A Study to Evaluate the Safety and Efficacy of BEAM-302 in Adult Patients With Alpha-1 Antitrypsin Deficiency (AATD)

Recruitment & Eligibility

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).

Study & Design

Arm && Interventions

Group	Intervention	Description
BEAM-302 Drug Product	BEAM-302	-

Primary Outcome Measures

Name	Time	Method
Phase 1 Dose Exploration: Rates of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)	2 years	Numbers and percentages of patients reporting a given AE
Phase 2 Dose Expansion: Absolute blood levels of total AAT	2 Years	Absolute Levels of AAT over time

Secondary Outcome Measures

Name	Time	Method
Phase 1 Dose Exploration: Absolute blood levels of total AAT	2 Years	Absolute Levels of AAT over time
Phase 2 Dose Expansion: Rates of TEAEs and SAEs	2 Years	Numbers and percentages of patients reporting a given AE

Recruitment & Eligibility