Targeting the Disease Mechanism in PFIC, With Hisamitsu Hayashi, PhD

For US clinicians managing progressive familial intrahepatic cholestasis (PFIC), approved drug therapy targets the itch, not the disease. The US Food and Drug Administration (FDA) has approved the ileal bile acid transporter (IBAT) inhibitor odevixibat (Bylvay) to treat pruritus in patients aged ≥3 months with PFIC.¹ Yet most patients still develop fibrosis and end-stage liver disease before adulthood.²

PFIC is a heterogeneous group of autosomal recessive disorders of childhood in which defects in hepatocellular transport genes disrupt bile formation.² Estimated incidence ranges from 1 in 50,000 to 1 in 100,000 births, and PFIC accounts for 10% to 15% of childhood cholestasis cases and 10% to 15% of pediatric liver transplant indications.²

PFIC1, caused by ATP8B1 mutations, and PFIC2, caused by ABCB11 mutations affecting the bile salt export pump (BSEP), usually appear in the first months of life with jaundice and severe pruritus.² Serum gamma-glutamyltransferase (GGT) activity is normal in both, a key clue distinguishing them from PFIC3, and diagnosis is confirmed through genetic testing.² PFIC1 can carry extrahepatic features including short stature, sensorineural deafness, diarrhea, and pancreatitis, while patients with PFIC2, particularly those with biallelic truncating mutations, face an estimated 15% risk of hepatocellular carcinoma or cholangiocarcinoma.²

A different approach now has regulatory backing. In August 2026, sodium phenylbutyrate (Buphenyl), a longstanding urea cycle disorder therapy, gained approval in Japan for PFIC types 1 and 2 based on a series of clinical studies and an investigator-initiated trial.³ Rather than targeting pruritus, the drug increases functional BSEP at the canalicular membrane to restore bile acid export.

Hisamitsu Hayashi, PhD, associate professor in the Laboratory of Molecular Pharmacokinetics at the University of Tokyo Graduate School of Pharmaceutical Sciences, led the laboratory work identifying the drug's effect on BSEP. Following PFIC Awareness Day on October 5, Hayashi spoke with HCPLive in a written interview about early diagnosis, the evidence for a disease-directed therapy, and how it could complement IBAT inhibitors.

Q&A: Restoring bile acid export in PFIC types 1 and 2

HCPLive: What should clinicians know about PFIC types 1 and 2, and what unmet needs remain for patients?

Hisamitsu Hayashi, PhD: PFIC types 1 and 2 are rare inherited cholestatic liver diseases caused by defects in ATP8B1 and ABCB11, respectively. Both typically present in infancy or childhood with cholestasis and severe pruritus, but importantly, they are progressive liver diseases. Over time, patients may develop fibrosis, cirrhosis, and ultimately require liver transplantation.

Pruritus has an enormous impact on quality of life, but controlling pruritus does not necessarily mean that progression of the underlying liver disease has been controlled. Therefore, we need to consider both symptom control and preservation of the native liver.

Now that medical treatment options are emerging, I think early diagnosis is becoming increasingly important. Rather than waiting until patients have advanced fibrosis or hepatic decompensation, we should aim to establish the molecular diagnosis and intervene as early as possible, when there may still be an opportunity to preserve liver function.

This also makes genetic diagnosis increasingly relevant, because PFIC is biologically heterogeneous and treatment response may depend on the underlying disease subtype and molecular defect.

HCPLive: How does sodium phenylbutyrate work in PFIC, and are some patients, such as those with particular genetic variants, more likely to respond?

Hisamitsu Hayashi, PhD: BSEP is located at the canalicular membrane of hepatocytes and exports bile acids from the liver into bile. Sodium phenylbutyrate increases the amount of functional BSEP at this membrane, in part by stabilizing BSEP that has reached the cell surface.

In PFIC2, some ABCB11 variants produce BSEP proteins that retain transport activity but have reduced expression at the canalicular membrane. For those patients, increasing the amount of functional BSEP at the membrane provides a clear mechanistic rationale for treatment.

However, sodium phenylbutyrate is not simply a mutation-specific chaperone. We originally found that it also increases the membrane expression and transport capacity of wild-type BSEP. This is particularly relevant to PFIC1, where ABCB11 itself is not mutated, but ATP8B1 deficiency can lead to secondary impairment of BSEP function. Enhancing functional wild-type BSEP may therefore improve bile acid excretion even when BSEP is not the primary genetic defect.

Biologically, this suggests that treatment response may depend on how much recoverable BSEP function remains. However, we do not yet have a validated genotype-based predictor of response, and the Japanese approval is not restricted to particular variants.

The effect on wild-type BSEP also raises the possibility that this mechanism could be relevant to other cholestatic conditions in which canalicular BSEP function is secondarily reduced. That is scientifically interesting, but at present this remains a research question; the approved indication is PFIC types 1 and 2.

HCPLive: How do you see sodium phenylbutyrate fitting alongside current options such as IBAT inhibitors, biliary diversion, and liver transplant?

Hisamitsu Hayashi, PhD: I think an important point is that the approved indications and therapeutic roles are different.

In Japan, IBAT inhibitors are approved specifically for the treatment of cholestatic pruritus associated with PFIC, not for PFIC itself as the approved indication. The approved indications are also pruritus-focused in the US, although regulatory labeling differs across regions.

Sodium phenylbutyrate, by contrast, is approved for PFIC types 1 and 2 themselves. It acts in the liver by increasing functional BSEP expression at the canalicular membrane and enhancing bile acid export from hepatocytes. From the current regulatory and clinical perspective, I therefore view sodium phenylbutyrate as a therapy directed at the underlying disease mechanism, whereas IBAT inhibitors are positioned primarily as treatments for cholestatic pruritus.

That distinction does not mean that IBAT inhibitors have no effect on disease biology. By reducing intestinal bile acid reabsorption and the circulating bile acid pool, they may have broader biological effects. But their approved indication in PFIC is cholestatic pruritus, whereas sodium phenylbutyrate is approved for PFIC1 and PFIC2 themselves.

Because they act at different points in bile acid physiology, these treatments may ultimately be complementary rather than competing. Future studies should determine how best to select, sequence, or potentially combine them according to disease subtype, genotype, residual BSEP function, and disease stage.

Biliary diversion remains an important option when medical therapy is insufficient, and liver transplantation remains essential for patients with advanced or decompensated liver disease. This is also why early diagnosis and early intervention are becoming increasingly important: once irreversible liver damage has developed, the opportunity for medical therapy to preserve the native liver becomes much more limited.

HCPLive: What did the clinical evidence supporting the approval show, and which outcomes do you think are most meaningful for patients?

Hisamitsu Hayashi, PhD: The multicenter investigator-initiated study enrolled 6 patients with PFIC2. The primary endpoint was change in liver histology at 24 weeks. Histological improvement was observed in 3 of the 6 patients, and liver biochemical parameters generally improved during treatment. PMDA [Pharmaceuticals and Medical Devices Agency] considered these findings meaningful in the context of a progressive disease in which spontaneous histological improvement would not generally be expected.

What I find particularly important is the long-term follow-up. Four patients who continued treatment were still receiving sodium phenylbutyrate as of March 2026 and had survived with their native livers for approximately 6.5 to 8 years. In our nationwide survey of Japanese patients with PFIC2, the historical disease course was characterized by frequent progression to liver transplantation at a young age. Against that background, the duration of native liver survival observed in the treated patients appears substantially longer than the clinical course we had historically observed in Japanese patients with PFIC2. Of course, this is not a controlled comparison, and the number of patients is very small, so we have to be cautious.

For PFIC1, the evidence came from an exploratory study in 3 patients. Pruritus improved during treatment and worsened again after discontinuation, providing supportive evidence of clinical benefit, although histological changes were not clearly demonstrated during the short treatment period.

For patients and families, I think the most meaningful outcomes are not laboratory values alone. They are relief from severe pruritus, preservation of growth and quality of life, prevention of progressive liver injury, and ultimately the ability to remain well with one's native liver for as long as possible.

HCPLive: Can you walk us through the path from your lab's initial sodium phenylbutyrate findings to its approval?

Hisamitsu Hayashi, PhD: Our starting point was not drug repurposing itself, but understanding the disease mechanism.

We were studying how impaired BSEP expression and function at the canalicular membrane contribute to cholestasis in PFIC. Our pathophysiological studies showed that some PFIC2-associated BSEP variants retain transport activity but have impaired trafficking to, or reduced stability at, the canalicular membrane. This led us to ask whether restoring functional BSEP expression at the hepatocyte membrane could become a therapeutic strategy.

In the course of that work, we discovered that sodium phenylbutyrate has a previously unrecognized pharmacological action that is completely different from its established nitrogen-scavenging effect in urea cycle disorders: it increases functional BSEP expression at the canalicular membrane and enhances bile acid transport.

We then moved step by step from mechanistic studies to translational research. We demonstrated the effect in experimental models and human liver samples, conducted exploratory clinical studies in both PFIC1 and PFIC2, and subsequently performed a multicenter investigator-initiated clinical trial in patients with PFIC2.

The development therefore followed a path from understanding disease biology, to discovering a new pharmacological action, to testing that mechanism in patients. Approximately 20 years after the initial discovery, sodium phenylbutyrate was approved in Japan in August 2026 for both PFIC types 1 and 2.

This long path required sustained collaboration among patients and families, clinicians, researchers, public funding agencies, and industry, and ultimately led to the regulatory submission by OrphanPacific.

HCPLive: What should US clinicians take away from this approval, and what research is needed next?

Hisamitsu Hayashi, PhD: I hope there are 2 major take-home messages.

The first is the importance of basic research into disease mechanisms. This development began with a very fundamental question: why does bile acid transport fail in PFIC? By studying the molecular and cellular mechanisms of the disease, we discovered an unexpected pharmacological action of an existing drug. That basic discovery eventually became a treatment for patients more than 2 decades later.

To me, this is an important example of how deep mechanistic research can reveal therapeutic opportunities that would not necessarily emerge from conventional drug screening or from the known pharmacology of an existing drug.

The second lesson is that successful development in rare diseases requires a sustainable ecosystem that extends beyond a single drug.

Based on what we learned during the development of sodium phenylbutyrate, we established CIRCLe, a research and clinical-development platform for rare disorders and undiagnosed conditions presenting with liver abnormalities in Japan. CIRCLe has already supported the development and post-marketing evaluation of IBAT inhibitors in Japan.

We are now also collaborating with other pharmaceutical companies on drug-development projects involving a broader range of rare and undiagnosed disorders with diverse liver manifestations, extending well beyond PFIC and cholestatic disease. CIRCLe is also expanding internationally through collaborations with medical institutions outside Japan.

We hope CIRCLe can serve not only as a platform for one disease or one therapeutic area, but as an infrastructure that helps accelerate the development of new treatments for rare disorders and undiagnosed conditions involving the liver more broadly.

For sodium phenylbutyrate itself, the next priorities include international validation, better understanding of genotype-response relationships, long-term evaluation of native liver survival, and determining how this therapy should be used alongside IBAT inhibitors and other emerging treatments.

Ultimately, our goal is not simply to develop one successful drug. It is to create an environment in which the knowledge gained from one successful development can make the next treatment easier to bring to patients.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Disclosures for Hayashi were not available at the time of publication.

References

1. Walter K. FDA approves odevixibat for PFIC. HCPLive. Published July 20, 2021. Accessed October 6, 2026. https://www.hcplive.com/view/fda-approves-odevixibat-pfic

2. Davit-Spraul A, Gonzales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4:1. doi:10.1186/1750-1172-4-1

3. OrphanPacific. Notice regarding approval of a partial change to the marketing authorization for sodium phenylbutyrate for progressive familial intrahepatic cholestasis (PFIC) types 1 and 2. Published August 24, 2026. Accessed October 6, 2026. https://en.cmicgroup.com/news-events/notice-regarding-approval-of-a-partial-change-to-the-marketing-authorization-for-sodium-phenylbutyrate-for-progressive-familial-intrahepatic-cholestasis-pfic-types-1-and-2/