Jerry Vockley, MD, PhD, Head of the Division of Medical Genetics at UPMC Children’s Hospital of Pittsburgh, gives an update on the phase 2 trial testing SYNB1618 to treat phenylketonuria (PKU).

PKU is a rare genetic metabolic disorder that results in reduced activity of phenylalanine hydroxylase that leads to an accumulation of phenylalanine in the body, which can cause significant organ damage, especially in the central nervous system. If left untreated, PKU patients can develop chronic intellectual, neurodevelopmental, and psychiatric disabilities, as well as seizures and heart problems. Lifelong restriction of phenylalanine intake through the diet is needed to prevent buildup of phenylalanine in the body. However, compliance is an issue with this type of diet. 

Interim data from the phase 2 SynPheny-1 clinical trial was recently presented at the International Congress of Inborn Errors of Metabolism (ICIEM) Meeting. These data show that treatment with SYNB1618, an investigational oral drug, resulted in significant reductions in plasma phenylalanine levels in patients with PKU. 

In an interim analysis of eight patients, treatment with SYNB1618 was associated with a 40% reduction in D5-phenylalanine absorption after a meal challenge. Treatment with SYNB1618 was also associated with a 20% reduction in mean fasting plasma phenylalanine across all subjects. 

According to Dr. Vockley, because patients tend to “behave themselves” when they know they will have their phenylalanine levels measured by a professional, patients in the study may have had lower-than-average plasma phenylalanine at baseline. Ultimately, this means that the 20% reduction seen in the interim analysis may be a smaller reduction than what would be seen in real-world settings and that treatment with SYNB1618 may actually lead to an even greater reduction in plasma phenylalanine. Finally, in the interim analysis, treatment with SYNB1618 was associated with >250 µM mean reduction in fasting plasma phenylalanine among responder subjects. Treatment with SYNB1618 was also generally well tolerated, with no serious adverse events and a tolerability profile consistent with results from previous Phase 1 studies.

To learn more about PKU and other rare metabolic disorders, visit