosing will be evaluated at the mid dose level. Subjects taking intravenous AAT augmentation therapy are not required to wash out from IV AAT in the low and mid dose cohorts. In the repeat dose and the high dose cohorts, subjects must wash out from IV AAT for at least 10 days, as applicable.

Conditions

Alpha 1-Antitrypsin Deficiency

Outcome Measures

Primary Outcomes (1)

• 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 (Cohorts 1, 2, 3); 3 months (Cohort 2b)

Secondary Outcomes (4)

• To assess the effect of KB408 on serum alpha-1 antitrypsin (AAT) concentration

  2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b)

• To assess the effect of KB408 on plasma neutrophil elastase (NE) concentration

  2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b)

• To evaluate the effect of KB408 on AAT concentration in the lung

  2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b)

• To evaluate the effect of KB408 on NE concentration in the lung

  2 months (Cohorts 1, 2, 3); 3 months (Cohort 2b)

Study Arms (4)

Cohort 1: Low dose KB408

EXPERIMENTAL

Single dose of KB408 (low dose)

Drug: KB408 (Nebulization)

Cohort 2: Mid dose KB408

EXPERIMENTAL

Single dose of KB408 (mid dose)

Drug: KB408 (Nebulization)

Cohort 3: High dose KB408

EXPERIMENTAL

Single dose of KB408 (high dose)

Drug: KB408 (Nebulization)

Cohort 2b: Mid dose KB408

EXPERIMENTAL

Multiple doses of KB408 (mid dose)

Drug: KB408 (Nebulization)

Interventions

KB408 (Nebulization) DRUG

Nebulized solution of KB408, a replication-defective HSV-1 vector expressing full length human SERPINA1

Cohort 1: Low dose KB408; Cohort 2: Mid dose KB408; Cohort 2b: Mid dose KB408; Cohort 3: High dose KB408

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 or PI\*ZNull genotype.
• Cohort 2b and Cohort 3: Subjects receiving AAT augmentation therapy must be willing to washout for at least 10 days prior to Screening and be willing to remain off augmentation therapy for the duration of the study.
• Cohort 2b and Cohort 3: 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.

You may not qualify if:

• Pulmonary function test with percent predicted forced expired volume in 1 second (ppFEV1) after inhalation of a bronchodilator is \<40% 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 (42 days) of first dose.
• Initiation of any new chronic therapy or any change in ongoing therapy routine within 28 days of first dose.
• 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.)

Sponsors & Collaborators

• Krystal Biotech, Inc.: lead

Study Sites (3)

University of Florida, Gainesville

Gainesville, Florida, 32610, United States

RECRUITING

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

RECRUITING

Renovatio Clinical

The Woodlands, Texas, 77380, United States

RECRUITING

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• David Sweet, MD, PhD

  Director of Clinical Development

  STUDY DIRECTOR

Central Study Contacts

David Sweet, MD, PhD

CONTACT

412-586-5830; dsweet@krystalbio.com

Brittani Agostini, RN, CCRC

CONTACT

412-586-5830; bagostini@krystalbio.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2023
• First Posted: September 21, 2023
• Study Start: February 15, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)