Overview

This is a Phase 1/2, multicenter, open-label, dose-exploration (Phase 1) and dose-expansion (Phase 2) study to evaluate the safety, tolerability, PK/PD, and efficacy of BEAM-302 in adult patients with AATD-associated lung disease and/or liver disease and to determine the optimal biological dose (OBD).

Eligibility

Part A:

Inclusion Criteria:

• Males or females 18 - 70 years of age inclusive at the time of consent.
• Diagnosis of AATD and homozygous for the PiZZ mutation (confirmed by genetic testing).
• Blood total AAT level <11 μM or equivalent protein in mg/dL.
• Patients receiving augmentation therapy in regions where augmentation is not SoC must be willing to washout augmentation therapy for at least 6 weeks prior to signing the ICF and for the length of the study (unless clinically indicated)
• A postbronchodilator FEV1 ≥40% of predicted and an FEV1/FVC <70% at screening. (PFTs obtained within 1 year of signing the ICF may be used for eligibility.)
• Evidence of emphysema on a historic CT scan or a DLCO ≤70% of the predicted value (corrected for hemoglobin) at screening. (PFTs obtained within 1 year of signing the ICF may be used for eligibility.)

Exclusion Criteria:

• Body mass index >30
• Lung or liver transplant or on waiting list for lung or liver transplant or status post lung volume reduction surgery.
• Clinical evidence of severe bronchiectasis as per the discretion of the investigator (eg, excessive sputum production or recurrent infections requiring antibiotic use [>4x/year]).
• Liver disease with any of the following:
  • FibroScan liver stiffness measurement ≥7.5 kilopascals (kPa). (For sites without access to FibroScan, APRI >0.5 can be used as a surrogate exclusion criterion [Yilmaz, 2011].
  • Known history of liver cirrhosis or complications of cirrhosis (eg, varices, ascites, hepatic encephalopathy).
  • Presence of ≥F2 liver fibrosis if a patient has previously had a liver biopsy.
  • Have ALT or AST > upper limit of normal (ULN).
  • Total bilirubin levels > ULN; if documented Gilbert's Syndrome, total bilirubin >2 × ULN.
  • INR ≥1.2 at screening. If deemed appropriate by the investigator and/or prescribing physician, the patient may stop taking anticoagulants for an appropriate washout period or reversal with vitamin K and if indicated, a repeat INR within <1.2 would be acceptable.
  • Seropositive for hepatitis B (positive surface Ag).
  • Active hepatitis C by hepatitis C virus (HCV) antibody. If HCV antibody positive, must be HCV RNA polymerase chain reaction (PCR) negative.

Part B:

Inclusion Criteria:

• Males or females 18 - 70 years of age inclusive at the time of consent.
• Diagnosis of AATD and homozygous for the PiZZ mutation (confirmed by genetic testing).
• Evidence of METAVIR F1, F2, or F3 liver fibrosis based on a central read of a baseline liver biopsy during the screening period or a histological diagnosis made no more than 6 months before enrollment and stage confirmed by central read.
• A postbronchodilator FEV1 ≥40% of predicted at screening. (PFTs obtained within 1 year of signing the ICF may be used for eligibility.)

Exclusion Criteria:

• Lung or liver transplant or on waiting list for lung or liver transplant or status post lung volume reduction surgery.
• Clinical evidence of severe bronchiectasis as per the discretion of the investigator (eg, excessive sputum production or recurrent infections requiring antibiotic use [>4x/year])
• Previous diagnosis of liver cirrhosis or complications of cirrhosis (eg, varices, ascites, hepatic encephalopathy).