MON-209 - Efficacy and Safety of Targeted BH4 Precursor Therapy with Sepiapterin in Phenylketonuria: A Systematic Review and Meta-Analysis

Introduction
Phenylketonuria is an inborn error of amino acid metabolism causing chronic hyperphenylalaninemia. Sepiapterin, a targeted tetrahydrobiopterin precursor, enhances endogenous BH4 availability and, following regulatory approval in 2025, represents an important precision treatment option.

Methods
We systematically searched multiple databases and clinical trial registries for studies evaluating sepiapterin and assessed risk of bias using the ROB 2.0 tool, with random-effects meta-analysis of efficacy and safety outcomes.

Results
Seven studies involving approximately 370 patients were included, with about 280 patients exposed to sepiapterin. In pooled analysis of randomized trials, sepiapterin produced a large and statistically significant reduction in blood phenylalanine compared with control. The pooled mean difference was −344 µmol/L (95% CI −420 to −268; p< 0.0001; I²=58%). The standardized mean difference was −1.45 (95% CI −1.90 to −1.00). The pooled responder rate was 73% (95% CI 66–79%). Achievement of guideline target phenylalanine levels (≤360 µmol/L) was significantly higher with sepiapterin (RR 9.0, 95% CI 3.6–22.6). Treatment-emergent adverse events were more frequent (RR 1.77, 95% CI 1.15–2.72), with no serious safety or QT concerns.

Conclusion
Sepiapterin is associated with clinically meaningful reductions in blood phenylalanine and increased achievement of guideline targets, with a favorable safety profile in phenylketonuria.

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