A Phase 1/2 Dose-Exploration and Dose-Expansion Study to Evaluate the Safety and Efficacy of BEAM-302 in Adult Patients with Alpha-1 Antitrypsin Deficiency (AATD)-Associated Lung Disease and/or Liver Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Beam Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

6 Feb 2025 → ongoing

Decision date (initial)

2025-02-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Phase 1 (Dose Exploration) Primary Objective:
• To evaluate the safety and tolerability of BEAM-302 in patients with AATD-associated lung and/or liver disease and to determine the optimal biological dose (OBD).
Phase 2 (Dose Expansion) Primary Objective
• To evaluate the efficacy as reflected by the pharmacodynamic (PD) activity of BEAM 302 in patients with AATD-associated lung and/or liver disease and to confirm the OBD.

Secondary objectives 5

1. Secondary objectives apply to the entire study unless preceded with “Phase 1 (Dose Exploration)” or “Phase 2 (Dose Expansion).” T
2. Phase 1 (Dose Exploration): To evaluate the PD activity of BEAM-302
3. Phase 2 (Dose Expansion): To evaluate the safety and tolerability of BEAM-302
4. To evaluate the pharmacokinetics (PK) of BEAM-302
5. To evaluate the potential immunogenicity of BEAM-302

Conditions and MedDRA coding

Alpha-1 Antitrypsin Deficiency (AATD)-Associated Lung Disease and/or Liver Disease

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

Yes

IPD plan description

The sponsor, people and companies working with or for the sponsor for the purpose of this study and the regulatory or government agencies worldwide may have access to deidentified individual clinical trial patient level data.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Part A: Males or females 18 – 70 years of age inclusive at the time of consent.
2. Part A: Diagnosis of AATD and homozygous for the PiZ mutation (confirmed by genetic testing).
3. Part A: Blood total AAT level <11 μM or equivalent protein in mg/dL.
4. Part A: Patients receiving augmentation therapy in regions where augmentation is not standard of care (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 per Section 6.5.1).
5. Part A: A postbronchodilator FEV1 ≥40% (Phase 1) or ≥35% (Phase 2) of predicted and an FEV1/FVC <70% at screening. (PFTs obtained within 1 year of signing the ICF may be used for eligibility.)
6. Part A: 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.)
7. Part A: Willingness to abstain from alcohol use, herbal supplements, and daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to not engage in strenuous exercise beyond their typical routine from start of screening period through 28 days post IMP administration.
8. Part A: Willingness to participate in this study and a long-term extension study with the understanding that the total study participation is 15 years.
9. Part A: Females of childbearing potential must be willing to use highly effective contraception (defined in Appendix 1) from the signing of the ICF through at least 6 months after administration of BEAM-302; males must be willing to use highly effective contraception from the time of dosing through at least 4 months after.
10. Part A: Able to understand the study and provide informed consent.
11. Part A: Willingness to not use any investigational product for the duration of the study. Exclusion Criteria
12. Part B: 1. Males or females 18 – 70 years of age inclusive at the time of consent.
13. Part B: 2. Diagnosis of AATD and homozygous for the PiZ mutation (confirmed by genetic testing).
14. Part B: 3. 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.
15. Part B: 4. A postbronchodilator FEV1 ≥40% of predicted at screening. (PFTs obtained within 1 year of signing the ICF may be used for eligibility.)
16. Part B: 5. Willingness to abstain from alcohol use, herbal medications, and daily use of NSAIDs and to not engage in strenuous exercise beyond their typical routine from start of screening period through 28 days post IMP administration.
17. Part B: 6. Willingness to participate in this study and a long-term extension study with the understanding that the total study participation is 15 years.
18. Part B: 7. Females of childbearing potential must be willing to use highly effective contraception (defined in Appendix 1) from the signing of the ICF through at least 6 months after administration of BEAM-302; males must be willing to use highly effective contraception from the time of dosing through at least 4 months after.
19. Part B: 8. Able to understand the study and provide informed consent.
20. Part B: 9. FibroScan ≤12 kPa.
21. Part B: 10. Willingness to not use any investigational product for the duration of the study.

Exclusion criteria 59

1. Part A: Lung or liver transplant or on waiting list for lung or liver transplant or status post lung volume reduction surgery.
2. Part A: COPD exacerbation (defined in Appendix 2) within 6 weeks of signing informed consent.
3. Part A: Clinical evidence of severe bronchiectasis as per the discretion of the investigator (eg, excessive sputum production or recurrent infections requiring antibiotic use [>4x/year]).
4. Part A: On long-term oxygen (ie, requiring continuous oxygen for everyday activities).
5. Part A: Body mass index >30.
6. Part A: Current or recent smoking history (regular smoking within 12 months prior to signing the informed consent form [ICF]) or not willing to abstain from smoking (including vaporizers/e-cigarettes, marijuana) for the duration of the study.
7. Part A: Liver disease with any of the following: o 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]. o Known history of liver cirrhosis or complications of cirrhosis (eg, varices, ascites, hepatic encephalopathy). o Presence of ≥F2 liver fibrosis if a patient has previously had a liver biopsy. o Have ALT or AST > upper limit of normal (ULN). o Total bilirubin levels > ULN; if documented Gilbert’s Syndrome, total bilirubin >2 × ULN. o 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. o Seropositive for hepatitis B (positive surface Ag). o Active hepatitis C by hepatitis C virus (HCV) antibody. If HCV antibody positive, must be HCV RNA polymerase chain reaction (PCR) negative.
8. Part A: Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <40%, transient ischemic attack, or cerebrovascular accident) within 6 months prior to screening.
9. Part A: A history of torsades de pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), heart block (excluding first-degree block), congenital long QT syndrome, new ST segment elevation or depression or new Q wave on electrocardiogram (ECG), or QT interval corrected using Fridericia’s method (QTcF) >450 msec.
10. Part A: Has a known history of alcohol abuse or daily heavy alcohol consumption (females: more than 14 units of alcohol per week; males: more than 21 units of alcohol per week [unit: 1 glass of wine (125 mL) = 1 measure of spirits = ½ pint of beer]).
11. Part A: Current illicit drug use.
12. Part A: Positive serology for human immunodeficiency virus (HIV) (HIV-1 or HIV-2).
13. Part A: Estimated glomerular filtration rate (eGFR) <60 mL/min by CKD-EPI equation (Miller, 2022).
14. Part A: Absolute neutrophil count (ANC) <1500 cells/mm3 OR platelet count <150,000 cells/mm3 OR hemoglobin <10 g/dL for males or <9 g/dL for females.
15. Part A: Active COVID infection as defined as clinical symptoms plus antigen test positivity or positive PCR test within 7 days prior to consent. (Must be symptom free and PCR negative before joining the study.)
16. Part A: Previous treatment with any cell, gene, or viral vector-derived experimental therapy.
17. Part A: Received an LNP treatment (eg, LNP mRNA-based COVID vaccinations) in the 1 month prior to enrollment.
18. Part A: Prior medically significant vaccine-related reaction (eg, severe hypersensitivity, myocarditis) to an LNP-based product (eg, mRNA-based COVID vaccinations).
19. Part A: Use of any investigational product within 30 days (or 5 half-lives, whichever is longer) prior to enrollment.
20. Part A: Initiation or increase in the dose of a medication that, in the judgment of the investigator, has known potential risk of increasing liver function tests (LFTs; eg, statins, ACE inhibitors, and antifungals) within 5 weeks prior to screening through the completion of the 28-day DLT period.
21. Part A: Use of systemic steroids above a stable dose equivalent to 10 mg/day daily of prednisone within the 5 weeks prior to screening or during the screening period.
22. Part A: Positive serum pregnancy test or breastfeeding at screening (female participants).
23. Part A: Known allergies to any component of BEAM-302.
24. Part A: Contraindication to short-term corticosteroid use or conditions that could worsen in the presence of corticosteroids as assessed and determined by the investigator.
25. Part A: Unwilling or unable to comply with protocol-required visit schedule and visit requirements or provide written informed consent.
26. Part A: Malignancy within 2 years except for basal or squamous cell carcinoma or carcinoma in situ of the cervix that has been successfully treated.
27. Part A: Serious intercurrent illness, infectious disease, abnormal laboratory result at screening, or medical condition including malignancy or extenuating circumstances that, in the opinion of the investigator, could impair the assessment of safety results or preclude compliance with the study.
28. Part B: 1. Lung or liver transplant or on waiting list for lung or liver transplant or status post lung volume reduction surgery.
29. Part B: 2. Current or recent smoking history (regular smoking within 12 months prior to signing the ICF) or not willing to abstain from smoking (including vaporizers/e-cigarettes, marijuana) for the duration of the study.
30. Part B: 3. Clinical evidence of severe bronchiectasis as per the discretion of the investigator (eg, excessive sputum production or recurrent infections requiring antibiotic use [>4x/year])
31. Part B: 4. 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.
32. Part B: 5. Finding on ultrasound or other that would preclude a safe biopsy at the discretion of the investigator.
33. Part B: 6. COPD exacerbation (defined in Appendix 2) within 6 weeks of signing informed consent.
34. Part B: 7. On long-term oxygen (ie, requiring continuous oxygen for everyday activities).
35. Part B: 8. Total bilirubin levels >ULN; if documented Gilbert’s Syndrome, total bilirubin >2 × ULN.
36. Part B: 9. ALT and AST >1.5X ULN.
37. Part B: 10. eGFR <60 mL/min by CKD-EPI equation (Miller, 2022).
38. Part B: 11. Seropositive for hepatitis B (positive surface Ag).
39. Part B: 12. Active hepatitis C by HCV antibody. If HCV antibody positive, must be HCV RNA PCR negative.
40. Part B: 13. Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <40%, transient ischemic attack, or cerebrovascular accident) within 6 months prior to screening.
41. Part B: 14. Previous diagnosis of liver cirrhosis or complications of cirrhosis (eg, varices, ascites, hepatic encephalopathy).
42. Part B: 15. A history of torsades de pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), heart block (excluding first-degree block), congenital long QT syndrome, new ST segment elevation or depression or new Q wave on ECG, or QTcF >450 msec.
43. Part B: 16. Has a known history of alcohol abuse or daily heavy alcohol consumption (females: more than 14 units of alcohol per week; males: more than 21 units of alcohol per week [unit: 1 glass of wine (125 mL) = 1 measure of spirits = ½ pint of beer]).
44. Part B: 17. Current illicit drug use.
45. Part B: 18. Positive serology for HIV (HIV-1 or HIV-2).
46. Part B: 19. ANC <1500 cells/mm3 OR platelet count <150,000 cells/mm3 OR hemoglobin <10 g/dL for males or <9 g/dL for females.
47. Part B: 20. Active COVID infection as defined as clinical symptoms plus antigen test positivity or positive PCR test within 7 days prior to consent. (Must be symptom free and PCR negative before joining the study.)
48. Part B: 21. Previous treatment with any cell, gene, or viral vector-derived experimental therapy.
49. Part B: 22. Received an LNP treatment (eg, LNP mRNA-based COVID vaccinations) in the 1 month prior to enrollment.
50. Part B: 23. Prior medically significant vaccine-related reaction (eg, severe hypersensitivity, myocarditis) to an LNP-based product (eg, mRNA-based COVID vaccinations).
51. Part B: 24. Use of any investigational product within 30 days (or 5 half-lives, whichever is longer) prior to enrollment.
52. Part B: 25. Initiation or increase in the dose of a medication that, in the judgment of the investigator, has known potential risk of increasing LFTs (eg, statins, ACE inhibitors, and antifungals) within 5 weeks prior to screening through the completion of the 28-day DLT period.
53. Part B: 26. Use of systemic steroids above a stable dose equivalent to 10 mg/day daily of prednisone within the 5 weeks prior to screening or during the screening period.
54. Patt B: 27. Positive serum pregnancy test or breastfeeding at screening (female participants).
55. Part B: 28. Known allergies to any component of BEAM-302.
56. Part B: 29. Contraindication to corticosteroid use or conditions that could worsen in the presence of corticosteroids as assessed and determined by the investigator.
57. Part B: 30. Unwilling or unable to comply with protocol-required visit schedule and visit requirements or provide written informed consent.
58. Part B: 31. Malignancy within 2 years except for basal or squamous cell carcinoma or carcinoma in situ of the cervix that has been successfully treated.
59. Part B: 32. Serious intercurrent illness, infectious disease, abnormal laboratory result at screening, or medical condition including malignancy or extenuating circumstances that, in the opinion of the investigator, could impair the assessment of safety results or preclude compliance with the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1 (Dose Exploration) Primary Endpoint: Rates of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
2. Phase 2 (Dose Expansion) Primary Endpoint: Absolute blood levels of total AAT, Z-AAT, and M-AAT

Secondary endpoints 8

1. Secondary endpoints apply to the entire study unless preceded with “Phase 1 (Dose Exploration)” or “Phase 2 (Dose Expansion).”
2. • Phase 1 (Dose Exploration): Absolute blood levels of total AAT
3. • Phase 2 (Dose Expansion): Rates of TEAEs and SAEs
4. • Change from baseline in blood levels of total AAT
5. • Blood levels of Z-AAT and M-AAT
6. • Change from baseline in blood levels of functional AAT
7. • Area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC∞), maximum concentration (Cmax), time to maximum concentration (Tmax), terminal half-life (t½) for the plasma levels of mRNA, gRNA, and lipids (ALC-0366 and ALC-0159)
8. • Blood anti-BEAM-302 antibodies and anti-ABE antibodies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Beam Therapeutics Inc.

Sponsor organisation

Beam Therapeutics Inc.

Address

238 Main Street

City

Cambridge

Postcode

02142-1016

Country

United States

Scientific contact point

Organisation

Beam Therapeutics Inc.

Contact name

Annie Woodland

Public contact point

Organisation

Beam Therapeutics Inc.

Contact name

Annie Woodland

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 43 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications