Daijiworld Media Network - New Delhi
New Delhi, Oct 7: A new therapeutic approach for progressive familial intrahepatic cholestasis (PFIC) is drawing attention after sodium phenylbutyrate received approval in Japan for PFIC types 1 and 2, offering a treatment aimed at the underlying disease mechanism rather than only its symptoms.
PFIC is a group of rare inherited liver disorders that usually begin in infancy or childhood. Defects in genes involved in bile formation and transport cause cholestasis, severe itching and progressive liver damage. The condition affects an estimated one in 50,000 to one in 100,000 births and accounts for a significant proportion of childhood cholestasis and paediatric liver transplant indications.
In the United States, the FDA has approved the ileal bile acid transporter (IBAT) inhibitor odevixibat for the treatment of cholestatic pruritus in patients aged three months and older with PFIC. However, patients can continue to develop fibrosis, cirrhosis and end-stage liver disease despite control of itching.
PFIC1 is caused by mutations in ATP8B1, while PFIC2 results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). Both commonly present with jaundice and severe pruritus and generally have normal gamma-glutamyltransferase levels.
PFIC1 can also be associated with short stature, sensorineural deafness, diarrhoea and pancreatitis. Patients with PFIC2, particularly those with biallelic truncating mutations, face an increased risk of hepatocellular carcinoma or cholangiocarcinoma.
Sodium phenylbutyrate, a drug long used to treat urea cycle disorders, received approval in Japan in August 2026 for PFIC types 1 and 2. Research led by Hisamitsu Hayashi, PhD, associate professor at the University of Tokyo Graduate School of Pharmaceutical Sciences, found that the drug increases functional BSEP at the canalicular membrane of liver cells, helping restore bile acid export.
According to Hayashi, some PFIC2-associated BSEP variants retain transport activity but have reduced expression at the canalicular membrane. Increasing the amount of functional BSEP at the membrane could therefore improve bile acid transport in these patients.
The mechanism may also be relevant to PFIC1. Although ABCB11 is not mutated in PFIC1, ATP8B1 deficiency can cause secondary impairment of BSEP function. Increasing functional wild-type BSEP could therefore improve bile acid excretion.
Hayashi noted that there is currently no validated genotype-based predictor of response, and the Japanese approval is not restricted to specific genetic variants.
Clinical evidence supporting the approval included a multicentre investigator-initiated study involving six patients with PFIC2. The primary endpoint was a change in liver histology after 24 weeks. Histological improvement was observed in three patients, while liver biochemical parameters generally improved during treatment.
Four patients who continued treatment were still receiving sodium phenylbutyrate as of March 2026 and had remained on treatment with their native livers for approximately 6.5 to 8 years. Hayashi cautioned that the number of patients was small and that the findings were not based on a controlled comparison.
For PFIC1, an exploratory study involving three patients found improvement in pruritus during treatment, with symptoms worsening again after treatment was discontinued. However, clear histological changes were not demonstrated during the short treatment period.
Hayashi said the treatment should not necessarily be viewed as a replacement for IBAT inhibitors. While IBAT inhibitors primarily target cholestatic pruritus by reducing intestinal bile acid reabsorption, sodium phenylbutyrate is directed at PFIC1 and PFIC2 themselves by increasing functional BSEP expression and enhancing bile acid export.
He said the two approaches could potentially complement each other, although further studies are needed to determine how they should be selected, sequenced or combined according to disease subtype, genotype, residual BSEP function and disease stage.
Biliary diversion remains an option when medical treatment is insufficient, while liver transplantation remains essential for patients with advanced or decompensated liver disease.
Hayashi stressed that early diagnosis is becoming increasingly important as more medical treatment options emerge. Establishing the molecular diagnosis before advanced fibrosis or hepatic decompensation may provide a better opportunity to preserve native liver function.
He also highlighted the role of CIRCLe, a research and clinical-development platform established in Japan for rare disorders and undiagnosed conditions involving liver abnormalities. The platform has supported drug development and post-marketing evaluation of IBAT inhibitors and is expanding collaborations with medical institutions outside Japan.
Future research on sodium phenylbutyrate will focus on international validation, understanding genotype-response relationships, long-term native liver survival and determining how the therapy can best be used alongside IBAT inhibitors and other emerging treatments.