Beam Therapeutics (NASDAQ:BEAM) outlined a new liver-targeted development program for phenylketonuria (PKU) and announced a large, non-dilutive financing tied to its sickle cell disease launch plans during its fourth-quarter and full-year 2025 results call.
New PKU program: BEAM-304
Chief Executive Officer John Evans said the company is expanding its liver franchise with BEAM-304, an in vivo base-editing program intended to correct disease-causing mutations in the phenylalanine hydroxylase (PAH) gene. Evans emphasized base editing’s ability to make precise single-base changes without double-stranded DNA breaks, which he said can drive “predictable and reproducible outcomes.”
PKU disease burden and target product profile
Chief Medical Officer Dr. Amy Simon reviewed the clinical impact of PKU and limitations of current management. She said PKU is typically identified through newborn screening, but many patients struggle with metabolic control over time. Simon cited data indicating that while most pediatric patients remain below guideline-recommended Phe levels through about age 12, control declines with age and only about 25% of adults remain under 360 micromolar.
Simon described the burden of a severely restricted diet and the need for costly, poorly tolerated medical foods. She noted that BH4 cofactor therapy can help patients with residual PAH activity, while more moderate-to-severe patients may require enzyme replacement therapy administered as daily subcutaneous injections, which can take one to two years to reach target levels and only does so in about 60% of patients. She also said discontinuation rates are high due to immune reactions and hypersensitivity.
Beam said its target product profile for BEAM-304 is anchored to regulatory precedent and clinician feedback and aims for significant, sustained Phe reduction below 360 micromolar, tolerability, diet normalization, and one-time administration.
Preclinical data and planned clinical path
Chief Scientific Officer Dr. Gopi Shanker said Beam has identified two development candidates within BEAM-304 targeting the two most prevalent PKU mutations, including R408W (the most common). He said the two candidates together could address nearly half of PKU patients, with research underway to cover additional pathogenic mutations over time.
Shanker presented mouse model data for R408W and a second mutation (“mutation B”), stating that a single 0.3 mg/kg dose of BEAM-304 led to a rapid reduction in plasma Phe levels by day seven. He said Phe levels fell below the therapeutic threshold even on an unrestricted protein-containing diet, alongside “robust on-target editing” in the liver. Shanker also described a dose-response relationship in which liver editing increased predictably with dose, and relatively low editing levels were sufficient to drive Phe below the therapeutic threshold.
Beam said it has held pre-IND interactions with the FDA and expects to file an IND for BEAM-304 in 2026. The planned Phase I/II trial is expected to be an open-label, single-ascending dose study initially enrolling PKU patients with the R408W mutation, with endpoints including safety, tolerability, and blood Phe reduction. Management also indicated that additional mutation-specific base editors could be brought forward within a single clinical program, largely by changing the guide RNA while keeping other components consistent.
During Q&A, Beam said its LNP approach for BEAM-304 is broadly similar to what it has used in BEAM-302 and BEAM-301, including the use of company-developed ionizable lipids and internal manufacturing leveraging prior work.
Regulatory innovation discussion and mutation expansion
Dr. Kiran Musunuru of the University of Pennsylvania, whose lab collaborated on foundational PKU base-editing work, discussed regulatory concepts for individualized therapies and “umbrella” trial approaches. He described prior engagements with the FDA in which the agency was agreeable to including multiple PAH variants under a single IND using a consistent LNP formulation with variant-specific guide RNAs, and to adding new variants via rapid IND amendments supported by in vitro on-target and off-target data without animal data.
Musunuru also discussed the FDA’s newly announced draft “Plausible Mechanism” framework and said it is explicitly aimed at ultra-rare diseases where randomized trials are not feasible, but he noted ambiguity in defining “ultra-rare,” particularly for conditions like PKU that include both common and very rare variants.
On practical development sequencing, Beam said its intention is to establish proof of concept first in R408W and then use adaptive trial designs to accelerate expansion to additional mutations. Shanker added that BEAM-304 is designed around mutation-specific guide RNAs and editors within one program. When asked about bystander editing, he said the company feels confident in the on-target editing and overall benefit-risk profile but did not provide details.
Beam also said many PKU patients are compound heterozygous; Shanker stated that correcting one allele can be sufficient to reduce Phe below threshold, citing compound heterozygous mouse work where editing one mutation drove therapeutic Phe reduction.
Financing update tied to sickle cell launch plans
Chief Financial Officer Sravan Emany said Beam entered a strategic financing agreement with Sixth Street providing up to $500 million in long-term, non-dilutive capital to support the anticipated launch of risto-cel, Beam’s investigational autologous cell therapy for sickle cell disease. The facility includes:
- $100 million funded at close
- Up to $300 million available upon regulatory, clinical, and commercial milestones for risto-cel
- An additional $100 million subject to mutual agreement during the seven-year term
Emany said repayment of principal is due in early 2033. Beam ended 2025 with $1.25 billion in cash, cash equivalents, and marketable securities, and with an anticipated minimum draw of $200 million from the facility, the company expects its runway to extend into mid-2029. He said this is expected to support pipeline execution through anticipated milestones including a risto-cel launch, BEAM-302’s pivotal plan, and clinical proof of concept for BEAM-304.
In closing remarks, Evans said Beam expects to provide updated Phase I/II data and next steps for BEAM-302 pivotal development in alpha-1 antitrypsin deficiency “this quarter,” followed by an anticipated risto-cel BLA submission “as early as year-end.” He also cited planned 2026 activities including the BEAM-304 IND filing, initial BEAM-301 data in GSD Ia, completion of the BEAM-103 healthy volunteer study, and continued advancement of in vivo HSC editing efforts.
About Beam Therapeutics (NASDAQ:BEAM)
Beam Therapeutics, Inc (NASDAQ: BEAM) is a biotechnology company dedicated to developing precision genetic medicines through its pioneering base editing platform. Headquartered in Cambridge, Massachusetts, with additional research facilities in Philadelphia, the company focuses on engineering molecular editors capable of making precise single-nucleotide changes in DNA. By harnessing its proprietary base editing technology, Beam aims to correct or disrupt disease-causing genetic variants at their source, offering the potential for novel therapies in areas with significant unmet medical need.
Founded in 2017 as a spin-out from Harvard University and the Broad and Whitehead Institutes, Beam was co-founded by leading academic researcher David R.
