New treatment option approved in Japan for rare genetic liver disorders

A new indication for an existing drug has been approved in Japan to treat patients with progressive familial intrahepatic cholestasis (PFIC) types 1 and 2, a group of rare genetic liver disorders. The condition typically appears in early infancy and childhood, causing severe itchiness, jaundice and progressive liver damage. A multi-institutional team of researchers, led by Associate Professor Hisamitsu Hayashi from the Graduate School of Pharmaceutical Sciences at the University of Tokyo, went from initial discovery through to investigator-initiated clinical trial now achieving regulatory approval. The active ingredient in the drug (brand name Buphenyl) is sodium phenylbutyrate (NaPB). It works to move bile acids from liver cells into bile, the accumulation of which is the main issue with PFIC types 1 and 2. This treatment is expected to improve liver condition and quality of life for children and adults with these disorders.

Oct. 5 is the awareness day for progressive familial intrahepatic cholestasis, also known as genetic cholestasis. These terms refer to a group of rare genetic liver disorders which disrupt how bile is released from the liver into the gut. Bile is essential for breaking down fats in our food so that we can absorb useful nutrients and remove waste. When this process is affected by PFIC, bile builds up in the liver, causing a range of symptoms, including severe itchiness throughout the body (when excess bile leaks into the bloodstream), jaundice and progressive liver damage.

There are multiple known subtypes of PFIC, caused by different genetic mutations. Symptoms typically start in early infancy or childhood, but people with milder or slower-progressing variants may not be diagnosed until adulthood. PFIC types 1 and 2 make up the majority of diagnosed cases, and many children with more severe forms of these PFIC types eventually require a liver transplant. Medical treatment for PFIC has traditionally focused on managing symptoms and providing nutritional support.

Now a new treatment option, which targets the mechanism behind bile movement and may help slow down liver damage, has been approved in Japan for patients with PFIC types 1 and 2. Rather than being an entirely new drug, the active ingredient - sodium phenylbutyrate, or NaPB - is already available as a treatment for patients with urea cycle disorders.

What we discovered was an entirely different and previously unknown effect of NaPB. It increases the number of bile salt export pump (BSEP) proteins at the surface of liver cells, which helps liver cells to move bile acids into bile more effectively, reducing toxic buildup in liver cells. Before the approval of NaPB, there was no established medical treatment for PFIC that had been shown to slow the progression of liver damage."

Hisamitsu Hayashi, Associate Professor, Graduate School of Pharmaceutical Sciences, University of Tokyo

It has taken about 20 years since the initial discovery of the effects of NaPB to finally make the drug Buphenyl available as an approved treatment for patients with PFIC types 1 and 2. As with other rare conditions, one of the main challenges towards this goal was the current lack of information about PFIC, including unanswered questions about how the disease changes over time and how to evaluate treatment.

"Without sufficient information about the disease and the patient population, it was difficult for pharmaceutical companies to judge whether clinical development was feasible. So, we had to build a step-by-step research program that moved from the laboratory to patients," explained Hayashi.

"First, we studied how problems with BSEP cause PFIC, which led us to discover the previously unknown effect of NaPB. After completing our basic research and clinical studies, we conducted an investigator-initiated clinical trial at several hospitals in Japan," he said. "The trial included six children with PFIC 2. Our findings showed that this treatment could slow liver damage caused by PFIC 2. Thanks to this combination of basic research, clinical studies and investigator-initiated clinical trial, we were able to get regulatory approval to treat PFIC types 1 and 2."

The challenges the team faced in conducting this work prompted them to establish the Comprehensive and Informative Registry System for Childhood Liver Disease (CIRCLe). This platform brings together patients with liver diseases that begin in childhood, their clinicians and experts in the field, while collecting clinical information and biological samples over time and providing access to specialized diagnostic testing. Researchers can then use this registry and biorepository to determine when a clinical trial is possible, who could take part, and how to tell if a treatment is working, providing a much-needed springboard for new research and drug development.

"CIRCLe is already functioning as the platform we intended it to be. We are using it to uncover disease mechanisms and identify new treatment ideas, while pharmaceutical companies are also using it to support drug development, clinical trials and follow-up studies after regulatory approval," said Hayashi.

He cautions, though, that as people respond differently to any treatment, the use of NaPB by people with PFIC types 1 or 2 will not necessarily prevent the need for a liver transplant at some point. Patients will also need to be monitored in the long term, to build a clearer picture of the treatment's benefits and safety, and who it will be most suitable for.

Even so, Hayashi is optimistic about what it can offer. "We hope that this important new treatment will broaden the choices available to people with PFIC and their families, and, over time, help to improve the course of the disease and patients' quality of life," he said. "Furthermore, our goal is to use CIRCLe to discover what causes childhood liver diseases, identify new ways to treat them, and shorten the path from those discoveries to treatments for patients."