Synlogic shuts down after PKU drug fails phase 3 trial

Shares in Synlogic have halved in value after the company reported that a phase 3 trial of its main pipeline drug for rare metabolic disorder phenylketonuria (PKU) failed to show efficacy, putting its future in doubt.

The Synpheny-3 trial of labafenogene marselecobac (SYNB1934) has been discontinued after an internal review of data concluded it was unlikely to meet its primary efficacy endpoint, and the decision was not based on any safety concerns, said the Cambridge, Massachusetts-based biotech.

“It is with a heavy heart that we share this news, and our resulting decision to end Synpheny-3,” said Synlogic’s chief executive, Aoife Brennan. “Based on the programme’s progress and data to date, we had expected the study to demonstrate the potential for SYNB1934 to provide an important new treatment option for those affected by PKU.”

The failure of the trial has driven the company to seek the dreaded “strategic options”, which could see the company dissolved, taken over or merged with another business. For its workforce, that is largely academic, as 90% are losing their jobs and will leave the company by the end of this month. A skeleton staff will remain to shut down the trial and plan the next steps.

Aside from SYNB1934, Synlogic’s pipeline includes two early-stage clinical candidates, SYNB1353 for classical homocystinuria and SYNB8802 for enteric hyperoxaluria, with preclinical-stage programmes in gout. The company also had around $48 million in cash as of the end of 2023.

PKU is a rare genetic disease that manifests at birth and is marked by an inability to break down phenylalanine (phe), an amino acid that is commonly found in many foods. Left untreated, high levels of the amino acid become toxic to the brain and may lead to serious neurological and neuropsychological issues.

At the moment, the main treatment strategy is to restrict phe in the diet, a lifetime commitment that often requires nutritional supplements to prevent deficiencies and, often, the method is unable to control levels of the amino acid effectively on its own.

Drug treatment is an option for some patients, with BioMarin’s enzyme-based therapies Kuvan (sapropterin) or Palynziq (pegvaliase) both approved to reduce levels of the amino acid, although they only work in a minority of patients and, in the case of Palynziq, can have serious side effects.

SYNB1934 is based on a non-absorbed strain of the bacterium Escherichia coli Nissle, engineered to break down phe in the gastrointestinal tract, which was dosed as a probiotic.