Practical Considerations for Odevixibat Treatment in Patients with Progressive Familial Intrahepatic Cholestasis: A Single-Center Case Series

Abstract

Background: Patients with progressive familial intrahepatic cholestasis (PFIC) experience cholestasis-associated symptoms, including severe pruritus. Odevixibat is an ileal bile acid transporter inhibitor indicated for treatment of PFIC in the European Union and for the treatment of pruritus in PFIC in the United States. The aim of the current study was to characterize the real-world effectiveness and safety of odevixibat in patients with PFIC. Methods: This retrospective study included 9 patients with PFIC treated with odevixibat in a single center in Tübingen, Germany. Data were recorded using case report forms. Results: Of the 9 patients (PFIC1, n = 2; PFIC2, n = 7), 5 had improved serum bile acid levels, pruritus, liver function tests, and sleep with odevixibat treatment. Two siblings with periodic relapses of PFIC symptoms also had improved pruritus and sleep within 4 months of treatment. Two siblings with complete loss of bile salt export pump (BSEP) protein did not respond to treatment; both underwent liver transplantation (indications: hepatocellular carcinoma [HCC] manifestation [n = 1] and severe failure to thrive and refractory pruritus [n = 1]). Four patients reported abdominal complaints that were transient or responded to dose reduction; no other safety issues were reported. Conclusions: In this case series, clinical benefits were observed in most patients with PFIC1 and PFIC2 treated with odevixibat. In patients with periodic relapse of PFIC symptoms, ≥3 months of treatment with odevixibat may be required for symptom control. Patients with complete loss of BSEP did not have consistent symptom relief and require careful monitoring. Effectiveness and feasibility results from our cohort demonstrate potential for long-term benefits with odevixibat in real-world treatment of patients with PFIC.

Keywords: odevixibat; progressive familial intrahepatic cholestasis; pruritus; serum bile acids.

Figure 1

Serum bile acid levels and dosing over time with real-world odevixibat treatment. For patients who participated in the PEDFIC clinical trials, dotted lines indicate time spent in the PEDFIC trials as well as time during real-world odevixibat treatment. Solid lines indicate real-world odevixibat treatment. ^a No BSEP protein expression. ^b Nonfasting sBA was measured as 312 μmol/L at 14.6 months of treatment for patient 7. ^c Outside of PEDFIC trials. BSEP, bile salt export pump; PFIC, progressive familial intrahepatic cholestasis; sBA, serum bile acid.

Figure 2

ALT (a) and total bilirubin (b) levels over time with real-world odevixibat treatment. For patients who participated in the PEDFIC clinical trials, dotted lines indicate time spent in the PEDFIC trials as well as time during real-world odevixibat treatment. Solid lines indicate real-world odevixibat treatment. ^a No BSEP protein expression. ALT, alanine aminotransferase; BSEP, bile salt export pump; PFIC, progressive familial intrahepatic cholestasis; TB, total bilirubin.

Figure 3

Screening for HCC in a patient with BSEP3 (patient 1). Panel (a): sonography showed focal liver lesions; largest legion in segment 7 with maximum diameter 1.5 cm. Panel (b): contrast-enhanced ultrasound showed enhancement of lesion without evidence of wash-out. Panel (c): liver MRI with gadobutrol showed hypointense signal on T1w (i) and hyperintense signal on T2w (ii). DWI showed increased signal at high b-values (iii) and slightly low signal intensity on ADC map (iv). Lesion showed enhancement on dynamic contrast-enhanced imaging without wash-out in the venous phase (v). Repeat MRI with a hepatospecific paramagnetic gadolinium-based contrast agent, gadoxetate disodium, also showed enhancement in the dynamic contrast-enhanced imaging without wash-out (vi). Panel (c(vi)): subtraction image of the late hepatobiliary phase taken at 25 min. Panel (d): visualization of the specific echogenic ultrasound needle and position of the needle tip in the lesion (i) and gas artifacts along the puncture canal (ii). Panel (e): H&E staining showed severe cholestatic hepatitis with giant cell transformation, hepatocellular and canalicular bilirubinostasis, ductular reaction, and inflammation. Panel (f): five-month follow-up MRI after biopsy showed a new lesion of 10 mm contiguous to the scar zone of the biopsy; slightly hyperintense on T2w (i) and hypointense on T1w (ii) with hyperarterialization on dynamic contrast-enhanced imaging (iii) and wash-out in the hepatobiliary phase ((iv)—transverse plane; (v)—coronal plane). The subtracted transverse plane of the hepatobiliary phase enhanced the wash-out phenomenon (vi). DWI showed increased signal at high b-values (vii) and low signal intensity on ADC map (viii). Panel (g): AFP levels. Panel (h): H&E staining of explanted liver showed hepatoid tumor cell infiltrates compatible with diagnosis of HCC. Scale bar = 200 µm. Arrows indicate lesion location. ADC, apparent diffusion coefficient; AFP, alpha fetoprotein; BSEP, bile salt export pump; DWI, diffusion-weighted imaging; H&E, hematoxylin and eosin; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; T1w, T1 weighted; T2w, T2 weighted.