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
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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 -
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
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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/
