A 20-Year Path from Discovery to Approval Gives Children with PFIC a New Option

Some drug approvals begin with a new molecule. This one began with a question about where a protein sits inside a liver cell. On August 24, 2026, Japan approved an expanded indication for Buphenyl, a sodium phenylbutyrate medicine already used for urea-cycle disorders, to include progressive familial intrahepatic cholestasis types 1 and 2. The decision turns roughly two decades of Japanese laboratory and investigator-led clinical work into a new treatment option for an ultra-rare disease that often begins in infancy. ^[3][4]

PFIC can make childhood revolve around itching, jaundice, blood tests, poor sleep and the fear of progressive liver damage. In severe disease, families may reach liver transplantation early. The new indication does not erase that possibility, and it should not be described as a cure. Its significance is more specific: researchers found an unexpected second use for an old drug, developed a disease-specific dosing strategy, assembled evidence from a handful of children, and persuaded regulators that the total evidence was strong enough for approval.

The result is also a case study in how rare-disease medicine is actually built. The science began with BSEP, the bile salt export pump that moves bile acids out of hepatocytes and into bile. The development challenge then expanded far beyond a protein: natural-history data, trial endpoints, multicenter coordination, pediatric liver biopsies, drug supply, regulatory dialogue and a patient registry all became part of the path to the prescription pad. ^[1][2]

Why bile becomes toxic when it cannot leave the liver

Bile acids are essential to digestion, but they are chemically harsh. Hepatocytes normally package and export them into bile, which flows toward the intestine. PFIC is a group of inherited disorders in which that system breaks down. Bile acids accumulate, cholestasis develops, and the liver can be injured over years—or, in severe forms, over months.

PFIC1 is associated with pathogenic variants in ATP8B1, which encodes the FIC1 protein. PFIC2 is associated with ABCB11, which encodes BSEP. Both can present in infancy with intense pruritus, jaundice and progressive liver disease. Japan lists PFIC as designated intractable disease No. 338. ^[12]

In a Japanese natural-history study of 14 PFIC2 patients, the median age at onset was 2.5 months. Twelve underwent living-donor liver transplantation, at a median age of nine months. It was a tiny retrospective cohort, not a national forecast for every child, but it illustrates why a therapy that can buy native-liver time matters. ^[9]

The key insight: some BSEP mutations leave a usable pump in the wrong place

The development story traces back to work showing that certain disease-causing BSEP variants do not necessarily destroy transport function itself. Instead, some mutations impair trafficking: too little BSEP reaches the canalicular surface of the hepatocyte, where it needs to work.

Hisamitsu Hayashi and colleagues then tested whether an existing compound might restore surface expression. In a 2007 Hepatology paper, sodium 4-phenylbutyrate increased the cell-surface expression and transport capacity of wild-type and mutant BSEP in experimental systems. That result offered a different therapeutic idea: rather than replacing the gene or the liver, increase the amount of functional transporter that reaches the right membrane. ^[6]

That is classic drug repurposing, but not the easy version of it. An old safety dossier does not automatically prove that a medicine works in a different disease, at a different regimen, in children whose livers are already compromised. The researchers still had to build a new clinical-development program.

Human evidence accumulated in steps, not in one decisive trial

Retrospective work in patients taking sodium phenylbutyrate for urea-cycle disorders supported the biological hypothesis by showing increased BSEP expression after treatment. Small exploratory PFIC studies then reported improvements in biochemical markers, symptoms and—in some PFIC2 patients—liver histology. ^[5][7]

The program also learned that administration timing mattered. A multicenter pharmacokinetic study found that giving sodium phenylbutyrate before food produced substantially higher phenylbutyrate exposure than giving it after a meal. The PFIC regimen therefore could not simply copy the established urea-cycle schedule. ^[8]

By 2017, the group moved to an investigator-initiated Phase II trial in PFIC2. Six sites were assembled around Japan, and the planned enrollment was six children. In most therapeutic areas, six would be a pilot. In PFIC2, it was close to the number investigators believed could realistically be recruited in the country. ^[5][3]

What the six-patient PFIC2 trial actually showed

All six enrolled patients received sodium phenylbutyrate. The primary evaluation used liver biopsy after 24 weeks. Three of six were judged improved; two were judged worse; one had no primary-endpoint data after stopping early for insufficient effect. The headline response proportion was therefore 50%. ^[3]

Those numbers need context. The study was open-label and uncontrolled. PMDA noted that the sample was necessarily tiny and that the primary endpoint had interpretive limitations, so the agency did not rely on the biopsy result alone. It considered the course of individual patients, liver-test trends, itching, natural-history evidence and longer follow-up. ^[3]

Five patients completed 52 weeks. According to the review report, four were still receiving the drug in March 2026 and were alive with their native livers, with native-liver survival ranging from 6 years 6 months to 8 years 1 month. That is encouraging, particularly against the severe Japanese PFIC2 natural history. But without a randomized control group, it does not prove that the drug caused transplant avoidance. PMDA framed the conclusion more cautiously: a degree of clinically meaningful efficacy could be expected. ^[3][9]

PFIC1 required an even more inferential regulatory judgment

The PFIC1 evidence reviewed by PMDA centered on an exploratory three-patient study involving patients aged 2, 6 and 16 years who continued to have intractable pruritus despite symptomatic treatment. During sodium phenylbutyrate therapy, the itching score improved; after therapy stopped, the score returned toward baseline. Clear histologic improvement was not demonstrated over the short study period. ^[3]

PMDA explicitly said that three patients were too few for a conventional efficacy assessment. The agency nevertheless considered the symptom pattern, the lack of histologic deterioration in a progressive disease, the mechanistic rationale and the broader evidence sufficient to expect a degree of benefit in PFIC1. This is what ultra-rare-disease regulation can look like: biology, natural history and coherent patient trajectories carry more weight because enormous trials are impossible.

Safety still matters when an old drug gets a new job

Repurposing can shorten parts of development, but it does not eliminate safety questions. In the 52-week PFIC2 dataset, five of six patients experienced adverse events and five of six had events classified as adverse drug reactions. Two patients had serious adverse events, but the review judged the serious events unrelated to sodium phenylbutyrate. No deaths were reported. ^[3]

The label also has to account for known risks. Sodium phenylbutyrate is rapidly metabolized to phenylacetate, and high phenylacetate exposure has been associated with neurologic symptoms. The formulation also carries a sodium load, which matters in patients vulnerable to sodium retention. PMDA concluded that safety was acceptable with appropriate warnings and monitoring—not that the drug was risk-free. ^[3]

PFIC treatment in Japan had already begun to change

The 2026 approval should not be written as though PFIC had no medicines until Buphenyl arrived. Japan approved the ileal bile acid transporter, or IBAT, inhibitor maralixibat in March 2025 and odevixibat in September 2025. These drugs reduce bile-acid reabsorption in the intestine, lowering the amount recirculated back to the liver and helping control cholestasis and pruritus. ^[10][11]

Sodium phenylbutyrate works at a different point in the system. The research program aims to increase BSEP expression at the hepatocyte canalicular membrane and improve bile-acid export from the liver itself. The University of Tokyo and collaborating institutions therefore describe the new approval as a mechanism-based treatment option for PFIC1 and PFIC2. ^[1][2]

That distinction matters clinically. The next questions are not merely whether each drug “works,” but which patients respond to which mechanism, whether certain genetic variants predict response, how treatment should change as disease advances, and whether the different approaches can be sequenced or combined safely.

The hardest part of rare-disease drug development may be the missing map

A pharmaceutical company can evaluate a common-disease program because it usually knows how many patients exist, how quickly the disease progresses and what endpoints regulators will accept. PFIC lacked much of that map. Patients were few and geographically scattered. Natural history was incomplete. Even identifying a feasible trial population required surveys of specialist centers.

The researchers turned that obstacle into infrastructure. The University of Tokyo says the development experience helped drive creation of CIRCLe, a pediatric liver-disease registry intended to connect diagnostic support, natural-history data, research, clinical trials and post-marketing surveillance. ^[1] In an ultra-rare disorder, a registry can be as important to the next therapy as a laboratory instrument.

Twenty years is a long time—and also a measure of what had to be built

The timeline is striking. Work on the cellular behavior of BSEP led to the 2007 phenylbutyrate finding. Human mechanistic evidence followed. Exploratory PFIC studies appeared. An investigator-led trial was organized in 2017. Dosing and natural history were refined. Orphan designation and regulatory review followed. Approval arrived in 2026.

The approval does not say that liver transplantation is obsolete. It says families and clinicians now have one more mechanism-based option to consider before the disease reaches that point.

That is the most durable lesson of the 20-year path. Rare-disease progress is often not a spectacular single breakthrough. It is a chain of small, defensible steps: a protein in the right membrane, an old drug seen differently, a six-child trial, a registry, a regulator willing to weigh imperfect evidence carefully. For children with PFIC1 and PFIC2, those steps have finally reached an approval.