Jerry Vockley, MD, PhD, Head of the Division of Medical Genetics at UPMC Children’s Hospital of Pittsburgh, gives an overview of the treatment landscape for phenylketonuria (PKU), going further into detail about the mechanism of action of SYNB1618, an oral drug being investigated for treatment of this disease.

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, this diet is particularly difficult to adhere to and better treatment options are needed. 

As Dr. Vockley explains, there have been a couple of drugs approved for the treatment of PKU. The first is sapropterin, a synthetic form of tetrahydrobiopterin (BH4), which is a cofactor in catabolism of phenylalanine. It acts by increasing PAH activity in patients who have residual enzyme function.

The second therapy is pegvaliase (Palynziq), which is a phenylalanine ammonia lyase (PAL) enzyme that temporarily restores the levels of deficient enzyme and reduces blood phenylalanine concentrations by converting phenylalanine to ammonia and trans-cinnamic acid. This therapy has been shown to be more effective in reducing phenylalanine levels than sapropterin; however, as this therapy is administered through subcutaneous injection, often twice a day, it is a difficult therapy to use.

SYNB1618 is an investigational oral drug being evaluated for the treatment of PKU. SYNB1618 is a genetically modified probiotic that introduces two enzymes that can metabolize phenylalanine as well as a carrier that allows the organism to take up the phenylalanine more readily. Recently interim data from the phase 2 SynPheny-1 clinical trial was presented at the International Congress of Inborn Errors of Metabolism (ICIEM) Meeting. These data show that treatment with SYNB1618 resulted in significant reductions in plasma phenylalanine levels in patients with PKU.

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