Slide 1: Rewriting the Code: Precision Delivery Vectors and Gene Therapy for Pulmonary Vascular Diseases
REWRITING THE CODE: PRECISION DELIVERY VECTORS AND GENE THERAPY FOR PULMONARY VASCULAR DISEASES The potential for base editing to treat diseases impacting the lungs: Ongoing data from the BEAM-302 clinical trial in alpha-1 antitrypsin deficiency (AATD) Amy Simon, MD Chief Medical Officer, Beam Thera
Slide 2: Base editing
Base editing
Slide 3: Base editing is an efficient, predictable, and potentially best-in-class gene editing technology
Base editing is an efficient, predictable, and potentially best-in-class gene editing technology NUCLEASE CRISPR, ZFN, TALENs BASE EDITING Precision Precision targeting targeting with CRISPR with CRISPR Double-stranded Enzymatic base breaks conversion …A C G - - - - G C A T… Lack of control of …A C
Slide 4: Base editing technology has multiple, highly versatile applications
Base editing technology has multiple, highly versatile applications CRISPR protein Correct Repairs the most common type of gene mutation, mutations single base changes Deaminase Guide RNA Silence Turns off gene with disease-causing activity proteins Activate Turns on genes to restore or increase the
Slide 5: What if we could use base editing to correct disease-causing mutations in vivo?
What if we could use base editing to correct disease-causing mutations in vivo?
Slide 6: Severe AATD (ZZ genotype) impacts ~100,000 individuals in the US, with limited treatment options
Severe AATD (ZZ genotype) impacts ~100,000 individuals in the US, with limited treatment options 1 Progressive lung disease due to:3 o Routine COPD care4 • Low and poorly functioning o Intravenous systemic M-AAT levels augmentation therapy • Circulating Z-AAT aggregates, given weekly is only causes
Slide 7: Potential for BEAM-302: a one-time treatment that restores gene function
Potential for BEAM-302: a one-time treatment that restores gene function to address the spectrum of AATD disease manifestations GOALS OF BEAM-302 TREATMENT • Liver produces M-AAT for the first time • Significantly reduces Durable, single- Z-AAT course treatment • Total AAT above 11 µM Address both C
Slide 8: BEAM-302 utilizes non-viral, lipid nanoparticle (LNP) delivery to target the liver and correct the SERPINA1 gene
BEAM-302 utilizes non-viral, lipid nanoparticle (LNP) delivery to target the liver and correct the SERPINA1 gene Nuclear import Lipid Base editor mRNA T Target DNA ▲ gRNA A binding Translation of Formulate LNP editor protein Correction A G editing Expression of Release of corrected mRNA & gRNA SERPI
Slide 9: Initial data from the Phase 1/2 study of BEAM-302
Initial data from the Phase 1/2 study of BEAM-302
Slide 10: Key elements of BEAM-302 phase 1/2 study design
Key elements of BEAM-302 phase 1/2 study design PART A: • Goal: assess early safety AATD-associated lung disease and efficacy and identify optimal dose for pivotal study DOSE ESCALATION • Key eligibility criteria: – 18-70 years of age; Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 homozygous for PiZZ
Slide 11: No serious adverse events or dose-dependent safety trends were observed in BEAM-302 single-dose cohorts
No serious adverse events or dose-dependent safety trends were observed in BEAM-302 single-dose cohorts Part A 15 mg 30 mg 60 mg 75 mg Patients, n (%) N=3 N=3 N=6 N=9 At least 1 TEAE 3 (100.0) 3 (100.0) 6 (100.0) 8 (88.9) Related to BEAM-302 2 (66.7) 0 (0) 3 (50.0) 5 (55.6) At least 1 TEAE ≥Grade 3
Slide 12: A single dose of BEAM-302 (≥60 mg) led to sustained total AAT levels above the protective threshold
A single dose of BEAM-302 (≥60 mg) led to sustained total AAT levels above the protective threshold (≥11 μM) Part A 20 15 mg 30 mg 60 mg 75 mg 18 16 14 Blood total AAT (μM) 12 11 μM protective 10 threshold1* 8 6 4 N= 6 6 6 6 6 6 6 5 5 3 9 9 9 9 7 6 6 6 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 0 B
Slide 13: A single dose of BEAM-302 (≥60 mg) led to ~80% reduction in circulating Z-AAT
A single dose of BEAM-302 (≥60 mg) led to ~80% reduction in circulating Z-AAT Part A Blood Z-AAT (%) 60 mg (N=6) 75 mg (N=9) Percentage change in -84% (6.2%) -79% (11.8%) steady state,* mean (SD) Data cutoff February 10, 2026. Z-AAT was measured by LC-MS. *Steady state is defined as the period begin
Slide 14: BEAM-302 treatment led to production of M-AAT for the first time in circulation
BEAM-302 treatment led to production of M-AAT for the first time in circulation that was sustained (green bars) Part A 15 mg 30 mg 60 mg 75 mg PiZ isoforms 120 PiM isoforms Proportion of total AAT (%) 100 MZ 80 genotype1 60 40 20 0 % M-AAT= 0 24 45 46 48 47 46 47 51 55 0 31 60 63 60 60 64 64 66 66 0
Slide 15: Human neutrophil elastase (HNE) activity was reduced in all participants following BEAM-302
Human neutrophil elastase (HNE) activity was reduced in all participants following BEAM-302 Part A HNE 60 mg 500 HNE concentration (ng/mL) 400 300 200 Lower limit of 100 quantification (LLOQ)* N= 6 6 5 6 5 0 At 60 mg dose, ~80% of participants had at least one measurement below LLOQ Data cutoff Febr
Slide 16: BEAM-302 restored physiologic AAT inducibility in a patient following a respiratory infection
BEAM-302 restored physiologic AAT inducibility in a patient following a respiratory infection Inflammation corresponding to infection* 35 Increased AAT level during upper respiratory 30 tract infection 29.5 μM 95% M-AAT 25 21.4 μM Total AAT (μM) New AAT baseline after 20 95% treatment with M-AAT BEA
Slide 17: Novel scientific discoveries, such as base editing, can provide new approaches to target the underlying cause of serious genetic diseases
Novel scientific discoveries, such as base editing, can provide new approaches to target the underlying cause of serious genetic diseases Base editing represents a promising new way to treat genetic diseases in vivo at the root cause BEAM-302 is a therapeutic base editor and the first to correct a d
Slide 18: Next steps
Next steps ► A pivotal cohort to support accelerated approval is scheduled to begin in second half of 2026 ► Based on the strong, consistent safety and efficacy profile across single dose cohorts, 60 mg of BEAM-302 selected as the optimal biological dose for the pivotal cohort Dan, living with AATD
Slide 19: Gene editing could potentially address genetic targets of pulmonary vascular disease
Gene editing could potentially address genetic targets of pulmonary vascular disease ► High value genetic targets such as BMPR2 and KCNK3 have been identified in pulmonary vascular disease ures Mod ► Next generation LNPs are being developed to target extrahepatic tissues l struct ific ati m ica on h
Slide 20: Acknowledgments
Acknowledgments Thank you to the study participants, their families, and their caregivers for their participation, and the study investigators for their contributions US UK AUS Andrew Wilson, MD Aishath Fazleen, MBBS Mark Holmes, MD PhD Boston Medical Center University Hospital Southampton Royal A
Slide 21: Thank You
THANK YOU