Japan Approves Buphenyl (Sodium Phenylbutyrate) for PFIC Types 1 and 2 After 20-Year Research Effort
核心洞察
Japan has approved a new indication for Buphenyl (sodium phenylbutyrate) to treat progressive familial intrahepatic cholestasis (搜索) types 1 and 2, rare genetic liver disorders.
The drug increases bile salt export pump (搜索) proteins at the liver cell surface, helping move bile acids into bile and reducing toxic buildup in liver cells.
An investigator-initiated trial in six children with PFIC type 2 showed the treatment could slow liver damage caused by the disease.
Japan has approved a new indication for an existing drug to treat patients with progressive familial intrahepatic cholestasis (搜索) (PFIC) types 1 and 2, a group of rare genetic liver disorders. The active ingredient in the drug, marketed under the brand name Buphenyl, is sodium phenylbutyrate (NaPB), which was already available as a treatment for patients with urea cycle disorders (搜索).
The approval follows roughly 20 years of work by a multi-institutional team led by Associate Professor Hisamitsu Hayashi of the Graduate School of Pharmaceutical Sciences at the University of Tokyo, spanning initial discovery, basic research, clinical studies and an investigator-initiated clinical trial.
Disease Burden and Unmet Need
PFIC, also known as genetic cholestasis, disrupts how bile is released from the liver into the gut. Bile is essential for breaking down fats in food so that nutrients can be absorbed and waste removed. When this process is impaired, bile builds up in the liver, causing severe itchiness throughout the body when excess bile leaks into the bloodstream, jaundice and progressive liver damage. Symptoms typically begin in early infancy or childhood, though people with milder or slower-progressing variants may not be diagnosed until adulthood.
Multiple subtypes of PFIC are caused by different genetic mutations, with types 1 and 2 accounting for the majority of diagnosed cases. Many children with more severe forms of these types eventually require a liver transplant. Medical treatment has traditionally focused on managing symptoms and providing nutritional support.
A Previously Unknown Mechanism
Rather than acting as an entirely new agent, NaPB was found to have a mechanism distinct from its established use. "What we discovered was an entirely different and previously unknown effect of NaPB," Hayashi said. "It increases the number of bile salt export pump (搜索) (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."
The new indication targets the mechanism behind bile movement and may help slow liver damage in patients with PFIC types 1 and 2, with the expectation of improving liver condition and quality of life for children and adults with these disorders.
Trial Evidence and Development Path
The regulatory decision rests on a stepwise research program that moved from laboratory work to patients. "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," Hayashi explained. "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."
As with other rare conditions, the main obstacle to development was the limited information available 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," Hayashi said.
Building Infrastructure for Rare Liver Disease Research
Those challenges prompted the team to establish the Comprehensive and Informative Registry System for Childhood Liver Disease (CIRCLe). The platform brings together patients with liver diseases that begin in childhood, their clinicians and field experts, collecting clinical information and biological samples over time and providing access to specialized diagnostic testing. Researchers can use the registry and biorepository to determine when a clinical trial is possible, who could take part, and how to tell whether a treatment is working.
"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," Hayashi said.
Long-Term Monitoring Still Required
Hayashi cautioned that because people respond differently to any treatment, use of NaPB by patients with PFIC types 1 or 2 will not necessarily prevent the need for a liver transplant at some point. Patients will also require long-term monitoring to build a clearer picture of the treatment's benefits and safety and to determine who it will be most suitable for.
"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."