Beam Therapeutics (BEAM) Conference presentation summary

Disease overview and unmet need

• Phenylketonuria (PKU) is a genetic metabolic disorder caused by recessive mutations in the PAH gene, leading to neurotoxicity from elevated phenylalanine (Phe) levels.

• Symptoms range from intellectual disability in children to cognitive impairment and psychiatric issues in adults, with risks for newborns of affected mothers.

• Management requires strict lifelong dietary restrictions and medical food, with current therapies offering limited efficacy and significant burden.

• Many patients struggle to maintain target Phe levels, resulting in suboptimal disease control.

BEAM-304 platform and preclinical development

• BEAM-304 is a base editing gene therapy platform targeting PKU, aiming for significant and sustained Phe reduction and potential diet normalization.

• BEAM-304A targets the common PAH-p.R408W mutation using an adenine base editor delivered via mRNA-LNPs.

• A single dose in mice resulted in potent, precise liver editing and dose-dependent reductions in plasma Phe below clinical targets, with effects seen in both homozygous and compound heterozygous models.

• Editing and Phe reduction occurred rapidly and were durable for at least 90 days post-dose.

Platform expansion and clinical development

• BEAM-304B is being developed to target a second PKU mutation, using the same delivery platform but different editor and guide RNA, potentially covering nearly half of US PKU patients.

• BEAM-304B also demonstrated potent editing and Phe reduction in preclinical models.

• Learnings from BEAM-304A are expected to expedite development and regulatory pathways for future variants, leveraging platform synergies and FDA guidance.

• A Phase 1/2 open-label, single-ascending dose trial for BEAM-304A in PKU patients with the R408W mutation is planned, focusing on safety, tolerability, and Phe reduction.