Odevixibat: a promising new treatment for progressive familial intrahepatic cholestasis

Abstract

Introduction:

Progressive familial intrahepatic cholestasis (PFIC) refers to a group of heterogeneous, mostly autosomal recessive disorders resulting from the inability to properly form and excrete bile from hepatocytes. The resulting shared phenotype is one of hepatocellular cholestasis. Clinical management targeting refractory itch and surgical interventions to interrupt the enterohepatic circulation are often pursued with variable efficacy. Recent development of the family of IBAT inhibitor therapeutics has introduced a novel tool in the armamentarium for the treatment of PFIC.

Areas covered:

Data from Phase 3 and 3 clinical trials were reviewed. The primary endpoints in most studies included effect on pruritus, serum bile acid levels, and quality of life metrics, with the duration of the study ranging between 24 and 72 weeks. Most common adverse events included diarrhea, vomiting, and elevation in transaminases.

Expert opinion:

IBAT inhibition with therapeutics such as odevibixat have shown that it is well-tolerated and efficacious in mitigating itch and reducing serum bile acid levels. While the few early published trials with odevixibat have shown good efficacy, what remains to be seen is long-term, sustainable improvement and if or how these medications will supplement or replace the current medical and surgical therapies available for managing PFIC disorders.

1. Introduction

1.1. Bile acid homeostasis

Bile is a complex biochemical mixture with a broad range of functions that is continuously made by the liver. While mostly water, bile also contains a complex composition of inorganic and organic solutes [1]. Organic solutes include bile acids (BAs), phospholipids, cholesterol, proteins, and bilirubin, while inorganic solutes are composed mostly of electrolytes [1,2]. An estimated 700–800 mL/day of bile traverses the bile ducts and drain into the small intestine. The two primary BAs (cholic acid and chenodeoxycholic acid) are synthesized by the liver from cholesterol through a series of complex chemical reactions catalyzed by specific hepatic enzymes [3]. The primary BAs are then transported into bile by the action of specific canalicular membrane transporters. Once in the canalicular space, BAs are transported with other bile products along the extensive network of intrahepatic ducts and into the intestine where they enable fat emulsification and absorption from the small intestine. BAs reaching the terminal ileum will undergo enterohepatic circulation, a process whereby they are re-absorbed, returned to the liver, and re-secreted into bile (Figure 1). Intestinal re-absorption of BAs occurs via the ileal sodium/bile acid cotransporter, also known as the apical sodium-bile acid transporter (ASBT) or the ileal bile acid transporter (IBAT) encoded by the SLC10A2 gene. In addition to its main role in determining the BA pool, ASBT is also important in the regulation lipid and cholesterol homeostasis and has been proposed as a promising target for several disease processes [4]. The efficiency of the enterohepatic circulation system is remarkable, and BAs may undergo 6–10 cycles/day of enterohepatic circulation. From the total BA pool excreted into the intestine (approximately 20–40 g), only 0.2–0.6 g/day of BAs are lost in the feces [5]. Recent advances have enabled a greater understanding of how BAs, and their disrupted homeostasis, may contribute to a broad range of gastrointestinal and hepatic disease [6], including the family of conditions broadly referred to as progressive familial intrahepatic cholestasis (PFIC).

Figure 1.

Enterohepatic circulation of bile acids and the effect of IBAT inhibition. Bile acids are synthesized in the liver from cholesterol and secreted into the small intestine where they function in a variety of processes including the absorption of lipids from the gastrointestinal tract. Most bile acids that make it to the terminal ileum are then re-absorbed via the IBAT transporter located on the apical surface of the enterocytes. IBAT inhibitors such as odevixibat, bind to the bile acid transporter, interrupting the enterohepatic circulation by increasing fecal excretion of bile acids.

1.2. Progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) refers to a group of heterogeneous mostly autosomal recessive disorders resulting from the inability to properly form and excrete bile from hepatocytes. The resulting shared phenotype is one of hepatocellular cholestasis, i.e. reduction or blockage of bile flow. Recent scientific discoveries have revealed multiple responsible proteins (Figure 2) with an ever-broadening clinical spectrum, ranging from benign recurrent cholestasis (BRIC) to traditional progressive cholestasis and end-stage liver disease [7] (Table 1). Insights into the cellular mechanism(s) by which reduced bile flow leads to liver injury are expanding [8]. As BAs are the major driving force for bile formation, defects in the excretion of bile acids from the canalicular membrane can lead to significant morbidity. The hepatotoxic effects of defective BA secretion can result from 1) inability to properly excrete BAs from hepatocytes, as is thought to occur with BSEP, FXR, and MYO5B defects, 2) inability to appropriately regulate canalicular membrane composition, as is thought to occur with MDR3 and FIC1 defects, or 3) leakage of BA from the canaliculi, as is thought to occur with defects in TJP2 and USP53. Clinically, affected individuals have similar phenotypes with hyperbilirubinemia, elevated transaminases, and elevated serum bile acids. Early onset disease can present in infancy with jaundice, destructive pruritus and hepatosplenomegaly developing over the first months of life. Severe disease often progresses to the development of portal hypertension in early childhood. In some disorders, extrahepatic disease can occur, as can the development of hepatocellular carcinoma. Beyond the pediatric population, the contributions to disease of the PFIC-associated genes mainly encompass the phenotypes of BRIC and intrahepatic cholestasis of pregnancy (ICP) [7]. Recently, investigators have found PFIC gene associated polymorphisms linked to both drug-induced liver injury (DILI) and cryptogenic cirrhosis [9,10], furthering the contributions that these genes may have on morbidity in adult populations. Furthermore, defects in MDR3 have been linked to the development of sclerosing cholangitis, biliary cirrhosis, and low-phospholipid cholelithiasis [11,12]. Notably, more recently identified genes, such as NR1H4, MYO5B, and USP53 were not investigated in these studies, suggesting the burden may still be higher (Table 1).

Figure 2.

Molecular mechanisms of PFIC. Dysfunction of several proteins are noted to result in the PFIC phenotype including FIC1 (familial intrahepatic cholestasis protein 1), BSEP (bile salt export pump), MDR3 (multidrug resistance protein 3), TJP2 (tight junction protein 2), FXR (farnesoid X receptor), MYO5B (myosin 5 B), and USP53 (ubiquitin specific peptidase 53).

Table 1.

Historical PFIC disorders.

Etiology	Genetic defect	Mechanism of disease	Clinical characteristics	Treatment
FIC1 Deficiency (Byler’s syndrome) [13]	ATP8B1	• Uncertain  • Possibly involved in maintenance of canalicular mem- brane integrity  • Possible effect on FXR with resultant BSEP down- regulation	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • + extrahepatic symptoms: diarrhea/ malabsorption • Symptom onset in infancy with progression over 1st decade • Phenotypes:  • PFIC1  • BRIC1  • ICP1  • Cryptogenic cirrhosis	• Supportive care • Biliary diversion • Liver transplantation  • Diarrhea may worsen after transplant  • Allograft steato- hepatitis can occur
BSEP Deficiency [13]	ABCB11	• Dysfunctional secretion of bile acids from hepatocyte into canalicular space	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • Symptom onset in infancy with rapid progression over 1st few years of life • High risk of development of hepatocel- lular malignancy • Phenotypes:  • PFIC2  • BRIC2  • ICP2  • DILI  • Cryptogenic cirrhosis	• Supportive care • Biliary diversion • Liver transplantation  • Antibody mediated recurrent disease can occur
MDR3 Deficiency [13]	ABCB4	• Decreased excretion of cytoprotective biliary phospholipids with resultant bile duct damage from the detergent activity of bile acids	• ↑ AST/ALT/bilirubin. ↑↑↑ GGTP • Symptom onset ranges from late infancy to early adulthood with more gradual disease course • Phenotypes:  • PFIC3  • ICP3  • DILI  • Low phospholipid associated cholestasis  • Cryptogenic cirrhosis	• Supportive care • Biliary diversion • Liver transplantation
TJP2 Deficiency [14]	TJP2	• Impairment of hepatocyte tight junctions with resultant leakage of biliary components into liver parenchyma	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • Liver disease if often refractory, requiring liver transplantation • Phenotypes:  • PFIC  • Cryptogenic cirrhosis	•Supportive care • Liver transplantation
Farnesoid X Receptor (FXR) [15]	NR1H4	• Loss of FXR function results in decreased BSEP promoter activation and absent BSEP expression in the canaliculus	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • Neonatal onset with rapid progression to ESLD Coagulopathy is common • ↑↑ AFP • Phenotypes:  • PFIC  • ICP  • DILI	•Supportive care • Liver transplantation
Myosin VB [16,17]	MYO5B	• Impaired targeting of BSEP to the canalicular membrane with decreased bile acid excretion	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • Presentation in the first months of life • Liver disease has been reported to be transient, recurrent, and/or progressive • Phenotypes • PFIC	• Supportive care
USP53 [18,19]	USP53	• Shown to co-localize with TJP2 and dysfunction thought to impair tight junction structure	• ↑ AST/ALT/bilirubin. ↓ /normal GGTP • Presentation reported in infancy and at older age as well • Liver disease has been reported to be transient, recurrent, and/or persistent • Phenotypes:  • PFIC  • BRIC  • Cholangiopathy	• Supportive care • Rifampicin responsiveness

AFP: alpha fetoprotein, GGTP: gamma-glutamyl transpeptidase, BRIC: benign recurrent intrahepatic cholestasis, BSEP: bile salt exporter pump, DILI: drug-induced liver injury, ESLD: end-stage liver disease, FIC: familial intrahepatic cholestasis, ICP: intrahepatic cholestasis of pregnancy, IHC: immunohistochemistry, PFIC: progressive familial intrahepatic cholestasis.

^*Supportive care refers to the general care of these patients and looks to address complications such cholestasis and progressive liver disease.

2. Overview of the market

The non-surgical treatment of PFIC disorders is largely comprised of supportive measures, including optimizing nutrition via caloric, fat and vitamin supplementation and managing complications of end-stage liver disease. As destructive itch is a dominant feature of PFIC, therapies are often trialed to lessen pruritus. Initial measures may include emollients, fingernail plate hygiene, and avoiding hot baths. Medications that have demonstrated utility in PFIC are listed in Table 2. Importantly, while treatment usually includes a combination of the therapies described, their overall effects remain sub-optimal.

Table 2.

Historical pharmacotherapy of pruritus in children.

Medicine	Dose	Mechanism of action
Ursodeoxycholic Acid (UDCA)	15–30 mg/kg/d	• Tertiary BA • Increases bile secretion • Reduces ileal absorption of hydrophobic Bas • Immunomodulating effect on hepatocytes by decreasing MHC Class I antigen expression. • Modulates expression of canalicular transporters such as the chloride-bicarbonate anion exchanger
Rifampicin	Initial dose: 4 mg/kg (max dose 20 mg/kg/d)	• PXR agonist • Induces CYP3A4 • Increases metabolism and renal excretion of pruritogenic substances • Antibacterial effect may modify intestinal metabolism of pruritogenic substances
Cholestyramine	Initial dose: 240 mg/kg/d (max dose 32 g/d)	•Ion exchange resin which acts as BA binder in the intestine • Decreased ileal BA absorption, Increased BA excretion (in feces)
Naltrexone	Initial dose: 0.25–5 mg/kg/d (max dose 50 mg/d)	• Opioid antagonist • Block the permissive activity on pruritus neuronal signaling
Sertraline	Initial dose: 1 mg/kg/d (max dose: 4 mg/kg/d)	• Serotonin reuptake inhibitor • Proposed mechanism includes increase in central serotonergic tone, which regulates pruritus
Hydroxyzine	Initial dose: 2 mg/kg/d (max dose <6 yr: 50 mg/d, >6 yr: 100 mg)	• Antihistamine • Selective histamine H1 receptor inverse agonist • Often ineffective as monotherapy

BA: bile acid, MHC: major histocompatibility complex, PXR: pregnane X receptor.

When symptoms are refractory to medical therapy, surgical interventions such as partial external biliary diversion (PEBD), partial internal biliary diversion (PIBD), and ileal exclusion have been considered to enable a bypassing of the enterohepatic circulation and/or decreasing reabsorption of bile salts (Figure 3). To date, data suggest such procedures generally, though not uniformly, resulted in marginal clinical improvement in PFIC patients [20–22]. Liver transplant (LT) is indicated in patients with a progressive course, or who develop hepatocellular carcinoma. Although both above mentioned interventions are viable treatment options for PFIC, post-surgical issues such as the presence of a stoma in PEBD, the need for lifelong immunosuppression after LT, in addition to the potential complications of the surgeries themselves highlight the need for less invasive treatment options that reduce debilitating pruritus, limit the progression of liver disease, and improve long-term prognosis.

Figure 3.

Surgical biliary diversion for PFIC. Three variations of biliary diversion include: 1) partial external biliary diversion (PEBD, black arrow) where an external stomal conduit (generally a cholecystojejunal cutaneous stoma) enables partial, unregulated external bile flow; 2) partial internal biliary diversion (PIBD, blue arrow) where a neo-conduit is created between the gallbladder and the colon; and 3) ileal exclusion (IE, white arrow) where the distal ~15 cm of the ileum is surgically bypassed. All techniques have been used in an effort to decrease bile acid reabsorption in the terminal ileum via IBAT.

Recent development of the family of medications referred to as the IBAT inhibitors has introduced a novel tool in the armamentarium for the medical treatment of PFIC. These compounds enable a pharmacological interruption of the enterohepatic circulation and have been shown in clinical studies to reduce the bile salt pool size, alleviate pruritus, and reduce the need for surgical intervention [23]. Importantly, several IBAT inhibitors are currently being evaluated in phase 2 and phase 3 clinical trials for pediatric patients with PFIC as well as Alagille syndrome (ALGS), another cholestatic disease in children that can share many symptoms of the PFIC disorders [24]. We note the development of maralixibat (LUM001 or SHP625), an orally administered, small-molecule IBAT inhibitor. It has been evaluated with two phase-2 studies (ITCH and IMAGO) and in three ongoing long-term phase 2 trials (ICONIC and IMAGINE-I and -II) [25]. Importantly, maralixibat received its first approval in the United States in the fall of 2021 for the treatment of cholestatic pruritus in patients with ALGS >1 year of age. Clinical development for additional cholestatic liver disorders, including the younger ALGS patients, PFIC, and biliary atresia, is ongoing [26]. Additionally, other IBAT inhibitors being investigated for the treatment of chronic constipation, nonalcoholic fatty liver disease, type 2 diabetes mellitus, hyperlipidemia, primary biliary cholangitis, and primary sclerosing cholangitis are beyond the scope of this article.

3. Introduction to the compound

Odevixibat is a small molecule inhibitor of the ileal bile acid transporter (IBAT) for the treatment of pruritus in cholestatic liver diseases including PFIC (Box 1). As of July 2021, it has been approved in the European Union and the United States for patients with PFIC (patient ≥6 months and ≥3 months respectively) [27]. It is also currently in clinical development for use in other cholestatic liver diseases including ALGS and biliary atresia. It is currently available in two forms: an oral pellet form intended for those less than 19.5 kg (200 μg and 600 μg) which can be opened, and the contents sprinkled on applesauce or other soft foods, or capsules (400 μg, 1200 μg) intended to be swallowed whole. The recommended starting dose is 40 μg/kg once daily in the morning with a meal and this dosage can be increased by 40 μg/kg increments up to 120 μg/kg if there is no clinical improvement in pruritus after 3 months. The maximum daily dose in the US is to not exceed 6 mg [27].

Box 1. Drug summary box.

Drug name: odevixibat

Phase: Phase 2 and Phase 3

Indication: Improvement in pruritus, reduction in serum bile acid levels

Mechanism of action: Selective, reversible inhibition of the Ileal Bile Acid Transporter (IBAT), and reduces the reabsorption of bile acids from the terminal ileum and ultimately reduces serum bile acid (sBA)

Route of administration: Oral pill or pellet form

Chemical structure: 2S)-2-{[(2 R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1 H-1λ⁶,2,5-benzothiadiazepin-8yl]oxy}acetamido)-2-(4-hydroxyphenyl)acetly]amino}butanoic acid [27].

Pivotal trials: NCT03566238 (PEDFIC1), NCT02630875, NCT03659916 (PEDFIC2, ongoing), NCT04483531 (Expanded access)

4. Chemistry and pharmacodynamics

The active ingredient in odevixibat is (2S)-2-{[(2 R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5- phenyl-2,3,4,5-tetrahydro-1 H-1λ⁶,2,5-benzothiadiazepin-8yl]oxy}acetamido)-2-(4- hydroxyphenyl)acetly]amino}butanoic acid [27]. It displays selective, reversible inhibition of the IBAT, and reduces the reabsorption of bile acids from the terminal ileum and ultimately reduces serum bile acid (sBA) levels [28] (Figure 1). Trials have shown that sBA concentrations decrease from baseline within 4–8 weeks of treatment compared to placebo, and there was no significant correlation in the extent of decrease in sBA levels and the dose of odevixibat [25].

5. Pharmacokinetics

Odevixibat is minimally absorbed following oral administration. In pediatric patients with PFIC who received odevixibat (40 μg/kg or 120 μg/kg once daily), the measurable odevixibat concentrations ranged from 0.06 to 0.72 ng/mL, and concentrations were below the limit of quantification (0.05 ng/mL) in the majority of plasma samples [27]. Sprinkling odevixibat pellets on soft food versus swallowing pills whole with food did not have a clinically significant effect on systemic exposure. Odevixibat C_max is reached between 1 and 5 hours following a single administration of 7.2 mg in healthy adults. Compared to administration under fasted conditions, concomitant consumption of a high-fat meal delayed median T_max from 3 hours to 4.5 hours and resulted in decreases of 72% and 62% in C_max and AUC_0–24h, respectively; however, this was not clinically significant. In adults, after ingestion of one oral dose, elimination was mainly in the feces (82.9%) and less than 0.002% in the urine. Odevixibat is a substrate of P-glycoprotein (P-gp) but not a substrate of breast cancer resistance protein (BCRP) [26,27]. As expected, coadministration with itraconazole (a strong P-gp inhibitor) with a single dose of 7.2 mg of odevixibat 7 increased odevixibat AUC_0–24h by 66% and Cmax by 52%, which is not expected to have a clinically significant effect [29]. Lastly, odevixibat has been shown to reduce absorption of several medications including fat soluble vitamin supplements [27]. Bile acid binding resins, like cholestyramine, colesevelam or colestipol may bind odevixibat in the gut which may reduce odevixibat efficacy and thus the administration of odevixibat and bile acid binding resins should be separated by 4 hours [27].

6. Clinical efficacy

Odevixibat was effective in reducing pruritus and sBAs in children with PFIC in a double-blind, randomized, placebo-controlled, Phase 3 trial (NCT03566238; PEDFIC1) (Table 3). The authors of this study investigated the efficacy and safety of low- vs high-dose odevixibat compared to placebo in children with PFIC types 1 and 2. Patients ranged from age 6 months to 18 years with genetically confirmed disease and elevated sBA. In the trial, they were randomized into odevixibat low dose (40 μg/kg, n = 23), high dose (120 μg/kg, n = 19), or placebo (n = 20) arms for 24 weeks. The median age (range) of the patients was 3.2 (0.5 to 15.9) years; 3 patients were older than 12 years of age. Of the 62 patients, 50% were male and 84% were white; 27% had PFIC1, and 73% had PFIC2. Baseline median (range) ALT, AST, and total bilirubin were 65 (16–798) U/L, 83.5 (32–405) U/L, and 2.2 (0.2–18.6) mg/dL, respectively [30].

Table 3.

Clinical reports on the efficacy of odevixibat.

Study	Study type	Dose	Patients (n)	Efficacy
NCT02630875* [31]	Phase 2, open label	10–200 μg/kg × 4 weeks	20 (2 FIC1, 9 BSEP, 2 MDR3, 2 MY05B, 5 non-PFIC)	• Mean sBA ↓ 123 umol/L (range −394 to 15) • Itch PRO  • VAS-itch ↓ 2.2 (range −6.1–1.7)  • PO-SCORAD itch ↓ 2 (range −6.7–1.6)  • Whitington itch ↓ 0.8 (−3 – 0.8) • PO-SCORAD sleep disturbance ↓ 1.8 (−5.8–1.2)
NCT03566238, PEDFIC1 [32]	Phase 3, double blind, randomized, placebo controlled	• Two treatment arms:  • 40 μg/kg/d × 24 weeks  • 120 μg/kg/d × 24 weeks  • Placebo?	62 (17 FIC1 and 45 BSEP)	• Mean sBA ↓ 114.3 umol/L in treatment arm vs +13.1 umol/L in placebo (p = 0.002) • Itch PRO  • ObsRO ↓ 42.9% in treatment vs 10.5% placebo (p = 0.018)
Ongoing studies
NCT03659916, PEDFIC2	Open label phase 3 extension to PEDFIC1	120 μg/kg/d × 72 weeks	Goal 120, still recruiting (FIC1, BSEP, and MDR3)	Not reported
NCT04483531	Expanded access	120 μg/kg/d	PFIC patients with pruritus and elevated serum bile acids who are not eligible for PEDFIC2	Not reported

^*Results presented for all 20 patients.

ObsRO: observer reported outcome, PO-SCORAD: partial patient-oriented scoring atopic dermatitis, PRO: patient reported outcome, sBA: serum bile acids, VAS: visual analogue scale.

The primary outcome was the effect on pruritus measured on a 5-point, patient reported outcomes instrument ObsRO (observer reported outcome). Patients in both the low-dose and high-dose treatment arms had significantly less pruritus over a 24-week period. A subsequent primary endpoint was the percentage of participants experiencing a ≥70% reduction in fasting sBA concentration from baseline or reaching a level ≤70 μmol/L at 24 weeks of treatment. Here, in the low-dose arm, 43.5% (n = 10) were responders vs. 0% of placebo (proportion of difference 0.435, CI 0.2195–65.51%, p = 0.0015). Similar findings were noted in the high-dose arm with 21.1% (n = 4) responders compared to 0 in the placebo group (p = 0.0174) [28].

PEDFIC2 is an ongoing, open-label, phase 3 extension study (NCT03659916). The study is enrolling 120 participants with either FIC1 or BSEP disease who will all receive 120 μg/kg odevixibat once daily for 72 weeks and the primary outcomes will look at the change in pruritus and the change in serum bile acid concentrations. This study included recruiting PEDFIC1 patients as well as new patients for a total pooled analysis of 77 patients. Nineteen patients received placebo in PEDFIC1 and rolled into PEDFIC2 and started odevixibat, 42 patients who received the drug in PEDFIC1 continued odevixibat in PEDFIC2, and 16 patients with either PFIC1 or 2 were newly recruited. Much of the clinical data from PEDFIC2 has thus far only been presented at scientific congresses. Preliminary data from pooled analysis of PEDFIC1 and PEDFIC2 data has shown that the median duration of exposure to the drug was 37 weeks. Over that time, mean serum bile acids, pruritus scores and need for soothing and growth were followed. There was a decrease in baseline serum bile acid after 4 weeks of treatment which was sustained to week 48 of treatment compared with placebo. There were also clinically meaningful improvements in growth parameters as well as decreased observer-reported need for soothing, sleeping with caregiver, and need for help falling asleep in weeks 37–48 [33].

Additionally, there have been case reports of off-label use of odevixibat to successfully curb post-transplant diarrhea and growth failure in PFIC1. In one such case, a patient with PFIC1 developed refractory post-LT diarrhea and failure to thrive with unsatisfactory response to bile acid resins. Surgical diversion was offered but deferred. After 6 months of off-label treatment with odevixibat, the patient showed less stool output, increased weight and height and improved physical energy levels [34]. Although US FDA approval for odevixibat is currently limited to treatment of pruritus, this may represent another avenue of continued research into the potential benefit of odevixibat and other iBAT inhibitors in aspects of care for patients with PFIC, specifically PFIC type 1.

7. Safety and tolerability

Odevixibat was generally well tolerated in pediatric patients. The most safety and tolerability data available is from the phase 3 PEDFIC1 trial. In the 24-week PEDFIC1 trial, there were no serious adverse events in the low-dose, 40 μg/kg/day arm, and there were 3 subjects who developed 4 serious adverse events in the high-dose arm, 120 μg/kg/day (1 supraventricular tachycardia, 1 urinary tract infection, 1 elevated liver transaminases, and 1 dehydration). The most common other adverse events for both arms included diarrhea (39.13% in LD, 21.05% in HD, 10% in placebo), followed by elevation in transaminases and vomiting [28].

PEDFIC1 enrolled patients uniformly had abnormal liver tests at baseline, still worsening of levels relative to baseline values were observed during the clinical trial. Treatment interruption days ranged from 3 days to 124 days and were mostly a result of abnormalities in AST, ALT, or total and direct bilirubin. Importantly, none of the patients in PEDFIC1 had to permanently discontinue treatment due to liver test abnormalities. ALT elevations of ≥150 U/L were observed in 9.5% (4/42 total patients) who received odevixibat, compared to 0% of the placebo group. Similarly, AST elevations of ≥150 U/L were seen in 9.5% (4/42 total patients) receiving treatment, with a greater proportion (15.8%, n = 3) from the high-dose arm [28].

In patients treated with 40 μg/kg/day, diarrhea was reported in 9 (39%) patients and when the dose was increased to 120 μg/kg/day, 4 (21%) odevixibat-treated patients noted diarrhea. This compared to 2 (10%) placebo-treated patients. The resultant diarrhea caused treatment interruption (range 3–7 days) in two patients with three events in the higher dosed cohort. One withdrew from the trial due to persistent diarrhea [30].

As previously noted, odevixibat may also affect the absorption of the fat-soluble vitamins (FSV) A, D, E, and K, which is important as PFIC patients often have FSV deficiency. New onset or worsening of existing FSV deficiency was reported in 1 (5%) placebo-treated patient, and 3 (16%) of odevixibat treated (120 μg/kg/day, high dose) patients; however, none of the patients treated with the lower dose (40 μg/kg/day) had new onset or worsening of existing FSV deficiency in the first principal efficacy trial. Regardless, it is recommended to obtain serum FSV levels at baseline and to continue monitoring during the treatment course [28]. Odevixibat treatment may thus need to be interrupted or discontinued for persistent diarrhea, FSV deficiency despite adequate supplementation, and LFT abnormalities.

8. Conclusions

PFIC disorders are a complex group of disorders which present both diagnostic and treatment challenges. While significant advancement in genetics and bile acid transport physiology has enabled broader understanding of the mechanisms driving disease development, the clinical management of these disorders has changed very little over the past several decades. Emerging medications, such as odevixibat and other IBAT inhibitors, have shown early efficacy and appear to provide a new treatment modality which has the potential to significantly advance the PFIC-treatment landscape for affected children and their families.

9. Expert opinion

First reported in 1969 in seven Amish children (from the original Byler kindred in Western Pennsylvania) was the progressive familial intrahepatic cholestasis phenotype [35]. Subsequent discovery of the causative ATP8B1 gene in 1998 [36] laid the groundwork for future efforts that would advance understanding of how genetic defects in proteins affect bile acid homeostasis and cause disease [8]. Despite this progress, little has changed about how patients affected by these disorders are managed in the clinic. In addition to aggressive supportive measures aimed at improving nutritional status and growth, medical therapies have primary targeted the refractory itch, often with sub-optimal results. Surgical intervention to interrupt the enterohepatic circulation of bile salts has been well established as a potential therapy [37]; however, the overall efficacy of the procedures can be hampered by the relative unregulated nature of the most common procedures offered (PEBD, PIBD). In other words, the amount of bile that bypasses enterohepatic circulation via excretion in the stoma bag (PEBD) or into the colon (PIBD) is variable and uncontrolled, leading to disparate results. One marker that has been shown to prognosticate both early response and long-term outcomes after diversion is a decrease is sBA measurements [37,38] and novel therapies which target sBAs hold immense promise improving treatment for PFIC. Here, IBAT inhibition with therapeutics, such as odevixibat, look to benefit the PFIC community by providing a well-tolerated oral medication, mitigating the terrible itch that often plagues affected patients, eliminating the need for invasive surgical diversion procedures, and increasing transplant-free survival.

The clinical efficacy that odevixibat has demonstrated in the few early published experiences, combined with its relatively benign safety profile, will likely place it, along with other IBAT inhibitors in development, near the top of the treatment paradigm for these complex disorders. Still, what remains to be seen is long-term, real-world experiences that extend these early findings into sustainable improvement. Additionally, how these medications act to replace, or merely supplement the current medical and surgical therapies needs further investigation. The benefit of these medications on the more contemporary PFIC disorders such as those associated with TJP2, MYO5B, NR1H4, and USP53, as well as the growing list of genetic-based disorders increasingly being collated under the umbrella term ‘PFIC’ is yet to be meaningfully studied, as is a deeper look into genotype-specific responses that have been appreciated with surgical diversion. Finally, how these medications are incorporated into treatment algorithms for the other disorders which share their genetic underpinnings (ICP, BRIC) is unknown.

In conclusion, the clinical approach to the PFIC disorders is entering a transformational era, driven by advanced understanding of how disruption in bile acid homeostasis contributes to disease and how targeted blocking of bile acids from entering the enterohepatic circulation may mitigate the most devastating manifestations. Future clinical trials for novel therapies, combined with comparative effectiveness studies will hopefully enable a more personalized approach to therapy and maximize the benefit of emerging therapeutics such as odevixibat.