CADTH Reimbursement Review

Odevixibat (Bylvay)

Sponsor: Medison Pharma Canada Inc.

Therapeutic area: Progressive familial intrahepatic cholestasis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on the Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Progressive familial intrahepatic cholestasis (PFIC) is a rare and life-shortening heterogeneous group of liver disorders of autosomal recessive inheritance that affects the production and/or composition of bile from the liver.¹ PFIC is categorized based on genetic defect, clinical presentation, laboratory findings, and liver histology.¹ At least 6 subtypes of PFIC have been described in the literature, although the nomenclature beyond types 1 to 3 is somewhat indeterminate. PFIC type 1 (PFIC1) and type 2 (PFIC2) represent approximately two-thirds of cases, and type 3 (PFIC3) represents a large portion of the remainder.^1-5 Patients with PFIC1 and PFIC2 generally present with jaundice and severe pruritus in the first few months of life, with 78% developing jaundice before the age of 12 months.⁶ PFIC3 can occur during infancy, childhood, and even into young adulthood. Although the genetic mutations underlying the PFIC subtypes differ, the common feature of all subtypes is elevated serum bile acid (sBA) concentrations and severe pruritus. PFIC is a rare disease that is estimated to affect from 1 in every 50,000 to 100,000 children born worldwide.^4,5 While global or country-specific prevalence estimates are not available for PFIC, it is believed to be responsible for approximately 10% to 15% of cholestatic liver diseases among children and 10% to 15% of liver transplant indications in children.^4,5

PFIC is characterized by the early onset of cholestasis (usually during infancy) with severe pruritus and fat malabsorption that progresses rapidly and leads to liver failure.¹ Elevated bile acid concentrations result in ongoing liver inflammation, fibrosis, cirrhosis and, eventually, liver failure. Intractable pruritus is the most troubling symptom of PFIC.

PFIC is a fatal disease. The survival rate in patients with PFIC who have not undergone surgical biliary diversion (SBD) or a liver transplant is 50% at age 10 and almost zero at age 20.⁶ PFIC may manifest with many symptoms, including jaundice, hepatomegaly, severe pruritus, splenomegaly, diarrhea, discoloured stools, failure to thrive, vitamin E deficiency, vitamin D deficiency, and pancreatitis (PFIC1).⁷

The clinical experts consulted by CADTH for this review stated that although there are numerous anti-itch medications, including antihistamines and other drugs like rifampicin that indirectly address itch, they may be effective for mild to moderate pruritus but are not effective therapies for severe pruritus. One clinical expert noted that accumulation of bile acids damages the liver; however, it is not clear whether a medication like ursodeoxycholic acid (UDCA) is able to address this key aspect of the pathophysiology of PFIC. Surgery is also a key nonpharmacological approach, although it is not always successful, carries a high risk of morbidity, and is not suitable for the subset of patients who have cirrhosis.

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of odevixibat at the approved doses compared with relevant comparators for the treatment of pruritus in patients aged 6 months or older with PFIC.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Input was received from the Canadian Liver Foundation (CLF). It surveyed patients and caregivers living with PFIC and received 14 responses (4 of these were from Canada).

Families expressed feelings of helplessness, anguish, and frustration, noting that a diagnosis of PFIC has severely impacted the lives of their loved ones and also their own daily activities. Respondents highlighted the significant impact that constant itch has on their daily lives, and how disrupted sleep leaves them and their loved ones chronically fatigued.

Respondents highlighted the importance of improving their quality of life as well as improving itch and sleep, achieving normal growth, maintaining energy, and slowing the progression of their disease. The CLF emphasized the need to ensure equitable access to therapies for PFIC across the country.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

According to the clinical experts consulted by CADTH for this review, there is a major unmet need in PFIC for a drug that can address the underlying pathophysiology of the disease, that can effectively control pruritus (particularly severe pruritus), and potentially slow progression of the disease.

The clinical experts did not identify a specific subtype of PFIC that is more likely to benefit from odevixibat; however, they did highlight the fact that randomized controlled trial (RCT) evidence is available only for the PFIC1 and PFIC2 subtypes. The clinical experts indicated that the severity of pruritus should be the main determinant of when to initiate therapy, with signs such as excoriations and significant lack of sleep as key indicators of severe itch. The clinical experts noted that the key indicator of treatment response is a reduction in itch, and this should be accompanied by improvement in sleep, feeding and, in older children, school performance, sports activities, and mood and/or energy levels. The clinical experts stressed that although sBA level can also be used to assess response, it does not always correlate well with itch and the assay is not widely available. According to the clinical experts, the main reason to discontinue odevixibat would be because the patient is undergoing a liver transplant. An additional consideration would be tolerability or safety issues.

Clinician Group Input

The Canadian Pediatric Hepatology Research Group (CPHRG), which functions under the aegis of the Canadian Association for the Study of the Liver, provided input for this review.

The CPHRG agreed with the clinical experts consulted by CADTH that current pharmacologic treatments have limited efficacy and do not address the underlying disease process, whereas surgical options carry a high risk of morbidity and mortality. They also agreed that a response to odevixibat would be indicated by improvement in pruritus and sleep, and indications for discontinuation would include continued progression of disease (e.g., liver transplant) and drug intolerance.

The CPHRG input did not state whether it had experience with odevixibat.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for odevixibat:

• consideration for initiation of therapy

• consideration of discontinuation of therapy

• consideration for prescribing of therapy

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs (Table 4).

Clinical Evidence

Systematic Review

Description of Studies

PEDFIC 1 (N = 62) was a phase III, multicentre (1 site in Canada), double-blind, randomized, placebo-controlled study to demonstrate the efficacy and safety of odevixibat 40 mcg/kg/day and 120 mcg/kg/day in children with PFIC1 or PFIC2.^8,9 The study included up to an 8-week screening period, a 24-week treatment period, and a 4-week follow-up period. The primary outcome of PEDFIC 1 was the proportion of patients who experienced at least a 70% reduction in sBA concentration from baseline to the end of treatment or a lowering of sBA to 70 µmol/L or less after 24 weeks of treatment.

This was the primary outcome used for submission to regulatory bodies outside of the US, including Canada, and was therefore considered the primary outcome of interest for the purposes of this report. Secondary outcomes included the following:

• proportion of positive pruritus assessments at the patient level over the 24-week treatment period based on the PRUCISION observer-reported outcome (ObsRO) instrument (this was the primary outcome for submission to the FDA)

• change in growth from baseline to week 24

• change from baseline in sleep parameters (awakenings) measured with the PRUCISION Patient-Reported Outcome (PRO) and ObsRO instruments at each 4-week interval over the 24-week treatment period

• proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level from weeks 0 to 4 and weeks 0 to 12

• number of patients undergoing biliary diversion surgery or liver transplant.

The median age of the patients in the PEDFIC 1 study was 3.2 years and ranged from 6 months to 15.9 years. Most patients (47 of 62; 76%) were between 6 months and 5 years of age; 12 (19%) were between 6 and 12 years of age, and 3 (5%) were between 13 and 18 years of age; a limited number of patients (10; 16%) were 8 years of age or older. Median height-for-age and weight-for-age z scores were −1.70 and −0.95, respectively, indicating the patients were below their age-matched peers for growth. Most (45 patients; 73%) had PFIC2 and 17 (27%) had PFIC1. According to the investigator, almost all patients (60; 97%) had a history of significant pruritus present and most (42; 68%) had sBA levels greater than 100 µmol/L (40.85 mcg/mL) within the 6 months before enrolment in the study. At study entry, 50 patients (81%) were on UDCA and 41 (66%) were on rifampicin. Overall, 8 patients (13%) reported prior biliary tract surgeries (all reports of biliary diversion). Median sBA levels were elevated at baseline at 228.0 µmol/L, 188.5 µmol/L, and 254.5 µmol/L in the odevixibat 40 mcg/kg/day, odevixibat 120 mcg/kg/day, and placebo groups, respectively. Median levels of hepatic biochemical parameters were elevated at baseline, including alanine aminotransferase (ALT) (approximately 2 × upper limit of normal [ULN]), aspartate aminotransferase (AST) (less than 2 × ULN), and total bilirubin (1.8 × ULN). Based on the Child-Pugh classification, 41 patients (66%) had mild hepatic impairment and 21 (34%) had moderate hepatic impairment; no patients had severe impairment.

Efficacy Results

Mortality

Mortality was reported as a safety outcome in the PEDFIC 1 study, and there were no deaths in that study.

Need for Surgery

The need for surgery was a secondary outcome in the PEDFIC 1 study, and there were no instances of surgeries for liver transplant or biliary diversion in that study.

Health-Related Quality of Life

Health-related quality of life (HRQoL) was assessed as an exploratory outcome using the Pediatric Quality of Life Inventory (PedsQL) instrument. It is scored on a 0 to 100 scale, with higher scores indicating improved quality of life. After 24 weeks, the least squares (LS) mean difference versus placebo for the odevixibat 40 mcg/kg/day group was ||||| |||| |||||||||| |||||||| ||||| ||||||| |||||| ||| ||| ||| ||| |||||||||| ||||| ||| |||| |||| ||| |||||| ||||||.

Pruritus

The sponsor designed its own instrument for assessing pruritus. The assessment of the proportion of positive pruritus responses at 24 weeks was a secondary outcome of the study. After 24 weeks of treatment with odevixibat, the between-group differences in the LS means for the comparisons of the 40 mcg/kg/day odevixibat group with placebo was 28.23% (95% confidence interval [CI], 9.83 to 46.64), and the 120 mcg/kg/day odevixibat group with placebo was 21.71% (95% CI, 1.87 to 41.54). ||||||||||| |||||| ||||||| |||| |||| |||||||| ||| ||||| |||| |||||| |||| |||||||||| |||||| ||||||| ||| ||| |||||||||| || |||||||||| ||||| || |||||| |||| ||| ||||| ||||||| ||| ||| ||| ||| ||||||||||||||| || |||||| |||| ||| ||||| |||||||| || ||||||| || ||| ||||||||||| |||||| ||||||| |||| |||||||| |||||||||||| || ||| |||||| ||||| |||||| |||| |||||||||| |||||| ||||||| ||| ||| |||||||||| || |||||||||| ||||| || ||||||||| ||| |||||| ||||||| ||| ||| ||| ||| |||||||||| ||||| || |||||| |||| ||| |||||| |||||||.

Serum Bile Acids

The primary outcome of PEDFIC 1 was the proportion of patients experiencing at least a 70% reduction in fasting sBA from baseline to end of treatment or a lowering of sBA to 70 µmol/L or less after 24 weeks. The adjusted difference in proportions between odevixibat 40 mcg/kg/day and placebo was 44.1% (95% CI, 23.6 to 64.6; P = 0.0015) and 21.6% (95% CI, −0.5% to 43.8%; P = 0.0174) between odevixibat 120 mcg/kg/day and placebo. ||||||||||||| ||||||||||| |||| ||||||| ||| ||| |||| ||||||| |||| |||||||| || || |||||| |||| || |||||||| |||||||||| || ||||||||||| ||||||| |||||||||| || |||||||||| ||| ||||||| ||| ||||| |||| ||| |||||| ||||||| ||| ||||||| |||||||||| ||| |||||||||| ||| ||||||| ||| ||||| |||| ||| ||||||| |||||||.

Growth

Improvement in growth (height, weight, body mass index [BMI]) was assessed as a secondary outcome by comparing changes from baseline in z scores relative to a typical pediatric growth chart. For height, the LS mean between-group difference for odevixibat versus placebo after 24 weeks was |||| |||| ||| ||||| ||||| ||| ||| || |||||||||| ||||| ||| |||| |||| ||| |||||| ||||| for the 120 mcg/kg/day group. For weight, the LS mean between-group difference was |||| |||| ||| |||||| ||||| ||| ||| || |||||||||| ||||| ||| |||| |||| ||| |||||| ||||| ||| ||| ||| |||||||||| |||||. For BMI, the LS mean between-group difference was |||| |||| ||| |||||| ||||| ||| ||| || |||||||||| ||||| ||| ||||| |||| ||| |||||| ||||| ||| ||| ||| |||||||||| |||||.

Number of Awakenings

The changes over time in sleep parameters, specifically awakenings, were assessed as a secondary outcome using data derived from the PRUCISION pruritus instruments developed by the sponsor. The LS mean between-group difference in number of awakenings from baseline to weeks 21 to 24 was |||| |||| ||| |||||| |||||| || ||| || |||||||||| ||||| ||| ||||| |||| ||| ||||||| ||||| || ||| ||| |||||||||| |||||.

Total Bilirubin

The change from baseline to week 24 in total bilirubin was an exploratory outcome. The LS mean between-group difference versus placebo in total bilirubin was |||||| |||||| |||||||| |||||| || ||| || |||||||||| ||||| ||| ||||| |||||| |||||||| |||||| || ||| ||| |||||||||| |||||.

Harms Results

Adverse Events

Overall, 35 of the 42 patients (83%) who received odevixibat experienced at least 1 treatment-emergent adverse event (TEAE), as did 17 of the 20 patients (85%) who received placebo; the overall incidence of TEAEs was similar in the odevixibat 40 mcg/kg/day and 120 mcg/kg/day treatment groups (83% and 84%, respectively). The most commonly reported types of events during the study were gastrointestinal disorders and infections. Overall, the most commonly reported TEAEs (≥ 10% overall) among patients who received odevixibat, with corresponding incidence for patients who received placebo, were diarrhea |||| || |||, pyrexia (29% versus 25%), upper respiratory tract infection (19% versus 15%), vomiting (17% versus 0%), ALT increased (14% versus 5%), and blood bilirubin increased (12% versus 10%).

Serious Adverse Events

Treatment-emergent serious adverse events (SAEs) were reported in 3 of the 42 patients (7%) who received odevixibat and in 5 of the 20 patients (25%) who received placebo. No treatment-emergent SAEs were reported in the 40 mcg/kg/day treatment group. The most commonly reported types of treatment-emergent SAEs were infections, reported in ||||||| of the 20 patients in the placebo group and in 1 of the 19 patients (5%) in the 120 mcg/kg/day group. The only event reported in more than 1 patient overall was urinary tract infection, which was reported in 1 patient each in the placebo and 120 mcg/kg/day groups. None of the treatment-emergent SAEs led to the discontinuation of treatment.

Withdrawals Due to Adverse Events

Dose interruptions due to TEAEs were reported at a higher incidence in patients who received odevixibat (9 of 42; 21%) compared with patients who received placebo (1 of 20; 5%). The highest incidence was reported among patients who received the 120 mcg/kg/day dose (6 of 19; 32%); while 3 of the 23 patients (13%) in the 40 mcg/kg/day group had treatment interruptions due to TEAEs. |||| ||| || |||||||| |||| ||||||||| ||||||||||||| ||| || |||||| ||| |||||| |||| ||||||| || |||||||||| || ||||||| ||||||||||| |||| ||||||| ||| ||||||||| ||| |||||||||||| |||||||| || ||| ||||||||| ||||| ||| ||||| |||| ||| ||||| |||| ||||||||||| ||| || ||||||| ||||||||||| |||| ||||||| ||||||||| |||||||||||| || ||| |||| |||||| |||||||||| ||||| ||| |||||||| ||| |||||| || ||||||| || ||| ||||||||| |||||||||| |||||||. All these patients completed the PEDFIC 1 study and rolled over to the extension (PEDFIC 2) to receive odevixibat, except 1 patient who discontinued the study due to the inability to attend clinic visits.

One patient receiving odevixibat 120 mcg/kg/day discontinued the study drug due to a TEAE of diarrhea.

Critical Appraisal

The PEDFIC 1 study was double-blinded, with steps taken to maintain blinding and allocation concealment during the randomization process. Despite randomization, there were imbalances in several baseline characteristics, suggesting that prognostic balance was not achieved; this is likely the result of the small sample size. Given the small size of the trial, a relatively large number of patients discontinued treatment and were rolled into the extension, where all patients were given the higher dose (120 mcg/kg/day) of odevixibat. Although steps were taken to account for these missing data points for outcomes such as pruritus and sBA, a number of key outcomes such as PedsQL had data missing for more than 20% of the population.

With respect to external validity, major issues included the fact that the enrolled population was limited to patients with PFIC1 or PFIC2, while the proposed indication is not restricted to any subtypes. Additionally, the PEDFIC 1 trial assessed 2 different doses of odevixibat, 40 mcg/kg/day and 120 mcg/kg/day, and this differs from the proposed labelling, which recommends that all patients begin at 40 mcg/kg/day and then titrate up to 120 mcg/kg/day if there is a lack of response at 12 weeks. The trial was not of sufficient size or duration to adequately assess key clinical outcomes such as mortality or the need for surgical intervention.

GRADE Summary of Findings and Certainty of the Evidence

CADTH’s selection of outcomes for a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and input received from patient and clinician groups and the public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• Clinical outcomes:

  • mortality

  • need for surgery (biliary diversion or liver transplant)

  • growth (change from baseline to week 24 in z scores for height, weight, and BMI)

• Patient-reported outcomes:

  • PedsQL (change from baseline to week 24 in the PedsQL Parent Report and Family Impact Module)

  • Pruritus (proportion of positive pruritus assessments at the patient level at week 24, weeks 0 to 4, and weeks 0 to 12)

  • Sleep parameters (change from baseline to weeks 21 to 24 in number of awakenings)

• Lab parameters:

  • sBA (proportion of patients with at least a 70% reduction in fasting sBA or an sBA of 70 µmol/L or less at week 24 and at week 12)

  • Liver function (change from baseline to week 24 in total bilirubin)

• Harms:

  • Clinically significant diarrhea

  • Adjudicated hepatic events

Table 2: Summary of Findings for ODE Versus PLA for Patients With PFIC1 or PFIC2

BMI = body mass index; CI = confidence interval; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; HRQoL = health-related quality of life; MID = minimal important difference; NA = not applicable; NR = not reported; ObsRO = observer-reported outcome; ODE = odevixibat; PLA = placebo; PRO = patient-reported outcome; RCT = randomized controlled trial; SE = standard error.

Note: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 2 levels for very serious imprecision, as there were no events and a small sample size; rated down 1 level for serious indirectness, as the follow-up for this outcome was determined to be insufficient in consultation with clinical experts.

^bRated down 2 levels for very serious imprecision, as there were no events and a small sample size; rated down 1 level for serious indirectness, as the follow-up for this outcome was determined to be insufficient in consultation with clinical experts.

^cRated down 1 level for serious concerns about risk of bias due to missing outcome data. Rated down 2 levels for very serious concerns regarding imprecision; there was no published between-group MID identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. The 95% CI for both doses overlapped with both benefit and harm.

^dThese analyses were not adjusted for multiplicity, are at increased risk of false-positive findings, and therefore should be considered as supportive evidence.

^eRated down 1 level for serious concerns about imprecision. No published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. Although the point estimate and entire CI excluded the null, the small sample size raises concern for potential overestimation of the true effect and there is evidence of prognostic imbalance. Because the effect appeared plausible, the CADTH review team rated it down only once.

^fRated down 1 level for serious concerns about imprecision. No published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. Though the point estimate suggested a benefit, the 95% CI also included the potential for little to no difference.

^gRated down 2 levels for very serious concerns about imprecision. No published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. Though the point estimate suggested a benefit, the 95% CI also included the potential for little to no difference and harm.

^hRated down 1 level for serious concerns about imprecision. No published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. Though the point estimate and entire CI excluded the null, the small sample size raises concern for potential overestimation of the true effect and there is evidence of prognostic imbalance. Because the effect appeared plausible, the CADTH review team rated it down only once. Rated down 1 level for serious concerns about indirectness; this is a surrogate outcome with an unclear relationship to the clinical outcomes of interest.

ⁱRated down 1 level for serious concerns about imprecision. No published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. Though the point estimate suggested a benefit, the 95% CI also included the potential for little to no difference (based on the judgment of the CADTH team). Rated down 1 level for serious concerns about indirectness; this is a surrogate outcome with an unclear relationship to the clinical outcomes of interest.

^jRated down 1 level for serious concerns about risk of bias due to missing outcome data. Rated down 1 level for serious concerns regarding imprecision; there was no published between-group MID identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. The point estimate suggests a benefit but the lower bound of the 95% CI includes the potential for little to no difference.

^kRated down 2 levels for very serious imprecision, as there was only 1 event in each group and a very wide CI, which included the potential for both benefit and harm.

Rated down 2 levels for very serious imprecision, as the very wide CI included the potential for both benefit and harm.

^lThese analyses were not part of the statistical analysis plan and were requested by CADTH to facilitate the GRADE assessment.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence and the Clinical Study Report for PEDFIC 1.

Long-Term Extension Studies

Description of Study

PEDFIC 2 is an ongoing phase III, multicentre, nonrandomized, open-label extension study to investigate the long-term efficacy and safety of a 120 mcg/kg/day dose of odevixibat in patients with PFIC (Figure 14).^10,11 Cohort 1 (n = 56) consists of children with PFIC1 or PFIC2 who participated in the PEDFIC 1 study. Cohort 2 (n = 58) consists of patients with PFIC1 or PFIC2 who have elevated sBA and cholestatic pruritus and either did not meet eligibility criteria for the PEDFIC 1 study or were eligible for enrolment in the PEDFIC 2 study after recruitment for PEDFIC 1 was completed. The primary outcome of the PEDFIC 2 study was change from baseline in sBA after 24 (or 72) weeks of treatment. Secondary outcomes included proportion of positive pruritus assessments at the patient level over the 24-week (or 72-week) treatment period using the PRUCISION ObsRO instrument, change from baseline in sBA at various time points, proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level using the PRUCISION ObsRO instrument at various time points, proportion of individual morning and evening assessments meeting the definition of a positive pruritus assessment at the patient level using the PRUCISION ObsRO instrument at various time points, and the number of patients undergoing biliary diversion surgery or liver transplant.

Efficacy Results

Serum Bile Acids

Median changes in sBAs levels from baseline in the PEDFIC 2 study to weeks 22 to 24 were 5.8 µmol/L (range, −151.5 to 125.0) in patients who had received 40 mcg/kg/day in the PEDFIC 1 study, and |||| ||||||| ||||| ||||||| || |||||||| ||| ||| |||||||| ||| ||||||||||| ||| |||||||| ||| ||| |||||||| ||||||| || |||||| || |||||| ||||||| ||||||| || |||| ||||| ||||||||| ||| ||||| || ||||||||| |||| |||||||||| ||| |||||||||| ||| |||| |||||||| |||||| ||||||| ||| ||| |||||||| || |||||||| |||| |||||||| |||||| ||||||.

Median changes (range) in sBAs levels from the PEDFIC 2 study baseline to weeks 70 to 72 were ||| ||||||| |||||| ||||||| || |||||||| ||| ||| |||||||| || |||||||||| || |||||| || ||| ||||| |||||||| |||||| ||||||| || |||||||| ||| ||| |||||||| ||| ||||||||||| ||| |||||||| ||| ||| |||||||| ||||||| || |||||| || |||||| ||||||| ||||||| || |||| ||||| ||||||||| ||| ||||| || ||||||||| |||| |||||||||| ||| |||||||||| ||| |||| |||||||| |||||| ||||||| ||| ||| |||||||| || |||||||| ||||| |||||||| |||||| ||||||.

Surgical Intervention

|||||||| |||||||| || |||| ||||| ||||||||| |||||||| |||||||||||| |||||||||||||||| ||| ||||||||| ||||||| ||||||||| ||||||| ||| || |||||||| ||| ||||||||| ||||| ||||||||||||||| ||||||||. There was 1 patient who had their surgery before completing 24 weeks of treatment, |||||||| ||| ||||| ||||||| ||||||| ||||| || ||| || ||||||||||| ||| ||||| ||||||| ||||||| ||||| || ||| ||| |||| || ||| || |||||||| ||| ||||| ||||||| ||||| |||||||||| ||| || ||||| ||||||||| ||||||.

Pruritus

Among patients who had received active treatment in the PEDFIC 1 study and those who were treatment-naive at study entry, the median (range) proportion of positive pruritus assessments was ||||| ||| |||||| ||||| || ||||| || ||||||||| ||| ||||| ||| |||||| ||||| || ||||| || ||| |||||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| ||| |||||||| ||| ||| |||||||| || |||||||||| || ||||||||| |||||||||||| || ||| |||||||||| || ||||| ||||||||| ||||| ||| |||||| ||||| || |||||| ||||| ||| |||||| ||||| || |||||| ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| ||| |||||||| ||| ||| |||||||| ||| |||||||||| ||| ||||| ||| ||||| ||||| || |||||| ||||| ||| |||||| ||||| || |||||| |||||||||| |||| |||||||| ||||||||| |||||||||| |||| ||||||| || |||||| ||| |||||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| || ||| ||||||| ||||| ||| ||||| |||||| |||||| |||| ||| ||||||| ||||||||| |||||| ||| ||||| |||||| |||||| |||| ||| ||||||| ||||||||| ||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| || ||| ||||||| ||||| ||| ||||| |||| ||| ||||||| ||||||||| |||||| ||| ||||| |||||| |||||| |||| ||| ||||||| ||||||||| ||||||.

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Harms Results

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No deaths occurred during the study.

Critical Appraisal

The PEDFIC 2 study was limited by its open-label and noncomparative design; since there is no comparator, it did not show the comparative benefit of odevixibat versus relevant comparators. Furthermore, the small sample size of PEDFIC 2 led to difficulties in drawing any firm conclusion on the efficacy and safety of odevixibat. Due to its open-label and nonblinding nature, the absence of blinding can lead to assessor bias, and the patient or caregiver would most likely be in favour of the intervention (i.e., odevixibat) for efficacy outcomes. Moreover, the subjective outcomes (e.g., pruritus assessments at the patient level and individual assessments meeting the definition of a positive pruritus assessment at the patient level) are at risk of bias, regardless of blinding.

Although there was an amendment to include a starting dose of 40 mcg/kg/day with the possibility to escalate the dose after 12 weeks to 120 mcg/kg/day if there is no improvement in pruritus, the rationale for selecting the optimal starting dose and titration strategy still remained unclear. As of July 31, 2022, the PEDFIC 2 study had not assessed the long-term efficacy and safety of the lower starting dose regimen of 40 mcg/kg/day.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Study

The Odevixibat Versus External Control (OvEC) study was conducted to evaluate the effect of odevixibat on clinical outcomes in children with SBD-naive PFIC1 or PFIC2 participating in the PEDFIC 1 and PEDFIC 2 studies (N = 69) compared with an external control cohort of children from the NAPPED study (the NAPPED cohort) with SBD-naive PFIC1 or PFIC2 (N = 80). The primary objective was to evaluate the effect of odevixibat on death, liver transplant, or SBD in children with PFIC1 or PFIC2. The primary end point was event-free survival (EFS), and the secondary end points included native liver survival (NLS), SBD-free survival (DFS), and overall survival (OS). The NAPPED study involved collecting retrospective data into a large database to investigate the natural history of PFIC.^12,13 The OvEC study used inverse probability of treatment weighting (IPTW) methods to reduce the impact of confounding in comparing the clinical outcomes. A cohort of 69 odevixibat-treated patients was compared with 80 patients (controls) from the NAPPED study. The median study duration in the odevixibat cohort was 22.6 months (range, 1.9 to 39.2 months). The follow-up duration in the NAPPED cohort was truncated accordingly.

Efficacy Results

Results comparing efficacy outcomes between the odevixibat cohort and NAPPED cohort are summarized in Table 26.

• EFS: In total, 6 patients (9%) in the odevixibat cohort had an EFS event versus 44 patients (55%) in the NAPPED cohort. The weighted hazard ratio (HR) was 0.20 (95% CI, 0.09 to 0.45; P = 0.0016).

• NLS: In total, 4 patients (6%) in the odevixibat cohort had an NLS event versus 21 patients (26%) in the NAPPED cohort. The weighted HR was 0.33 (95% CI, 0.11 to 1.03; P = 0.0900).

• DFS: In total, 2 patients (3%) in the odevixibat cohort had a DFS event versus 31 patients (39%) in the NAPPED cohort. The weighted HR was 0.13 (95% CI, 0.04 to 0.39; P = 0.0023).

• OS: No patients died in the odevixibat cohort whereas 4 patients (5%) died in the NAPPED cohort. The weighted HR was 0 (95% CI, 0 to not estimable; P = 0.0845).

Critical Appraisal

Patients in the PEDFIC 1 and PEDFIC 2 studies were compared with the NAPPED cohort using IPTW methods in an attempt to minimize the impact of confounding on the results. It should be noted that this method cannot control for substantial differences resulting from the different study designs between the 2 cohorts (RCT versus retrospective registry review). Details of the NAPPED cohort were limited; it is not clear how patients were selected into the cohort (i.e., potential for selection bias is unknown), what their characteristics were before weighting, or what treatments they received. Similarly, the data-collection methods for the NAPPED cohort, how missing data were accounted for, the number of losses to follow-up, and outcome definitions have not been reported. The authors appropriately used eligibility criteria for the NAPPED cohort that were considered similar to those used for the PEDFIC studies; however, the characteristics of patients at baseline and the overlap in covariates before weighting were not described. Thereafter, the primary method to compare the 2 cohorts was based on using stabilized weights computed from the propensity score (PS) model. The dosing used in the PEDFIC 1 and PEDFIC 2 studies did not align with the proposed product monograph for all patients, as some started on 120 mcg/kg/day and others escalated to this dose despite responding to the lower dose. The treatments used among patients in the registry were not described; therefore, it is not clear whether these treatments would correspond to those currently used for PFIC in Canada (the date that patients were added to the registry is also unclear). For some outcomes, the follow-up time was likely to be too short and/or the sample size too small to capture relevant events. Numerous methodological limitations within the study limit the generalizability of the findings.

Conclusions

One pivotal, sponsor-funded multinational double-blind RCT was included in this review. The PEDFIC 1 study randomized 62 patients with either PFIC1 or PFIC2, in a 1:1:1 manner, to odevixibat 40 mcg/kg/day, 120 mcg/kg/day, or placebo over a treatment course of 24 weeks. The odevixibat 40 mcg/kg/day dose is the proposed starting dose for odevixibat, with a proposed dose escalation to 120 mcg/kg/day after 12 weeks if the patient’s condition does not respond to treatment; therefore, it is the 40 mcg/kg/day dose that is the focus of this review. It should be noted that there is limited clinical evidence to support dose escalation in the manner described in the proposed product monograph. Compared with placebo, treatment with odevixibat at a dose of 40 mcg/kg/day likely improves pruritus within 4 weeks, and this improvement is likely to be maintained to at least 24 weeks. Odevixibat 40 mcg/kg/day may elicit reductions in sBA at 12 weeks of therapy; however, the clinical significance and the impact of these reductions on mortality risk and risk of surgery are uncertain due to the sample size and limited duration of follow-up. Additionally, odevixibat may improve growth (height and weight z scores), but it is not clear whether the magnitude of these benefits is clinically important. The impact of odevixibat on HRQoL, sleep (number of awakenings), and total bilirubin is very uncertain, largely due to a wide variation in responses and the risk of bias due to missing data. There were no clear indications of any safety or tolerability issues with odevixibat in either the 24-week double-blind phase or the extension phase. It is important to note that only the extension phase included other PFIC subtypes aside from PFIC1 and PFIC2. This is consistent with the proposed indication, which is not restricted to any subtype. Data from the open-label extension phase suggest there are patients who may respond to a dose escalation from 40 mcg/kg/day to 120 mcg/kg/day; however, there are also patients who may not, and it is unclear whether patients’ conditions are responding to the increased dose or longer duration of therapy. Additionally, unlike the proposed dosing in the product monograph, which requires that the condition fail to respond after 12 weeks before undergoing dose escalation, all patients in the extension were escalated, regardless of the response after 24 weeks. There was no indirect comparison available that would compare odevixibat with other drugs used for PFIC, although the drugs used for PFIC are generally used off label. The sponsor did submit an IPTW that compared results from the odevixibat groups in the PEDFIC 1 and PEDFIC 2 studies with registry data in an effort to demonstrate the potential benefits of odevixibat for clinical outcomes such as EFS, NLS, DFS, and OS; however, due to multiple limitations with the sponsor’s analysis, no conclusions can be drawn from it.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of odevixibat administered orally as 40 mcg/kg or 120 mcg/kg once daily in the morning for the treatment of pruritus in patients aged 6 months or older with PFIC.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

PFIC comprises a rare and life-shortening heterogeneous group of liver disorders of autosomal recessive inheritance that affects the production and/or composition of bile from the liver. PFIC is categorized based on genetic defect, clinical presentation, laboratory findings, and liver histology.¹ At least 6 subtypes of PFIC have been described in the literature, although the nomenclature beyond subtypes 1 to 3 is somewhat indeterminate. PFIC1 and PFIC2 represent approximately two-thirds of cases, and PFIC3 represents most of the remainder.^1-5 Patients with PFIC1 and PFIC2 generally present with jaundice and severe pruritus in the first few months of life, with 78% developing jaundice before the age of 12 months.⁶ PFIC3 can occur during infancy, childhood, and even into young adulthood. Although the genetic mutations underlying the PFIC subtypes differ, the common feature among all subtypes is elevated sBA concentrations and severe pruritus. PFIC is a rare disease that is estimated to affect between 1 in every 50,000 to 100,000 children born worldwide.^4,5 While global or country-specific prevalence estimates are not available for PFIC, it is believed to be responsible for about 10% to 15% of cholestatic liver diseases among children and 10% to 15% of liver transplant indications in children.^4,5

PFIC is characterized by the early onset of cholestasis (usually during infancy) with severe pruritus and fat malabsorption that rapidly progresses and leads to liver failure.¹ Elevated bile acid concentrations result in ongoing liver inflammation, fibrosis, cirrhosis and, eventually, liver failure. Intractable pruritus is the most troubling symptom of PFIC.

PFIC is a fatal disease. The survival rate in patients with PFIC who have not undergone SBD or a liver transplant is 50% at age 10 and almost zero at age 20.⁶ PFIC may manifest with many symptoms, including jaundice, hepatomegaly, severe pruritus, splenomegaly, diarrhea, discoloured stools, failure to thrive, vitamin E deficiency, vitamin D deficiency, and pancreatitis (PFIC1).⁷ In a qualitative study with patients and caregivers on the daily impacts associated with PFIC and other pediatric cholestatic liver diseases, severe pruritus was the most common and debilitating symptom, occurring most frequently at night, with pruritus-related sleep disturbance reported by 67% of patients with PFIC.¹⁴ Significant pruritus can lead to severe cutaneous mutilation (often drawing blood), loss of sleep, irritability, poor attention, and impaired school performance.³

Diagnostic Testing Requirements

Most patients with PFIC treated by pediatric hepatologists or gastroenterologists are referred by a pediatrician, family physician, or emergency department physician due to symptoms of a suspected liver problem. PFIC is generally suspected in children with a clinical history of cholestasis of unknown origin.^1,5 Liver function tests, tests for sBA levels, and imaging studies help to rule out the other causes of liver disease.¹ A high sBA concentration excludes primary bile acid synthesis disorders. Patients with PFIC1 or PFIC2 have normal serum gamma-glutamyl transferase (GGT) activity, while patients with PFIC3 have high serum GGT activity. Patients with PFIC3 can also be distinguished from PFIC1 and PFIC2 in that they rarely present with cholestatic jaundice at the neonatal period, but rather later in infancy, childhood, or young adulthood.

According to 1 of the clinical experts consulted by CADTH on this review, a biopsy in PFIC1 shows bland cholestasis, whereas in PFIC2 it shows severe hepatitis; in PFIC3, features consistent with bile duct obstruction or damage are present. Special staining methods (immunohistochemistry) can show the decreased expression or lack of a bile salt export pump (BSEP), which is diagnostic of PFIC2, or multidrug resistance protein 3 in the bile canalicular membrane, which is diagnostic of PFIC3.

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

According to the clinical experts consulted by CADTH for this review, the main treatment goals are to provide relief from itch, improve sleeping and quality of life for both the patient and caregiver(s), support normal growth and development, prolong adequate liver function, and avoid PFIC complications such as hepatocellular carcinoma.

The clinical experts emphasized the importance of managing pruritus, as severe itch impacts sleep, which then impacts nutrition, growth and development, and the school performance of children and has significant effects on caregivers. The clinical experts noted that current pharmacologic treatments for PFIC are intended to address symptoms and are not curative. The clinical experts stated that although there are numerous anti-itch medications, including antihistamines and other drugs such as rifampicin that indirectly address itch, they may be effective for mild to moderate pruritus but are not effective therapies for severe pruritus. One clinical expert noted that accumulation of bile acids damages the liver; however, it is not clear whether a medication like UDCA is able to address this key aspect of the pathophysiology of PFIC.

Nonpharmacologic measures, including maintaining an adequate diet, are an important part of meeting treatment goals, according to the clinical experts. Surgery is also a key nonpharmacological approach. The clinical experts noted that surgery is not always successful, carries a high morbidity risk, and is not suitable for the subset of patients who have cirrhosis. One expert noted that liver transplant outcomes are better for patients who have normal nutrition and development.

The clinical experts highlighted the limited efficacy of currently available treatments when addressing unmet needs and added that a medication that could modulate disease progression to, for example, fibrosis, cirrhosis, or liver failure, and is able to address cholestatic pruritus would be a welcome addition to the treatment armamentarium.

Drug Under Review

The recommended dosage for odevixibat is 40 mcg/kg administered orally once daily in the morning. If an adequate clinical response has not been achieved after 3 months of continuous therapy, the dose may be increased to 120 mcg/kg/day, with a maximum daily dose of 7,200 mcg. Odevixibat is a reversible and selective inhibitor of the ileal bile acid transporter. This transporter, expressed mainly in the distal ileum, is a key element in the enterohepatic circulation of bile acids and is responsible for the reabsorption back to the liver of 95% of the intestinal bile acids; therefore, blockade of this transporter is thought to reduce the reuptake of bile acids, facilitating their excretion.

Odevixibat was approved by Health Canada for the treatment of pruritus in patients with PFIC aged 6 months or older. The sponsor is requesting reimbursement for odevixibat per the Health Canada indication. It has been approved by the FDA, with an indication for the treatment of pruritus in patients with PFIC who are 3 months of age or older, and by the European Medicines Agency, with an approved indication identical to the proposed indication in Canada.

Key characteristics of odevixibat and other treatments available for PFIC are summarized in Table 3.

Table 3: Key Characteristics of Odevixibat, UDCA, Rifampicin, and Cholestyramine

CYP450 = cytochrome P450; DRESS = drug reaction with eosinophilia and systemic symptoms; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid.

^aHealth Canada–approved indication.

Sources: Gunaydin et al. (2018)¹ and PEDFIC 1 Clinical Study Report (2020).⁸

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section of this report.

CADTH received 1 patient group submission from the CLF. CLF is an organization dedicated to promoting liver health, increasing public awareness and understanding of liver disease, and providing support to individuals affected by liver disease. CLF advocates for all people in Canada affected by liver disease, from newborns to seniors, including patients and their caregivers.

CLF conducted an online survey of patients and caregivers between June 27 and July 11, 2023. A total of 14 people responded, including 4 patients and caregivers in Canada. The patients and caregivers provided first-hand qualitative input regarding their experience with respect to the patient’s PFIC diagnosis, experience as the caregiver and/or loved one of someone with PFIC, experience with the disease, experience with previous therapies, and experience with the therapy under review.

Most families affected by PFIC expressed feelings of helplessness, anguish, and frustration. Respondents indicated how a PFIC diagnosis has severely impacted the lives of their loved ones and their day-to-day activities while adding physical and emotional stressors and worries.

Some of the respondents explained the impact of PFIC using the following phrases: constant itch, lack of concentration, lack of sleep, tiredness, weakness, bathroom issues, frequent hospitalization, emotional disorder due to fear and stress, and emotionally draining for both the caregiver and child with the disease.

In terms of current therapy options, some of the respondents identified the following unmet needs: available medications did not decrease itching or improve overall feelings of health, comfort, and vitality; while the medications do help, they do not halt the disease’s progress, nor do they particularly ease symptoms.

Regarding the important outcomes, the patient group identified improving HRQoL as a key priority. Additionally, the patients and caregivers indicated that continuous and peaceful sleep, reduction in itching, normal growth and weight gain, good energy levels, and slowing down the progression of the disease are valued outcomes. They also mentioned they hoped to have a treatment that is effective in the short-term and has no side effects in the long term.

Five respondents indicated having experience with odevixibat through a clinical trial. Respondents reported that this medication was the only thing that worked for them and that it was life-changing for both the patient and the whole family. One patient reported not experiencing side effects for 1 year then experienced diarrhea, which was managed with dose reductions.

CLF believes it is important to ensure greater and more equitable access to important treatments for patients with PFIC while expanding therapeutic options for patients and health care professionals. CLF indicated it is crucial that patients across the country have equitable access to all treatments for liver disease and that provincial borders should not be a barrier.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the review of odevixibat, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with PFIC, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion follows. This discussion applies specifically to PFIC1 (FIC1 deficiency) and PFIC2 (BSEP deficiency), conditions for which clinical research data are under consideration.

Unmet Needs

According to the clinical experts, the current anti-itch therapies are used off label and address only mild to moderate itch; therefore, effective pharmacological therapies for pruritus are oral medications. One clinical expert noted that the pruritus associated with PFIC is often debilitating and is highly distracting, akin to chronic pain. In children, pruritus has a negative impact on feeding, learning, and sleeping, as well as a negative impact on family functioning.

Additionally, there are no therapies that modify disease progression (i.e., fibrosis, cirrhosis, liver failure) and this is an unmet need for patients with PFIC and related biliary diseases. The clinical experts noted that surgical interventions carry a high morbidity and are not always successful. They are not suitable for the subset of patients with cirrhosis. One clinical expert went on to note that although partial external biliary diversion is an option, it necessitates the creation of a stoma in the front of the abdomen, which means the patient must wear a bag over it, and dehydration can occur. This clinical expert also noted that they consider liver transplant to be a last resort to be reserved for patients whose disease has failed to respond to other treatments. Additionally, the clinical expert noted that clearing bile acids, which tend to damage the liver when retained, may reduce liver damage, and it is unclear whether treatment with UDCA is able to accomplish this. This clinical expert noted that UDCA has other beneficial effects, most notably that it replaces the more toxic hydrophobic bile acids, potentially reducing intrahepatic damage, but it does not reduce the bile acid pool, nor does it relieve itch. Another clinical expert added that UDCA may qualify, according to some experts, as the standard of care irrespective of pruritus, and they also noted that it does not always improve things for patients with PFIC1. One clinical expert summarized the issues as follows:

• Not all patients respond to available treatments.

• If they do respond, their condition may become refractory to those treatments.

• Treatments may have untoward side effects (e.g., sedation due to phenobarbital) and they may be unpalatable, (e.g., cholestyramine, which is notoriously bad tasting).

• Surgical interventions can be problematic.

The clinical experts noted that none of the available medical treatments clearly reverse the course of the liver disease, and this would be a key outcome of interest. It is desirable to have medical interventions to address key outcomes (in this case, normal nutrition, neurodevelopment, and sleeping).

Place in Therapy

The clinical experts agreed that since none of the other off-label treatments are effective for severe pruritus, odevixibat would likely become the first treatment for front-line therapy for PFIC in patients with severe pruritus. One clinical expert believed there may be some flexibility on when to use odevixibat, given the spectrum of pruritus severity. The clinical experts noted, for example, that if a patient were doing well on their existing therapy, they would likely not switch them to odevixibat until their pruritus became more severe. This clinical expert stated that for pruritus that is mild or not incapacitating, other treatments would likely be tried first, and also noted there is some limited evidence of possible synergy between therapies, such as rifampicin and odevixibat. This clinical expert noted that if odevixibat proves to be highly effective, then it would likely become the treatment of choice. They also noted that, because the clinical situations in PFIC1 and PFIC2 are so varied, there should not be any artificial restrictions imposed (such as intolerance or contraindications to available treatments, or the character of the underlying disease, or requiring that the patient’s condition fail to respond to current conventional therapies). The clinical expert also noted that it is not clear whether odevixibat will reverse established liver disease, although this is theoretically possible. The clinical experts appeared to agree that odevixibat will shift the treatment paradigm in PFIC.

Patient Population

One clinical expert noted that the patients most in need of odevixibat are those with severe itch related to elevated sBA, and the other clinical expert mentioned that these were the patients who were the focus of research (although the patients in the studies specifically had PFIC1 or PFIC2).

One clinical expert mentioned that identifying patients with severe itch would be straightforward (some of these patients have chronic excoriations, for example); however, there are various “itching scales” that could be used to help. The other clinical expert noted that patients with cholestasis and itch do not necessarily require sBA testing, as long as no other cause of itch is clearly identified, although the clinical experts agreed that a high sBA level does support the diagnosis of PFIC. This clinical expert went on to mention that underdiagnosis of PFIC rarely occurs but has been found in older patients with cryptogenic liver disease but with no pruritus. One clinical expert went on to note specific lab findings that can also aid in diagnosis, such as low or normal serum GGT along with obvious cholestatic liver disease. GGT can be assessed with a simple lab test. PFIC3 can pose some problems for diagnosis because serum GGT is elevated, but these issues can be sorted out through standard diagnostic algorithms. This clinical expert went on to state it is unclear to them whether PFIC subtypes like PFIC1 or PFIC2 can be used to predict a favourable response.

The clinical experts agreed with the sponsor’s estimate of a global prevalence of 1 in 50,000 for PFIC, although they added that with improvements in diagnostics, particularly in the availability of genetic testing and a better understanding of the various genotypes involved, this number may rise. The clinical experts also noted that given the severity of the disease and the high mortality rate, a successful therapy could and should result in an increase in the number of patients with PFIC who live into adulthood.

One clinical expert noted that adult patients with PFIC are relatively rare, more challenging to diagnose, and tend to have less severe disease. These adults with PFIC may or may not have pruritus, and this clinical expert noted that if they had an adult patient with cholestatic pruritus of any cause (mainly comprising patients with primary biliary cholangitis or primary sclerosing cholangitis, which has a prevalence of approximately 1 in 3,000) they would consider starting them on odevixibat if they thought the patient would benefit. This clinical expert also noted that in decades of practice, they had encountered only 1 adult with PFIC, and this patient did not have pruritus.

Assessing the Response to Treatment

The clinical experts noted that improvement in pruritus would be the outcome of most importance for assessing response, with 1 clinical expert adding that improvement in the condition of the skin and general well-being would also be important. The clinical experts agreed that routine monitoring of sBA is of less importance for assessing response, and that pruritus should be readily assessed because it is a prominent symptom and may be measured more objectively. One clinical expert added that in older children, additional variables of potential interest would include school performance, ability to participate in sports activities, and mood and energy levels. One clinical expert added that slowing disease progression and reducing the need for partial external biliary diversion or liver transplant are other relevant outcomes that would also be of importance, while the other clinical expert was unsure whether avoiding surgical interventions (mainly liver transplant) should be a treatment outcome. One clinical expert mentioned that features of a clinically meaningful response would include decreased pruritus to nonproblematic levels (able to sleep, focus on school and play, able to socialize) improved skin condition, and good nutrition, whereas stabilization of symptoms would be clinically apparent but important.

The clinical experts agreed that response could be assessed early, likely earlier than the 12 weeks suggested in the proposed product monograph. The clinical experts reiterated that itch is such a bothersome symptom for many patients that a positive response would be easily detected. The clinical experts were also clear that pruritus is the obvious outcome of interest, and that if a patient had a clear improvement in itch but not a commensurate improvement in sBA, they should still be kept on the drug because it is treating the itch that is of paramount importance.

Discontinuing Treatment

The clinical experts agreed that liver transplant would be an indication for discontinuing odevixibat, and 1 clinical expert also added that adverse events (AEs) may lead to modulation of treatment, depending on their severity. One clinical expert added that it is unclear to them whether odevixibat would serve as a bridge to partial external biliary diversion, as that has not been established by current research, and they would consider odevixibat to be a means for avoiding this intervention. This clinical expert also noted that surgery represents some degree of permanent alteration, and its efficacy drops off over time.

Although elevations in liver enzymes was a discontinuation criterion in the PEDFIC 1 study, the clinical experts did not consider this to necessarily be a criterion for discontinuation in real-world use. The clinical experts believe that these elevations in liver enzymes due to odevixibat are likely transient, and it is also difficult to determine whether any elevations in hepatic enzymes are due to the underlying disease process or to the drug itself.

Otherwise, the clinical experts noted diarrhea and associated abdominal cramping as a potential tolerability issue. An additional concern with the cramping is that it may negatively impact feeding in younger children.

Prescribing Considerations

The clinical experts agreed that specialist intervention would be required for diagnosis, treatment, and monitoring by, specifically, a pediatric hepatologist or gastroenterologist for pediatric patients. One clinical expert added that odevixibat treatment could likely be managed by a general pediatrician in rural areas, with supervision at a distance by a pediatric hepatologist or gastroenterologist. Adult patients would be managed by an adult hepatologist or gastroenterologist.

The clinical experts did not rule out the possibility of using odevixibat as a combination therapy with 1 of the existing therapies that are currently being used off label for PFIC, and they noted that many of the patients in the pivotal trial were on 1 of these therapies; however, the clinical utility of adding 1 or more of these off-label therapies to odevixibat may be difficult to establish without data from large registries, according to the clinical experts. The clinical experts did note that monotherapy would be desirable for patient adherence. One clinical expert also noted that the capsule formulation would not work with infants and, in such cases, an elixir might be needed. Additionally, this clinical expert pointed out that rounding rules will need to be established, for example, whether to round up or down to a convenient dose. This clinical expert also pointed out that response will need to be assessed frequently in infants, as significant changes over relatively short periods of time are common in this age cohort.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section of this report.

CADTH received 1 clinician group submission from the CPHRG, which operates under the aegis of the Canadian Association for the Study of the Liver, a nonprofit organization that seeks to eliminate liver disease through research, education, and advocacy. CPHRG gathered data and information about the drug under review from a review of the published literature about PFIC, from attendance at conferences, and from abstract presentations.

CPHRG stated there are currently no curative medical therapies for PFIC liver disease, and the management strategies described are all standard of care in Canada. CPHRG reported there are no practice guidelines due to the rarity of the disease, and limited published data that meet the standards for a guideline; however, multiple review articles encompass this information.

According to CPHRG, some of the unmet needs of standard-of-care treatments are lack of efficacy or being only transiently effective for patients, so that surgical options such as external biliary diversion must be considered. CPHRG noted that this surgical option leaves the child with a stoma, which is considered unacceptable to most families. CPHRG reported that another unmet need in this field is reducing significant mortality and morbidity from major liver transplant surgery and lifelong immune suppression, which is the only option for patients with PFIC whose SBD fails or who will not accept this treatment approach. CPHRG believed that a clinically meaningful response would be patients and their families reporting an improvement in pruritus and improvement in sleep duration, which can be measured by asking how often the child wakes at night or by documenting improvements in skin excoriations. CPHRG noted that sBA levels can also be used; however, in clinical practice, this is not done routinely due to cost and logistics (i.e., this test is often sent to specialized laboratories and is not readily available in all gastroenterology practice settings).

CPHRG indicated that patients with PFIC and cholestatic pruritus that is persistent on standard-of-care treatments would be eligible for the drug under review. CPHRG reported that patients with adequately controlled pruritus would also be eligible for treatment to improve liver disease outcomes and prevent or delay the need for a liver transplant. The clinician group noted that since the mechanism of action of the drug under review is inhibiting the ileal bile acid transporter to lower sBAs, they thought it reasonable to anticipate that patients with elevated sBAs are most likely to respond to treatment. CPHRG mentioned that the most likely reason to discontinue treatment would be if the liver disease of a patient with PFIC progresses and they undergo a liver transplant. Other factors that CPHRG indicated should be considered when deciding to discontinue treatment would be treatment-associated AEs. CPHRG noted that the drug under review should be prescribed and monitored by a pediatric gastroenterologist or hepatologist in a specialty clinic setting.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = Canadian Drug Expert Committee; PFIC = progressive familial intrahepatic cholestasis; UDCA = ursodeoxycholic acid.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of odevixibat at approved doses in the treatment of PFIC in patients aged 6 months and older. The focus will be placed on comparing odevixibat with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of odevixibat is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes a sponsor-submitted long-term extension study. The third section would normally include indirect evidence from the sponsor; however, none was submitted. The fourth section includes an additional study that was considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal RCT identified in the systematic review

• 1 long-term extension study

• 1 additional study addressing gaps in evidence.

Systematic Review

The contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Study

Characteristics of the included study are summarized in Table 5.

Table 5: Details of the Study Included in the Systematic Review (PEDFIC 1)

ALT = alanine aminotransferase; APRI = AST to platelet ratio index; AST = aspartate aminotransferase; BSEP = bile salt export pump; FIB-4 = Fibrosis-4 Index for Liver Fibrosis; GGT = gamma-glutamyl transferase; GI = gastrointestinal; GIC = Global Impression of Change; GIS = Global Impression of Symptoms; iBAT = ileal bile acid transporter; INR = international normalized ratio; MELD = model for end-stage liver disease; p-C4 = plasma 7 alpha-hydroxy-4-cholesten-3-one; PedsQL = Pediatric Quality of Life Inventory; PELD = pediatric end-stage liver disease; PFIC = progressive familial intrahepatic cholestasis; ObsRO = observer-reported outcome; PRO = patient-reported outcome; ULN = upper limit of normal.

Note: Two additional reports were included (Clinical Study Report for PEDFIC 1, sponsor’s submission).

Source: PEDFIC 1 Clinical Study Report (2020).⁸

PEDFIC 1 (N = 62) was a phase III, multicentre (1 site in Canada), double-blind, randomized, placebo-controlled study that aimed to demonstrate the efficacy and safety of odevixibat 40 mcg/kg/day and 120 mcg/kg/day in children with PFIC1 and PFIC2 (Figure 1).^8,9 The study included up to an 8-week screening period, a 24-week treatment period, and a 4-week follow-up period.

Two screening visits were conducted: visit 1 occurred within 35 to 56 days before the first dose of the study drug, and visit 2 was within 7 to 28 days before the first dose. The screening procedures included a review of medical and surgical history and concomitant medications, genetic confirmation for PFIC1 or PFIC2, a physical examination, a skin examination, measurement of vital signs, clinical chemistry tests, and an sBA assessment. At visit 1, all patients and/or their caregivers were given an electronic diary (eDiary) and instructed on its use. Data were to be entered twice daily, once in the morning and again in the evening. The eDiary included patient-reported and observer-reported outcome items from the PRUCISION PRO and ObsRO instruments for the evaluation of itching, scratching, and sleep disturbance throughout the study. The eDiary was used by patients 8 years of age and older (PRO) and by caregivers for patients of all ages (ObsRO). The diaries could be completed by the patient’s caregiver or the caregiver’s designee. Ideally, the same caregiver completed the eDiary for a given patient throughout the study. If a new caregiver began entering ObsRO on the PRUCISION instrument, they were trained in how to use the diary before they began making entries. Caregivers also used the eDiary to report the time at which each dose of the study drug was administered. At the second screening visit (visit 2), additional laboratory samples, including sBA and liver function tests, were collected for eligibility assessments.

After completion of the screening period, eligible patients were randomized on day 0 (visit 3) in a 1:1:1 fashion to receive odevixibat 40 mcg/kg/day, odevixibat 120 mcg/kg/day, or matching placebo. Note that under the proposed dosing in the draft product monograph, all patients would begin on odevixibat 40 mcg/kg/day and would escalate to 120 mcg/kg/day if they were not responding after 12 weeks; therefore, the odevixibat 120 mcg/kg/day group in the PEDFIC 1 study is not relevant to the proposed dosing; however, it was agreed that data for the odevixibat 120 mcg/kg/day dose should be reported so that decision-makers could gauge how well the dose performs with respect to efficacy and harms. Eligibility for randomization was determined using the eDiary pruritus data obtained in the 14 consecutive days before visit 3, a clinical genetic confirmation of the PFIC diagnosis, and the liver biochemistry evaluations, including sBA levels, from the previous screening visits. Randomization was stratified according to PFIC type (type 1 and type 2) and age (6 months to 5 years, 6 to 12 years, and 13 to ≤ 18 years).

The design of the study was discussed with the FDA and European Medicines Agency; based on these discussions, different primary end points were chosen for the US (change in pruritus) and for Europe and rest of the world (rate of sBA response).

Patients who completed the PEDFIC 1 treatment period (week 24) could continue into an optional 72-week open-label extension study (PEDFIC 2) in which all patients received odevixibat (described in more detail in the long term extension section).

Inclusion and Exclusion Criteria

Eligible patients were between the ages of at least 6 months and no more than 18 years and had a genetically confirmed diagnosis of PFIC1 or PFIC2. Based on the level of reduction from baseline for the primary sBA analysis (reduced by at least 70% or to 70 µmol/L or less), the eligibility criteria required patients in the trial to have elevated sBA levels of at least 100 µmol/L at baseline. Patients were to demonstrate significant pruritus based on a caregiver-observed scratching average, as reported in the eDiary, of at least 2 (on a 0 to 4 scale) in the 2 weeks before randomization. Patients with PFIC2 with variations of the ABCB11 gene that predicted a complete absence of the BSEP protein were excluded, as odevixibat may not be effective in these patients. Patients were also excluded if they had a past medical history or presence of other liver disease, clinically significant infection, suspected or confirmed cancers, inflammatory bowel disease, chronic kidney disease, or other primary pruritic skin diseases. Eligible patients could not have undergone SBD within the 6 months before the start of the screening period or a previous liver transplant or planned liver transplant within 6 months of randomization. The original protocol was amended on March 1, 2019, to allow for the inclusion of patients post SBD.

Figure 1: PEDFIC 1 Study Design

EMA = European Medicines Agency; MAA = Marketing Authorization Application; NDA = New Drug Application; PFIC = progressive familial intrahepatic cholestasis.

Sources: Thompson et al. (2022),⁹ PEDFIC 1 Clinical Study Report (2020).⁸

Interventions

Odevixibat (40 mcg/kg/day or 120 mcg/kg/day) or placebo was administered orally once daily by patients or caregivers. The number and type of capsules that were administered varied by the body weight of the patient and the randomized dose. Patients were to take their daily dose in the morning with food.

To facilitate blinding of the treatment assignment, the study drug and matching placebo had the same shape and size. Labels on the study drug containers did not identify the randomized treatment assignment. The traceability of the treatment was ensured by the study drug number, which corresponded to the randomization arm and was assigned by an interactive web response system (IWRS).

Treatment was to be interrupted if a patient developed diarrhea with at least 1 of the following concomitant signs or symptoms: grossly bloody stools, vomiting, electrolyte imbalances and/or dehydration requiring treatment with oral or IV rehydration, fever (38°C or greater), and/or the diarrhea persisted for 7 or more days. If the symptoms were resolved, the patient was allowed to restart the treatment. If the diarrhea reoccurred within 1 week with no alternate etiology, dosing was to be permanently discontinued.

Treatment was also interrupted if any of the following criteria were met:

• ALT or AST level 3 times greater than baseline or more, or 800 IU/L or greater, whichever came first, and total bilirubin greater than 2 times the ULN

• ALT or AST level greater than 10 times the ULN or 5 times greater than baseline, or an absolute threshold of 800 IU/L or greater, whichever came first, in the presence of normal lactate dehydrogenase and creatine phosphokinase

• total bilirubin increased, unrelated to hemolysis (elevated reticulocyte count) or established genetic diseases such as Gilbert syndrome:

  • doubling of total bilirubin if it was less than 3 mg/dL (equivalent to 51.3 µmol/L) at baseline, or

  • increase by more than 3 mg/dL (equivalent to 51.3 µmol/L) if total bilirubin was 3 mg/dL or greater (equivalent to 51.3 µmol/L) at baseline

• INR increase refractory to vitamin K administration:

  • INR greater than 1.5 if INR was normal at baseline, or

  • increase by greater than 0.4 if INR was abnormal at baseline

• any increase in total bilirubin and transaminases if accompanied by either a symptom of clinical hepatitis (e.g., vomiting, nausea, pain in right upper quadrant) or immunological reaction (rash or greater than 5% eosinophilia).

If any of the criteria were met, a drug-induced liver injury work-up for alternative etiologies was initiated, including a liver profile (AST, ALT, total bilirubin, direct bilirubin), and prothrombin time or INR was repeated within 48 to 72 hours and the patient was monitored using close observation. If underlying cholestatic liver disease variability or another alternative etiology was identified and liver tests returned to baseline, a rechallenge could be considered after consultation with the medical monitor. If ALT or total bilirubin elevations were observed after a rechallenge, then a repeat rechallenge was discouraged. In the case of a possible or probable drug-induced liver injury and/or if a decompensation event had occurred (e.g., variceal hemorrhage, ascites, hepatic encephalopathy), dosing was to be permanently discontinued.

From the first day of screening to the last day of the treatment period, medications with effects on the concentration of bile acids in the gastrointestinal tract (e.g., cholestyramine, colesevelam, colestipol), drugs with known effects on gastrointestinal motility (e.g., sucralfate, loperamide, codeine, erythromycin), and other investigational products used to treat PFIC (e.g., 4-phenylbutyrate) were not allowed.

Other drugs or natural products with possible effects on gastrointestinal motility (e.g., selective serotonin reuptake–inhibiting drugs, tetracyclic antidepressants, fibre supplementation, yogourt variants) were allowed provided there was stable usage of the product at least 4 weeks before enrolment until treatment discontinuation.

Treatment with UDCA, rifampicin, and/or antihistamines was also allowed provided the patient was on a stable dosage at least 4 weeks before enrolment and no dosage changes were planned during the entire study period. Topical treatment was allowed without restriction.

Outcomes

Mortality

Deaths were reported under harms.

Need for Surgery

The number of patients undergoing biliary diversion surgery or liver transplant was a secondary outcome of the study.

Pediatric Quality of Life Inventory

The PedsQL is designed to examine problems within 4 functional domains: physical, emotional, social, and school.¹⁵ Different versions of the PedsQL were used, depending on the age of the patient: child and parent report core modules for 5-to-7-year-olds, 8-to-12-year-olds, and 13-to-18-year-olds, and a parent report core module for toddlers (2 to 4 years old). The caregiver was also asked to complete the PedsQL Family Impact Module (domains: physical, emotional, social, cognitive, communication, worry, daily activities, family relationships) designed to measure the impact of pediatric chronic health conditions on parents and the family.

The PedsQL questionnaire is scored based on the questionnaire taken (i.e., the report for toddlers is scored differently than the report for young children). The scoring scale for the PedsQL is based on the publication by Mapi Research Trust¹⁶ and is summarized in Table 4. The raw scores are then reverse scored on a scale from 0 to 100, where higher scores indicate improved HRQoL.

The minimal important difference (MID) for the PedsQL total score for the Child Self-Report and Parent-Proxy Report has been reported to be 4.4 and 4.5 for within-group differences, respectively.¹⁷

Pruritus

Albireo Pharma conducted a literature review with the objective of identifying any instruments that are currently used to measure pruritus in adolescents and adults but did not identify any publicly available instruments that adequately assess the symptoms and impact of the disease on the pediatric patient with PFIC and/or provide the caregiver perspective. Therefore, Albireo developed the novel (PRUCISION) PRO and ObsRO instruments for pediatric patients with cholestatic liver disease to assess itching, scratching, and sleep disturbance.^18,19 The quantitative measurement characteristics of these instruments, including the assessment of the performance and psychometric properties (reliability, validity, and sensitivity to change) of individual items, were established through an analysis of the final data from the PEDFIC 1 study, which was conducted by a group independent of the sponsor.¹⁹ The small sample size (n = 10) precluded the psychometric validation of the PRO instrument.¹⁹ The ObsRO (n = 62) was found to have acceptable reliability (i.e., moderate to strong interitem correlations and moderate to good test–retest reliability, depending on the item).¹⁹ Construct validity was demonstrated by moderate to strong correlations with some of the scales within other tools (i.e., GIS and PedsQL); additionally, known-groups analyses versus the GIS severity categories showed ObsRO scores changing in the expected direction.¹⁹ Similarly, analyses of sensitivity to change showed PRO and ObsRO scores changing in the expected direction for patients (“improved” versus “not improved”) and for most scales on related tools (GIS and PedsQL).¹⁹ Using distribution and anchor-based methods, the minimally clinically important within-person change was determined to be a reduction of 1 point.¹⁹ Further analyses in other populations are needed to confirm the reliability and validity of the tool.

The final ObsRO and PRO instruments focused on the key symptoms of pruritus, sleep disturbance and associated tiredness, and used pictorial response scales from 0 to 4, where each response was distinguished by a unique facial expression, verbal anchor, number, and colour code.

The PRO consisted of 7 questions that included 2 response formats:

• rating scales for morning diary questions 1, 2, 3, and 5, and evening diary questions 1 and 2 (e.g., 0 = no itching, 1 = a little itching, 2 = medium itching, 3 = a lot of itching, and 4 = the worst itching)

• binary responses for morning diary question 4 (i.e., no, yes).

For the rating scales, higher scores indicate a greater amount of itching, sleep disturbance, or tiredness.

The ObsRO consisted of 9 questions that included 3 response formats:

• rating scales for morning diary question 1 and evening diary questions 1 and 2 (e.g., 0 = no scratching, 1 = a little scratching, 2 = medium scratching, 3 = a lot of scratching, and 4 = worst possible scratching)

• binary responses for morning diary questions 2, 3, 4, 5 and 7 (i.e., no, yes)

• numeric responses of 0 to 99 for morning diary question 6.

For the rating scales, higher scores indicate a greater amount of scratching, sleep disturbance, or tiredness.

Completion of the PRO items was required only for patients 8 to 18 years of age. For patients 8 to 12 years of age, the caregivers were to read the PRO items along with the child and record the child’s response. A guide was to be provided to the caregivers that had standardized explanations of the PRO items in case the patient was confused or required clarification. The ObsRO items were completed by the caregivers of all patients. Itching (PRO), observed scratching (ObsRO), and sleep disturbance (PRO and ObsRO) were recorded twice daily in the eDiary. Patients and/or caregivers were to complete the eDiary every day in the morning and in the evening. The morning diary was to be completed shortly after the patient woke up and was used to record nighttime itching and scratching severity, aspects of sleep disturbance, and tiredness upon waking (morning scores). The evening (bedtime) diary was to be completed just before the patient went to bed to record the severity of the patient’s itching, scratching, and tiredness during the day (evening scores). Both morning and bedtime diaries included PRUCISION ObsRO and PRO items.

For the US, the primary efficacy end point was the proportion of positive pruritus assessments at the patient level over the 24-week treatment period. This was a secondary end point for Europe and the rest of the world. A positive pruritus assessment was defined as a scratching score of 1 or less, or at least a 1-point drop from baseline on the PRUCISION ObsRO instrument. Both morning and evening pruritus assessments were included in the analysis of this end point. All morning scores from the 14 days before or on the first dose day of the study medication were averaged to provide the morning baseline score. All evening scores from the 14 days before the first dose of the study medication were averaged to provide an evening baseline. The baseline score was rounded to an integer to evaluate the positive pruritus assessments for the primary analysis. For the primary end point analysis, if a patient’s baseline average score was 1 or less, then only the criterion of a 1-point drop from baseline on the PRUCISION ObsRO instrument was used to determine whether or not a pruritus assessment was positive.

Serum Bile Acid

The primary efficacy end point was the proportion of patients experiencing at least a 70% reduction in the concentration of sBAs from baseline to the end of treatment, or a lowering of the sBA level to 70 µmol/L or less after 24 weeks of treatment. Blood samples for the analysis of sBAs were drawn at all visits. Patients were to fast (only water intake was permissible) for at least 4 hours before the collection of samples. Exceptions could be made for infants younger than 12 months of age if they were unable to fast for the full 4 hours. For any visit at which the result of a bile acids sample was unreportable, an additional unscheduled visit for a repeat sample was requested. All sBA results during the treatment period and at follow-up were blinded. A central laboratory performed the quantitative assessment of the sBA levels, utilizing a validated commercial enzyme cycling assay.

Sleep Parameters

This outcome was assessed using the data gathered from the PRUCISION ObsRO and PRO instruments.

Growth

Growth was measured as height and weight using a certified weight scale. BMI was calculated as weight (kg) divided by height (m²). Change in growth parameters was assessed using linear growth deficit (weight, height, and BMI for age) compared with a standard growth curve (z score, standard deviation [SD] from the 50th percentile). For children aged 2 years and older, the software and/or methods used were from the Centers for Disease Control and Prevention; for children younger than 2 years of age, the WHO website was used. It is not clear why different sources were used for these 2 age groups.

Total Bilirubin

Total bilirubin was assessed at weeks 4, 12, and 24. No further details were provided by the sponsor.

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6 followed by descriptions of the outcome measures. The summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review by the clinical experts consulted by CADTH and in the stakeholder input from the patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to inform the deliberations of CADTH’s expert committee and finalized this list of end points in consultation with members of that committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

BMI = body mass index; ObsRO = observer-reported outcome; PedsQL = Pediatric Quality of Life Inventory; PRO = patient-reported outcome; sBA = serum bile acid.

Source: Details included in the table are from the sponsor’s summary of clinical evidence.

Of the various outcomes used to assess sBA, in consultation with the clinical experts consulted by CADTH, it was decided that assessments at weeks 12 and 24 would be informative; the week 12 data were included to help determine the extent of response at a time point that is consistent with the proposed dosing instructions (i.e., to consider a dose increase if there is no response after 12 weeks). The proportions of positive pruritus assessments at 4, 12, and 24 weeks were also included. The 12-week time point is consistent with the proposed label, and the clinical experts believed that patients would be more appropriately assessed for pruritus response at this time point rather than simply using sBA level. It was also agreed that data for week 4 would be included, as the clinical experts believed it was important for decision-makers to know how early a response occurs.

The HRQoL outcomes reported by the sponsor in its summary of evidence were assessed using GRADE (for both the PedsQL Parent Report and Family Impact Module), as it was clear in the patient and clinician input that PFIC has a significant impact on HRQoL, both on patients and their families. The global assessment of symptoms was not assessed using GRADE because it was believed to be more important to focus on HRQoL and pruritus, which is by far the most important symptom of PFIC. Of the numerous sleep parameters reported by the sponsor in its summary of clinical evidence and in consultation with the clinical experts, it was decided that awakenings would be the most relevant and objective measure; thus, it was included in the review. The clinical experts also agreed that all growth parameters were relevant (BMI, height, and weight); therefore, all 3 were assessed using GRADE. After discussion with the clinical experts, it was decided that total bilirubin was the most relevant biochemical assessment of liver function for this disorder, as it relates directly to the pathophysiology of PFIC; therefore, outcomes related to liver enzymes were not included. The clinical experts were also skeptical of the value and/or generalizability of other biochemical assays to assess liver function and/or damage, such as the AST to platelet ratio index, Fibrosis-4 Index for Liver Fibrosis, and FibroScan; therefore, these were not included.

After consultation with the review team, the notable harms, hepatic and gastrointestinal AEs, were assessed using GRADE. The clinical experts believed that gastrointestinal AEs were likely to be the primary tolerability issue with odevixibat.

Table 7: Summary of Outcome Measures and Their Measurement Properties

BMI = body mass index; CaGIC = Caregiver Global Impression of Change; CaGIS = Caregiver Global Impression of Symptoms; CI = confidence interval; GIC = Global Impression of Change; GIS = Global Impression of Symptoms; HRQoL = health-related quality of life; MID = minimal important difference; ObsRO = observer-reported outcome; PedsQL = Pediatric Quality of Life Inventory; PRO = patient-reported outcome; sBA = serum bile acid; SD = standard deviation.

Statistical Analysis

For the primary end point used in Canada and the rest of the world outside of the US (proportion of patients experiencing at least a 70% reduction in fasting sBA concentration from baseline to the end of treatment or a lowering of sBA to 70 µmol/L or less), statistical analyses were performed using the Cochran-Mantel-Haenszel (CMH) test stratified by PFIC type and age category to compare the proportion of the responders at the end of treatment in the active and placebo groups. The stratification factors used in the analysis were based on actual strata and not as recorded in the IWRS. The proportion, together with the corresponding Clopper-Pearson exact 95% CI, odds ratio and corresponding 95% CI, and P value from the CMH test, were presented. The proportion difference with corresponding exact unconditional 95% CI without adjusting for stratification factors was also presented. The Miettinen-Nurminen (score) CI adjusting for the stratification factors was reported for common risk difference (i.e., the proportion difference) and the exact CI was reported for the common odds ratio by using an algorithm based on Vollset, Hirji, and Elashoff.²⁰ The concentration of sBAs at baseline was calculated as the average of the last 2 values before the first dose. If only 1 nonmissing value was available, it was used as the baseline. If a patient’s baseline value was 70 µmol/L or less, then only the criterion of at least a 70% reduction in fasting sBA concentration was used to determine whether or not the patient was a responder for the analysis. The end value was calculated as the average of the values at weeks 22 and 24 after the start of treatment. If 1 value was missing, then the nonmissing value was used as the end value. If both values were missing, then the end value was considered missing. Patients who dropped out or who completed treatment but had a missing average at the end of treatment, and those in need of surgical rescue (i.e., biliary diversion and/or liver transplant) were classified as having a nonresponsive condition. Sensitivity analyses were performed that excluded patients with a baseline sBA value of 70 µmol/L or less; used a logistic regression model that included treatment arm, baseline value, and stratification factors; and included a tipping point analysis.

For the primary end point for the US (proportion of positive pruritus assessments at the patient level at week 24, which was the secondary end point in Europe and the rest of the world), the data were analyzed using an analysis of covariance (ANCOVA) model that included treatment arm, rounded morning and evening baseline pruritus scores, and stratification factors (i.e., PFIC type and age category). At each assessment, the morning score was compared with the rounded baseline morning average, and the evening score was compared with the rounded baseline evening average. LS mean and standard error (SE), LS mean difference and SE, 95% CIs, and P values (where applicable) between treatments versus placebo were summarized. If there were concerns on model assumptions, normality was checked based on a Shapiro-Wilk test, and the homogeneity of variances was checked based on a Levene test. For normality testing, a Shapiro-Wilk test was performed for each arm. The P value from each arm was combined to get an overall P value based on a Fisher combined probability test. All intermittently missing assessments were classified as negative pruritus assessments.

Change in sBAs, ALT, and growth were analyzed using a mixed-model for repeated measures (MMRM), including terms for baseline, PFIC type, age category, treatment, visit, treatment-by-baseline interaction, and treatment-by-visit interaction. For sBAs, the MMRM analysis may be performed based on log-transformed values, if deemed appropriate.

The proportion of responders at weeks 12 and 24 based on the ObsRO instrument was analyzed using the same model specified for the primary analysis of sBAs. The proportion of individual assessments meeting the definition of a positive pruritus assessment at the patient level from weeks 0 to 4, 0 to 8, 0 to 12, 0 to 18, and 0 to 24, and the proportion of positive pruritus assessments at each 4-week interval over the 24-week treatment period for morning or evening, were analyzed using the same model specified for the primary analysis for the proportion of positive pruritus assessments at the patient level at week 24. This analysis was performed separately for the PRO and ObsRO instruments. The proportion of patients achieving a positive pruritus assessment more than 50% of the time was analyzed using the same model specified for the primary analysis for the proportion of positive pruritus assessments at the patient level at week 24. This analysis was also performed separately for morning-only and evening-only pruritus assessments.

The number and percent of patients undergoing SBD and/or liver transplant were summarized using descriptive statistics. Kaplan-Meier curves were used when appropriate for the time-to-event data. Median event-free times and associated 95% CIs were calculated for each treatment group using Brookmeyer and Crowley methodology and a log–log transformation for constructing CIs.

Exploratory parameters, including total bilirubin, additional PRUCISION PRO and ObsRO sleep parameters, and PedsQL scores were analyzed descriptively. For continuous data, the change from baseline was analyzed in addition to the presentation of actual visit values. For categorical data, shift tables or frequency and percentages of patients are presented, as appropriate. A line graph of PRUCISION PRO and ObsRO itching and scratching daily severity scores over time for each patient was produced. Mortality was reported under Harms, and there were no analyses planned for this data.

Comparisons of the change from baseline at week 24 in the PedsQL total score (calculated as the average score of all answered items) between the treatment groups were conducted using an ANCOVA. The model included terms for baseline, PFIC type, age category, and treatment. The analysis was conducted based on the total scores reported by child (≥ 5 years of age) and by parent (including only parents of patients ≥ 5 years of age) separately. If the data reported by children aged 5 years or older was based on a sample size that was less than 10, then the ANCOVA was not conducted. The PedsQL total score for the Family Impact Module was analyzed similarly. The total score and the domain scores were summarized descriptively.

Sample Size and Power Calculation

The study planned to enrol 60 to 70 patients to obtain at least 20 evaluable patients in each arm. For each primary end point, simulations with 5,000 iterations using 20 patients per arm were conducted to estimate the power after multiplicity adjustment, resulting in an SE of less than 0.7% for each estimated power.

Based on the data from the phase II study (A4250-003), both low- and high-dose groups were assumed to have the same positive treatment effects in both the sBA and pruritus end points in the simulation. For sBAs, binomial distributions were used to simulate the proportion of responders to estimate the power. The simulated proportions were analyzed using the CMH test to generate 1-sided P values for the following comparisons: both odevixibat arms pooled versus placebo, low dose versus placebo, and high dose versus placebo. Assuming a response rate of 60% in the odevixibat arms and 10% in the placebo arm, the power to claim significance for a particular odevixibat arm after multiplicity adjustment was approximately 94%. The probability to claim significance for at least 1 arm and for both arms was approximately 99% and 91%, respectively. If the response rates were 50% in the odevixibat arms and 10% in the placebo arm, with 20 patients per arm, the probability to claim significance for a particular odevixibat arm after multiplicity adjustment was approximately 82%. The probability to claim significance for at least 1 arm and for both arms was approximately 91% and 73%, respectively.

For the proportion of positive pruritus assessments at the patient level in pruritus scores, beta-binomial distributions were used for power simulations. The effect size was 1.0526 from the original sample size calculation using change from baseline as the end point. The same effect size was assumed for the current end point for the low and high dose versus the control. Differences of 15%, 20%, 25%, and 30% in the proportion of positive pruritus assessments were considered in the power simulation. Within each difference, proportions of positive assessments in the placebo arm ranging from 15% to 35% were considered. Subsequently, the proportion of positive assessments in an active arm, the SD, and the corresponding beta-binomial parameters were calculated to satisfy the assumed effect size. These parameters were used to simulate correlated binary results for each patient. The simulated proportions were analyzed using an ANCOVA to generate 1-sided P values for the following comparisons: both odevixibat arms pooled versus placebo, low dose versus placebo, and high dose versus placebo. The simulation in each scenario was repeated for 5,000 iterations using the current sample size of 20 patients per arm. The simulated power to claim significance for a particular arm after multiplicity adjustment was quite consistent under different scenarios and was approximately 89%. The probability to claim significance for at least 1 arm and for both arms was approximately 95% and 83%, respectively.

Multiplicity Control

For the primary end point, a pooled analysis for the closed testing procedure was applied to control the 1-sided overall type I error rate for the 2 treatment comparisons versus placebo at the 0.025 level. In the closed testing procedure, the first comparison was the pooled result from the low- and high-dose odevixibat groups compared with placebo. If the 1-sided P value was 0.025 or less, the 1-sided P values for the low-dose group versus placebo and the high-dose group versus placebo were calculated. If both individual P values were 0.025 or less, a significant treatment effect was declared for both dose groups. If only 1 was 0.025 or less, a significant treatment effect was declared on the corresponding dose group.

Analyses of the secondary and exploratory end points were intended to provide supportive efficacy and safety information regarding the differences between the treatment groups. No adjustments were performed for multiple comparisons when testing these secondary and exploratory end points.

Subgroup Analyses

Subgroup efficacy analyses on the primary end point and selected secondary end points (changes from baseline to each visit in sBA, ALT, and growth) were performed by age group (6 months to 5 years, 6 to 12 years, and 13 to 18 years), by PFIC type (1 and 2), baseline sBAs level (250 µmol/L or greater and less than 250 µmol/L), Child-Pugh classification (A, B, C), patients with the BSEP type of PFIC2, and the use of UDCA and rifampicin (alone or either). A statistical analysis was performed only when the sample size was 10 or greater in each treatment group. If the sample size was less than 10 in any treatment group, only summary statistics are provided; the P value is not reported. Forest plots were also produced. Due to the anticipated small sample size in these subgroups, analyses by subgroups did not include the stratification factors.

Table 8: Statistical Analysis of Efficacy End Points From the PEDFIC 1 Study

ANCOVA = analysis of covariance; CI = confidence interval; CMH = Cochrane-Mantel-Haenszel; MMRM = mixed-model for repeated measures; NA = not applicable; PedsQL = Pediatric Quality of Life Inventory; PFIC = progressive familial intrahepatic cholestasis; sBA = serum bile acid.

Sources: Details included in the table are from the sponsor’s summary of clinical evidence and from the Clinical Study Report for PEDFIC 1.

Analysis Populations

Table 9: Analysis Populations of PEDFIC 1

FAS = full analysis set; PP = per protocol.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Results

Patient Disposition

A total of 107 pediatric patients were screened and 62 were enrolled into the study (Table 10). The specific reasons for the 45 screening failures were not reported; however, the sponsor noted that the majority were due to patients not having significant pruritus. Overall, 49 patients (79%) completed the planned 24-week treatment period, 11 patients rolled over to the long-term extension trial before completion of 24 weeks of treatment per protocol due to intolerable symptoms after completing between 12 and 18 weeks, 1 patient discontinued treatment due to an AE of diarrhea, and 1 patient discontinued for other reasons (noncompliance or inability to travel to the site).

There were numerically more patients who withdrew from treatment in the placebo group (25%) compared with the odevixibat 120 mcg/kg group (16%), and all patients in the placebo group discontinued due to lack of efficacy or intolerable symptoms.

Baseline Characteristics

The baseline characteristics of the PEDFIC 1 study are summarized in Table 11. The median age of the patients was 3.2 years and ranged from 6 months to 15.9 years. Patients treated with odevixibat 120 mcg/kg/day were older (median age 4.9 years) compared with patients in the placebo group (2.8 years) and patients in the 40 mcg/kg/day group (3.2 years). Most patients (47 of 62; 76%) were between 6 months and 5 years of age, 12 (19%) were between 6 and 12 years of age, and 3 (5%) were between 13 and 18 years of age; a limited number of patients (n = 10; 16%) were 8 years of age or older and were eligible to complete the PRUCISION PRO instrument.

Table 10: Summary of Patient Disposition for the PEDFIC 1 Study

FAS = full analysis set; PP = per protocol.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Consistent with patients with PFIC having impaired growth, the median height-for-age and weight-for-age z scores were −1.70 and −0.95, respectively, indicating the patients were below their age-matched peers for growth. A review of the z scores across the treatment groups indicates that patients in the placebo and 120 mcg/kg/day groups had more impaired growth, including in both height and weight, compared with patients in the 40 mcg/kg/day group.

All 62 patients had genetic confirmation of PFIC based on central reader review. Patients with PFIC1 or PFIC2 were included in the study, most (45 patients; 73%) had PFIC2 and 17 (27%) had PFIC1. Almost all patients (60; 97%) had a history of significant pruritus present per the investigator, and most (42 patients; 68%) had levels of sBAs greater than 100 µmol/L within 6 months before enrolment in the study.

The majority of patients (55; 89%) were receiving UDCA and/or rifampicin at study entry, with 50 patients (81%) on UDCA and 41 (66%) on rifampicin. At baseline, a smaller proportion of patients randomized to the 120 mcg/kg/day group were receiving UDCA (68%) compared with patients randomized to the 40 mcg/kg/day group (83%) and to the placebo group (90%). For rifampicin, a smaller proportion of patients in both active treatment groups were receiving this medication at baseline (57% and 58% in the 40 mcg/kg/day and 120 mcg/kg/day groups, respectively) compared with the placebo group (85%). Overall, 8 patients (13%) reported prior biliary tract surgeries (all reports of biliary diversion).

Median levels of sBAs were elevated at baseline at 228.0 µmol/L (93.1 mcg/mL), 188.5 µmol/L (77.0 mcg/mL), and 254.5 µmol/L (104.0 mcg/mL) in the odevixibat 40 mcg/kg/day, odevixibat 120 mcg/kg/day, and placebo groups, respectively. Median levels of hepatic biochemical parameters were elevated at baseline, including ||| ||| |||| ||||||||||||||||| ||| ||||| |||| |||| ||||||||| ||| ||||| ||||||||| ||||| ||||||| ||| |||||| |||||||. Based on the Child-Pugh classification, 41 patients (66%) had mild hepatic impairment and 21 (34%) had moderate hepatic impairment; no patients had severe impairment.

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

Table 11: Summary of Baseline Characteristics From the PEDFIC 1 Study (FAS)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; FAS = full analysis set; PFIC = progressive familial intrahepatic cholestasis; SD = standard deviation; SE = standard error; UDCA = ursodeoxycholic acid.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Exposure to Study Treatments

The median duration of exposure was approximately 24 weeks in all treatment groups and ranged from 4 to 27.6 weeks (Table 12). The majority of patients, including 34 of 42 (81%) in the overall odevixibat group and 15 of 20 (75%) in the placebo group, received 20 or more weeks of study treatment. Study drug compliance was checked through eDiary responses. Additionally, the study-site staff were to count all of the unused study drug that the patients returned at visits 4 through 9 (week 4 to week 24) and record details in the electronic case report form. Overall, adherence with the daily dosing of the study drug was high, with a median overall adherence rate, calculated from the eDiary, of 93% and 99% for the overall odevixibat and placebo groups, respectively. Compliance as calculated from the case report form was also high, with a median overall compliance of ||| ||| ||||, respectively.

All 62 patients took at least 1 concomitant medication during the treatment period. Most patients received concomitant medications for the treatment of pruritus and vitamin supplementation (Table 10). Note that for patients receiving medication for pruritus, the dose and/or regimen was not to change. Generally, the types and use of these medications were similar across the treatment groups, with the exception that a higher percentage of patients in the placebo group reported using other bile acids and derivatives (UDCA) and other antibacterials (rifampicin). Two patients (1 patient each in the placebo and odevixibat 120 mcg/kg/day groups) initiated treatment with rifampicin during the treatment period, which was prohibited by the protocol.

Efficacy

Mortality

There were no deaths in the study.

Surgical Intervention

None of the 62 patients underwent biliary diversion surgery or liver transplant during the study.

Table 12: Summary of Patient Exposure and Concomitant Use From the PEDFIC 1 Study (Safety Analysis Set)

SD = standard deviation.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Health-Related Quality of Life

Pediatric Quality of Life Inventory

HRQoL was assessed as an exploratory outcome using the PedsQL instrument, with higher scores indicating improved quality of life (Table 13). After 24 weeks, the LS mean difference versus placebo for the odevixibat 40 mcg/kg/day group was ||||| |||| |||||||||| |||||||| ||||| ||||||| |||||| ||| ||| ||| ||| |||||||||| ||||| ||| |||| |||| ||| |||||| ||||||.

Table 13: Summary of Change From Baseline to Week 24 in the PedsQL (Full Analysis Set)

CI = confidence interval; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; LS = least squares; PedsQL = Pediatric Quality of Life Inventory; SE = standard error; vs. versus.

^aA Parent Report was completed only for patients who were 2 years of age or older.

^bThese analyses were not conducted a priori as part of PEDFIC 1 but were instead requested by CADTH to facilitate GRADE assessment.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Serum Bile Acid

Proportion of Patients With at Least a 70% Reduction From Baseline in the Concentration of sBAs or Reaching a Level of 70 µmol/L or Less After 24 Weeks of Treatment

After 24 weeks of treatment, for the proportion of patients with at least a 70% reduction in sBA concentration from baseline or reaching a level of 70 µmol/L or less, the between-group differences compared with placebo were 0.441% for odevixibat 40 mcg/kg/day (95% CI, 0.236 to 0.646; adjusted P = 0.0015), and 0.216% for odevixibat 120 mcg/kg/day (95% CI, −0.005 to 0.438; adjusted P = 0.0174) (Table 14). Results in the per-protocol analysis set were consistent with the full analysis set.

||||| ||||||||||| |||||||| |||| ||||||||| ||| ||| ||||||| |||||||| || ||||| |||| ||||| ||||||||||||||||| |||||||||| ||||||||| || |||||||| ||||||||| |||||||| ||||| |||||||| ||||| ||| ||| ||||||| |||||||||| ||||| ||||||||| || ||||| |||| || ||||| |||| ||||| |||||||||| || ||| ||||||| |||||| ||| |||||||| |||||||||| ||||| ||| ||| ||||||||| ||| ||| |||||| ||||||||||| |||||||||||||||||||||| || ||| ||||||| ||| |||||||||||||| ||||||| ||| |||||||| ||||| |||| ||||| |||||| ||| ||||||| ||||||| || ||| |||||||| || ||| |||||||||| || ||||| |||| ||||| |||||||||| ||||||||| ||||||||||||| |||| |||||||||| |||| ||| ||||||| ||||||||| ||| ||| ||||||| ||||| ||||||||| |||| ||||||||||||| |||||||| |||| ||||||| |||| || |||| ||||| |||| |||||||| || || ||||||| || ||||||||| |||||||| |||| ||||||||||||| |||||||| || ||||| ||| ||| |||||||| |||||| || || ||||||||||||||| ||| ||| ||||||| |||||||||| ||||| || |||| |||||||||| ||||||.

Subgroup

In patients aged 6 months to 5 years (n = 47) and patients between 6 and 12 years of age (n = 12), the proportion of patients who received odevixibat and met the sBAs end point was ||||||| |||||| ||| |||||| ||| |||||||||||||| ||||||| ||| |||||||||| || |||||| ||||||||||||| ||| ||| |||||||||| || ||| ||||||| |||||||||| |||||||| ||| |||||||||| ||| |||||||| |||||||||| ||| |||| ||| ||||| || |||| ||||||| ||||||||| || ||| ||| |||||||||| ||||| ||| ||| |||| ||| |||||||||| |||||||| |||| |||| |||||||||| ||| ||||| |||||||| ||||||| ||||||||| || ||| || |||||||||| |||||| |||||||||||| || ||||| |||| ||||| |||| |||| ||||| ||| ||||||||| ||| |||||.

For patients receiving odevixibat, the proportion of sBA responders was higher for patients with PFIC2 (12 of 30 patients; 40.0%) compared with patients with PFIC1 (2 of 12 patients; 16.7%), although the comparison of each group with placebo had widely overlapping CIs.

The proportion of sBA responders in the odevixibat groups was ||| |||| ||| |||||||| |||| |||||||| ||||| |||| |||| ||||||||||||| |||| |||||| || || || ||||||||| |||||| ||| |||| |||||| || || || ||||||||| ||||||| |||||||| |||| || |||||||| || ||| ||||||| ||||||.

Subgroup analyses based on concomitant use of UDCA and/or rifampicin were not informative due to the small number of patients who did not use concomitant medication during the study.

Table 14: Summary of Key Efficacy Results From the PEDFIC 1 Study (FAS)

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; LS = least squares; ObsRO = observer-reported outcome; PFIC = progressive familial intrahepatic cholestasis; SD = standard deviation; SE = standard error; vs. = versus.

^aClopper-Pearson exact CI is reported for the percentage of responders, and the exact unconditional CI is reported for the proportion difference without adjusting for stratification factors.

^bThe Miettinen-Nurminen (score) CI is reported, adjusting for stratification factors.

^cBased on the Cochran-Mantel-Haenszel test adjusting for stratification factor (PFIC type).

^dFor an individual dose, the adjusted P value was calculated as the maximum value of the unadjusted P value for all doses of odevixibat and the unadjusted P value for the individual dose.

^eThe analysis was based on an ANCOVA model with rounded baseline scores as covariates, and treatment group and stratification factors (PFIC type and age category) as fixed effects.

^fThese P values were not adjusted for multiplicity.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Pruritus Assessments

Proportion of Positive Pruritus Assessments at the Patient Level (ObsRO Instrument)

Based on the results of the ANCOVA model, the between-group difference in the LS means for the comparisons of the 40 mcg/kg/day odevixibat group with placebo was 28.23 (95% CI, 9.83 to 46.64; 1-sided adjusted P = 0.0016), and the 120 mcg/kg/day odevixibat group with placebo was 21.71 (95% CI, 1.87 to 41.54; 1-sided adjusted P = 0.0163) (Table 14). Data were consistent in the per-protocol analysis set for the 40 mcg/kg/day groups, and although the results were numerically higher for the 120 mcg/kg/day group compared with placebo, the difference did not reach statistical significance.

Proportion of Positive Pruritus Assessments at the Patient Level Over Time (ObsRO Instrument)

Figure 2 presents the proportion of positive pruritus assessments at the patient level over time on treatment by grouped weeks for the morning and evening pruritus scores combined.

Figure 2: [Redacted]

Sleep Parameters

Sleep Parameters Based on the ObsRO

The changes over time in sleep parameters, specifically awakenings, was assessed as a secondary outcome using data derived from the PRUCISION pruritus instrument developed by the sponsor (Table 15). The LS mean between-group difference in number of awakenings from baseline to weeks 21 to 24 was |||| |||||||||| |||| ||| |||||| |||||| || ||| || ||||| ||||| ||| ||||| |||||||||| |||| ||| ||||||| ||||| || ||| ||| |||||||||| |||||.

Table 15: Summary of Sleep Parameters From the PEDFIC 1 Study (FAS)

CI = confidence interval; FAS = full analysis set; GRADE = Grading of Recommendations Assessment Development and Evaluation; LS = least squares; ObsRO = observer-reported outcome; PFIC = progressive familial intrahepatic cholestasis; SE = standard error; vs. = versus.

^aCalculated from an analysis of covariance model with baseline total scores for the number of awakenings (ObsRO) as covariate, and treatment group and stratification factors (PFIC type and age category) as fixed effects. These analyses were not conducted a priori as part of PEDFIC 1 but were instead requested by CADTH to facilitate GRADE assessment.

Growth Parameters

Improvement in growth (height, weight, BMI) was assessed as a secondary outcome by comparing changes from baseline in z scores relative to a typical pediatric growth chart. For height, the LS mean between-group difference between odevixibat and placebo after 24 weeks was |||| |||| ||| ||||| ||||| ||| ||| || |||||||||| ||||| ||| |||| |||| ||| |||||| ||||| ||| ||| ||| |||||||||| ||||| (Table 16). For weight, the LS mean between-group difference was |||| |||| ||| |||||| ||||| ||| ||| || |||||||||| ||||| ||| |||| |||| ||| |||||| ||||| ||| ||| ||| |||||||||| |||||. For BMI, the LS mean between-group difference was |||| |||| ||| |||||| ||||| ||| ||| || |||||||||| ||||| ||| ||||| |||| ||| |||||| ||||| ||| ||| ||| |||||||||| |||||.

Laboratory Parameters

The change from baseline to week 24 in total bilirubin was an exploratory outcome. The LS mean between-group difference versus placebo in total bilirubin was |||||| |||||| |||| ||| ||||||| |||||| || ||| || |||||||||| ||||| ||| ||||| |||||| |||| ||| ||||||| |||||| || ||| ||| |||||||||| ||||| (Table 17).

Harms

Refer to Table 18 for harms data.

Table 16: Summary of Change From Baseline to Week 24 in Growth Parameters (Full Analysis Set)

BMI = body mass index; CI = confidence interval; LS = least squares; ODE = odevixibat; PLA = placebo; SE = standard error.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Table 17: Summary of Change From Baseline to Week 24 in Biochemical Parameters (Full Analysis Set)

GRADE = Grading of Recommendations Assessment Development and Evaluation; LS = least squares; PFIC = progressive familial intrahepatic cholestasis; SE = standard error; vs. = versus.

^aCalculated from an analysis of covariance model with baseline total bilirubin (µmol/L) as covariate, and treatment group and stratification factors (PFIC type and age category) as fixed effects. These analyses were not conducted a priori as part of PEDFIC 1 but were instead requested by CADTH to facilitate GRADE assessment.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Table 18: Summary of Harms Results From the PEDFIC 1 Study (SAS)

AE = adverse event; CI = confidence interval; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; NC = not calculable; RD = risk difference; RR = relative risk; SAE = serious adverse event; SAS = safety analysis set; TEAE = treatment-emergent adverse event; vs. = versus.

^aThese analyses were not conducted a priori as part of PEDFIC 1 but were instead requested by CADTH to facilitate GRADE assessment.

Source: PEDFIC 1 Clinical Study Report (2020).⁸

Adverse Events

Overall, 35 of the 42 patients (83%) who received odevixibat experienced at least 1 TEAE, as did 17 of 20 patients (85%) who received placebo; the overall incidence of TEAEs was similar in the odevixibat 40 mcg/kg/day and 120 mcg/kg/day treatment groups (83% and 84%, respectively). The most commonly reported types of events during the study were gastrointestinal disorders and infections. Overall, the most commonly reported TEAEs (≥ 10% overall) among patients who received odevixibat versus those who received placebo were diarrhea (31% versus 5%), pyrexia (29% versus 25%), upper respiratory tract infection (19% versus 15%), vomiting (17% versus 0%), ALT increased (14% versus 5%), and blood bilirubin increased (12% versus 10%).

Treatment-Emergent Serious Adverse Events

Treatment-emergent SAEs were reported in 3 of 42 patients (7%) who received odevixibat and in 5 of 20 patients (25%) who received placebo. No TESAEs were reported in the 40 mcg/kg/day treatment group. The most commonly reported types of TESAEs were infections, reported in 4 of 20 patients (20%) in the placebo group and in 1 of 19 patients (5%) in the 120 mcg/kg/day group. The only event reported in more than 1 patient was urinary tract infection, reported in 1 patient each in the placebo and 120 mcg/kg/day groups. None of the TESAEs led to discontinuation of treatment.

Withdrawals Due to Adverse Events

Dose interruptions due to TEAEs were reported at a higher incidence in patients who received odevixibat (9 of 42; 21%) compared with patients who received placebo (1 of 20; 5%). The highest incidence was reported among patients who received the 120 mcg/kg/day dose (6 of 19; 32%); in the 40 mcg/kg/day group, 3 of the 23 patients (13%) had treatment interruptions due to TEAEs. In || ||| || |||||||| with treatment interruptions due to TEAEs, the events were related to elevations in hepatic biochemical test results and treatment was interrupted, as required by the protocol. All | of the cases where the study drug was interrupted due to hepatic biochemical test results underwent adjudication by the study’s data safety monitoring board, and all such events were assessed as being related to the patient’s underlying disease. ||| ||||| ||||| |||||||| ||||||||| ||||||||| |||||| |||| || |||||||| ||||||| ||||||||||. Patient ||||||||| discontinued from the study due to the inability to attend clinic visits.

One patient receiving odevixibat 120 mcg/kg/day discontinued the study drug due to a TEAE of diarrhea.

Mortality Due to Adverse Events

There were no deaths in the study.

Notable Harms

Clinically Significant Diarrhea

A medical review of all cases of diarrhea was conducted to determine if any met the criteria for clinically significant events as follows:

• diarrhea with duration of at least 21 days without other etiology

• diarrhea of severe intensity or reported as an SAE

• diarrhea with concurrent dehydration requiring treatment with rehydration and/or other treatment intervention.

Based on medical review, |||||||| ||| ||| |||||||| ||| |||||||||| ||||||||||| ||||||||| |||||||||||||||| || |||| ||||||||| |||||.

Hepatic Adverse Events

|||||||| |||| |||| || |||||||| ||||||||| |||||| ||| |||||||||||| || ||| |||| |||||| |||||||||| ||||| ||| ||||||| |||||| |||||| ||| |||||| ||||||||| || ||||| || || |||||||| ||| |||||||| |||||||||| |||||||| || || |||||||| ||| |||||||| |||||||| ||| ||||||||| ||| ||| || || || ||||||||| || ||| || |||||||||| ||||| ||| ||| || || || ||||||||| || ||| ||| |||||||||| |||||| |||||| ||| || ||||||||| || |||||| ||| || ||||||||||||| ||||||||| || |||||| |||||||||| || ||| || |||||||||| |||||| || |||||| || |||||||||| || ||| ||| |||||||||| |||||| ||| || |||||| |||||||||| || ||| ||||||| |||||| ||||| || ||||||||||| ||||||| ||| ||||| |||| ||||||||||| || ||| || ||| ||||||||| |||||||||| ||||||| || ||| || ||||| ||||| |||||| ||||||||||||||| |||||||| |||||||||.

Two patients, 1 in each of the odevixibat dose groups, had TEAEs in the hepatobiliary disorders System Organ Class, ||||||||| |||| |||||||||||| ||| |||||||||||||| |||||||| |||||||| || ||| |||||||||||||| ||||| ||| |||| |||||||| ||||||||| || ||| || |||||||||| ||||||.

A total of 11 of the 42 patients (26%) in the overall odevixibat group experienced liver-related TEAEs, as did 4 of the 20 patients (20%) in the placebo group. The incidence rate was 22% (5 of 23 patients) in the 40 mcg/kg/day group and 32% (6 of 19 patients) in the 120 mcg/kg/day group. ||| |||| |||||| ||||||||||||| ||||| || |||||||| || ||| ||||||||||||| |||| ||| ||||||||| || ||||||||| || ||| |||||||||| || || || ||| ||||||| |||||| ||| ||||| ||||||||| ||||||||| |||||||||||| || ||| |||||||||| |||||||||| || || ||| ||||||| ||||||| ||| ||||| ||||||||||||||||||||| ||||||||||||| ||||| |||| |||||||| ||||||||||||||||||| |||||||.

None of the 62 patients had a liver decompensation event.

Critical Appraisal

Internal Validity

In the PEDFIC 1 study, adequate methods were used for randomization and to maintain allocation concealment (use of an IWRS). Despite this, there were imbalances in several baseline characteristics that suggest prognostic balance across the groups was not achieved. These imbalances may have resulted from chance, given that the sample size was small and, based on the available characteristics, did not appear to be systematically favouring any treatment group, according to the experts consulted by CADTH. The investigators took adequate measures to facilitate adequate blinding of the participants and personnel involved in the trial (use of a matched placebo). Diarrhea was a relatively frequent event (39% of patients in the odevixibat 40 mcg/kg/day group versus 5% in the placebo group) and is a known and anticipated adverse effect of treatment, given the mechanism of the drug; therefore, it is possible that this may have resulted in unblinding for some patients, their caregivers, and trial investigators. There is a risk that this could have introduced bias (likely favouring odevixibat) in the care provided to patients and the measurement of the subjective outcomes.

There was no control for multiple comparisons outside of the primary outcome, which was controlled for multiple comparisons (2 doses of odevixibat versus placebo). The lack of multiplicity control for all subsequent outcomes increases the risk of finding a statistically significant difference between odevixibat and placebo where, in reality, none exists. However, aside from the pruritus assessment, other outcomes included in this report failed to reach statistical significance based on a conventional alpha of 0.05.

There was a relatively large proportion of patients who discontinued treatment during the PEDFIC 1 trial, 21% overall, although 11 of these patients (18% overall) continued into the extension phase (PEDFIC 2) where they all received the higher dose of odevixibat (120 mcg/kg/day). The discontinuations were highest in the placebo group (25%) and lowest in the odevixibat group (16%). For the primary outcome of sBA responders and the secondary outcome of pruritus responses, patients with missing values at week 24 were treated as nonresponders. Given that most patients, including all patients in the placebo group, discontinued due to lack of efficacy or intolerable symptoms, the impact of this missing data for assessing week 24 responses might have been mitigated. For most other outcomes, however, there was no attempt to account for missing data. Therefore, for outcomes such as the PedsQL, growth, awakenings, and total bilirubin, there is a high risk of bias due to missing outcome data.

The PedsQL scale was used to assess HRQoL and appears to be a well-established and validated scale in pediatrics, according to the clinical experts consulted by CADTH for this review. Due to the young age of many patients in the PEDFIC 1 study, the sponsor relied heavily on proxy reports, notably the PedsQL Parent Report, to gather data. Although there is evidence supporting the validity of using this proxy approach with the PedsQL in pediatric populations,²¹ it is still important to note that there may be a difference in what the proxy thinks and the child thinks with respect to their HRQoL and symptoms. ||| ||||||| ||||||||| || ||||||||||||||||||||| ||| ||| ||| |||||| |||||; therefore, the clinical significance of the between-group differences for the Parent Report and the Family Impact Module cannot be determined. The PRUCISION pruritus scale used to assess pruritus and its impact on other outcomes, such as sleep, was developed by the sponsor, and that includes the MID they used to indicate a “positive” response. The sponsor’s rationale for creating its own instrument was that there was no publicly available pruritus scale at the time of study initiation; however, it remains unclear whether a new instrument was necessary when it was known that another was already developed, and it is not ideal that the instrument used by the sponsor has only been validated within its own trial, rather than being externally validated in another separate trial that they were not sponsoring. MIDs were also not available for other assessment measures, such as growth, number of awakenings, and total bilirubin, making it difficult to assess the clinical significance of the reported differences between odevixibat and placebo.

There were prespecified subgroup analyses planned by the sponsor; however, the findings from these analyses are limited by the small sample size in the PEDFIC 1 study. For example, for some of the smaller subgroups (e.g., those based on age), the sponsor had to resort to reporting individual patient data, and samples that small are not useful for drawing conclusions about efficacy or harms.

External Validity

The dosing used in the PEDFIC 1 trial is not consistent with that proposed in the draft product monograph. The current proposed dosing recommendations are for patients to begin on 40 mcg/kg/day and then escalate to 120 mcg/kg/day after 12 weeks if there is a lack of response. However, in the pivotal trial, PEDFIC 1, patients began on either 40 mcg/kg/day or 120 mcg/kg/day, and there was no group that underwent this up-titration in the proposed dosing. As a result, information is lacking on the efficacy of odevixibat if it were used as intended in the draft product monograph in terms of dose escalation (it is unclear if it would differ from the findings herein). Most patients in the PEDFIC 1 study were on either UDCA or rifampicin or both, and these are the key standards of care for patients with PFIC1 and PFIC2, although both have limited efficacy, according to the clinical experts. The clinical experts consulted by CADTH for this review believe it is possible that odevixibat might be used in combination with some of these therapies.

PEDFIC 1 was not of sufficient size or duration to adequately assess key clinical outcomes, such as mortality or the need for surgical intervention (liver transplant or biliary diversion). Both of these limitations are understandable, given the rarity of the disease and the fact that this was a placebo-controlled trial in a pediatric population in a disease with a very severe clinical course. Nevertheless, both outcomes are of interest to patients and the lack of data for each is a limitation of the PEDFIC 1 study.

PEDFIC 1 enrolled patients with PFIC1 and PFIC2; however, the current proposed indication does not restrict the use of odevixibat based on PFIC subtype. According to the clinical experts consulted by CADTH for this review, there is no way to determine for certain whether odevixibat will work in other subtypes; however, there is no reason to think it would not work. That said, the clinical experts were clear that if clinicians were to follow evidence-based practice, they would limit prescribing odevixibat to PFIC subtypes 1 and 2.

The primary outcome of PEDFIC 1 for jurisdictions outside of the US, and the only outcome controlled for multiplicity, was the proportion of patients experiencing an sBA response. The precise relationship between sBA levels and disease progression and pruritus has not been established, and it is clear from patient input that pruritus and disease progression (need for surgery, mortality) are the outcomes that are most important to patients. Additionally, the clinical experts consulted by CADTH for this review believed the use of a cut-off of a 70% reduction in sBA for response was too conservative, and questioned how that threshold was chosen. In its comments on the Clinical Review Report, the sponsor revealed that this threshold was determined from a systematic review and meta-analysis that evaluated the relationship between liver biochemistry and improvement in pruritus. The sponsor reported that it found that sBA levels of less than 70 µmol/L or a decrease of more than 70% from baseline predicted a pruritus response with good sensitivity and specificity.²² The clinical experts also noted it is unlikely that sBA would be routinely used to monitor treatment in patients with PFIC, as the assay is not widely available and pruritus is a much more readily monitored and clinically relevant outcome to patients. Similarly, HRQoL is a key outcome for patients, but was only an exploratory outcome in the PEDFIC 1 study and, due to missing data, the findings were difficult to interpret.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE working group:^23,24

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

• For RCTs: Following the GRADE approach, evidence from RCTs starts as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of the evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for odevixibat versus placebo.

Long-Term Extension Studies

Contents within this section have been informed by materials submitted by the sponsor. The following was summarized and validated by the CADTH review team.

Description of Study

PEDFIC 2 is an ongoing phase III, multicentre, nonrandomized, open-label extension study to investigate the long-term efficacy and safety of a 120 mcg/kg/day dose of odevixibat in patients with PFIC (Figure 3).^10,11 The study includes an 8-week screening period (cohort 2 only), a 72-week treatment period, and a 4-week follow-up period. An optional extension period for continued treatment follows the 72-week treatment period. Patients who complete treatment through week 72 and elect to continue receiving treatment with odevixibat in the optional extension period return to the clinic for visits every 16 weeks.

PEDFIC 2 is currently ongoing, and interim data were presented by the sponsor based on a cut-off date of July 31, 2022. This planned interim analysis was completed for regulatory submission purposes to supplement the efficacy and safety data from the PEDFIC 1 study. The planned final analysis for the PEDFIC 2 study will occur once all patients complete the week 72 assessment or are off study, whichever occurs first.

Figure 3: PEDFIC 2 Study Design [Redacted]

Populations

Cohort 1 consists of children with PFIC types 1 and 2 who participated in the PEDFIC 1 study. Cohort 2 consists of patients with PFIC who have elevated sBAs and cholestatic pruritus and who either did not meet the eligibility criteria for the PEDFIC 1 study or were eligible for enrolment in the PEDFIC 2 study after recruitment to PEDFIC 1 was completed.

For cohort 1, patients were eligible if they completed 24 weeks of treatment in the PEDFIC 1 study (note that before amendment 6, [June 24, 2019], patients who withdrew early from the PEDFIC 1 study after a minimum of 12 weeks of treatment due to intolerable symptoms were also eligible to enter this study). Patients who withdrew from the PEDFIC 1 study due to a study drug–related AE or who were noncompliant with treatment in the PEDFIC 1 study were not eligible.

For cohort 2, patients of any age with a clinical diagnosis of PFIC and with a body weight of 5 kg or greater at screening and clinical genetic confirmation of PFIC were eligible. The study was amended on December 21, 2021, to provide access to odevixibat for patients with an episodic form of PFIC (i.e., benign recurrent intrahepatic cholestasis). Up to 40 patients post biliary diversion surgery could participate in cohort 2. Other eligibility criteria for cohort 2 were identical to the criteria for the PEDFIC 1 study (Table 3), except the following exclusions were removed:

• patient with a past medical history of chronic kidney disease with impaired renal function and a glomerular filtration rate of less than 70 mL/min/1.73 m²

• patient with a surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months before the start of the screening period

• patient who has been previously treated with an ileal bile acid transporter inhibitor whose pruritus has not responded to treatment.

Interventions

For all patients who entered the study, odevixibat therapy was initiated at a dosage of 120 mcg/kg taken orally once daily. However, this dosing regimen did not align with the proposed product monograph, which recommends dose escalation for lack of response. In the event a patient was unable to tolerate the odevixibat dose of 120 mcg/kg/day after a minimum of 1 week, for reasons other than new liver findings or severe diarrhea, the dose could be down-titrated to 40 mcg/kg/day. Patients who were down-titrated could return to the higher dose as soon as the investigator considered it appropriate. More than 1 upward-dose titration (from 40 mcg/kg/day directly to 120 mcg/kg/day) for the same event was not recommended.

The study protocol was amended on December 21, 2021, to include a starting dose of 40 mcg/kg/day with the possibility to escalate to 120 mcg/kg/day after 12 weeks if there is no improvement in pruritus, based on investigator judgment.

Permitted concomitant therapies were the same as what was described for the PEDFIC 1 study.

Outcomes

The outcomes assessed in the PEDFIC 2 study were similar to PEDFIC 1 (Table 19). The time point for analysis for this interim study is after 24 weeks of treatment; the final analyses will be based on the week 72 time point. This report will focus only on the relevant PEDFIC 2 outcomes that align with those from the PEDFIC 1 study.

Table 19: Outcomes Assessed in the PEDFIC 2 Study

ALT = alanine aminotransferase; APRI = AST to platelet ratio index; AST = aspartate aminotransferase; FIB-4 = Fibrosis-4 Index for Liver Fibrosis; GGT = gamma-glutamyl transferase; GIC = Global Impression of Change; GIS = Global Impression of Symptoms; INR = international normalized ratio; MELD = model for end-stage liver disease; p-C4 = plasma 7 alpha-hydroxy-4-cholesten-3-one concentration; PedsQL = Pediatric Quality of Life Inventory; PELD = pediatric end-stage liver disease; ObsRO = observer-reported outcome; PRO = patient-reported outcome.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Statistical Analysis

All analyses for this report were conducted on the full analysis set, defined as all patients who received at least 1 dose of the study drug in the PEDFIC 2 study.

Descriptive statistics were used unless otherwise specified. Data were summarized by cohort or treatment subgroup and overall in tabular format. Continuous variables were summarized using descriptive statistics, including the number of patients with nonmissing values (n), mean, median, SD or SE, minimum, and maximum. For categorical variables, summaries include counts of patients (frequencies) and percentages. Descriptive summaries of change from baseline in categorical variables were provided using shift tables, as applicable.

No imputations were conducted for missing data. Any assessments after intercurrent events (death or initiation of rescue treatments such as biliary diversion surgery or liver transplant) or follow-up assessments (≥ the last dose day plus 15 days) are excluded from analysis. For the analysis of the eDiary data, the data after premature treatment discontinuation (i.e., the last dose of study treatment) are excluded from analysis.

Results

Baseline Characteristics

The baseline characteristics in the PEDFIC 2 study are summarized in Table 20, excluding || patients enrolled with benign recurrent intrahepatic cholestasis (BRIC) (due to the small number of patients with BRIC enrolled at the time of data cut-off, no results are presented for these patients). The median age at study entry was ||| ||||| ||| |||||| |||| ||| || |||| |||||| |||| |||||||| |||| ||||| ||||||| |||| ||||||| |||||||| |||||||||||| || |||| ||||||| ||| ||||| |||||| ||||| ||||| ||| |||| |||||| ||| |||| |||||| |||||||| || ||||||||| |||||||| ||||| ||||| ||| ||| |||||| || |||||||| |||| |||||||| |||||||||||| ||| || ||||||| || ||||| || |||||||| ||||| ||||| |||||||| |||| ||||||| || || |||||||| || |||| ||||||| ||| |||||||| || |||||||| ||||||| |||| ||||||||| |||| |||||| |||||||||| || ||||| ||||| |||| ||||| || |||| ||| ||||| || ||||||||||| |||||| |||||||| ||||||| ||| ||||| ||||||| ||||||||| |||||||.

Patient Disposition

Patient disposition at the time of the data cut-off for the PEDFIC 2 study is summarized in Table 21. A total of ||| patients were enrolled in the PEDFIC 2 study as of the data cut-off of July 31, 2022; all patients had received treatment as of the data cut-off (|||||||||| || |||||| |||||| |||| |||| |||||| || || |||||||| || |||||| || ||| |||||||| |||||||||| ||||||||| || ||||| |||| ||| ||||| ||| ||||||||| ||||| || ||||| |||||||| ||| |||||||||| |||||||| ||| |||||| ||||||| |||||||| |||||||||||||| || ||||| |||| |||| |||||||||| |||||||| |||| |||||| || ||| || |||||||| || ||||||||| ||| |||||| |||| |||| |||||| || || ||| |||||||||| |||| ||||||| |||| |||||||||| ||| || ||| |||||||| |||||||| ||||| || || ||| ||| |||||||| ||| |||||||||| |||| |||||||.

As of the data cut-off date, of the ||| |||||||| || ||| |||||| || |||||||| |||||||||| || |||||||| || ||||||||| || |||||||| || |||||| || ||| ||||||||| ||| || |||| ||||||||| ||||||| || |||||||| ||||||||||||||||| || ||||||||| || |||||||| || |||||| || |||| |||||||||| ||| ||| || |||||||| ||| || ||||| ||||||||| |||||| ||| || |||||||| |||||||||| || |||||||| || ||||||||| || |||||||| || |||||| || ||| |||||||||||| ||||||||| ||||| || |||| ||| ||||| ||| || |||||||| ||| ||||||||| || ||||| || |||||||||| || |||||||| ||||||| ||| |||||||| ||||||||| |||||| |||||| |||| || || ||| |||| |||||| |||||||||| || || |||||||| |||||||||| || |||||||| ||| ||||| |||||||||| ||||||||| |||||| ||| || |||||||| ||| |||| |.

Exposure to Study Treatments

Study Treatments

Median overall duration of exposure to odevixibat 120 mcg/kg/day in the PEDFIC 2 study was 80.9 weeks and ranged from 4.3 weeks to 189.3 weeks at the time of the data cut-off (Table 22).

Median duration of exposure was approximately |||| ||| ||| ||| weeks in patients who had received 40 mcg/kg/day, 120 mcg/kg/day, or placebo in the PEDFIC 1 study, respectively. In cohort 2, which started enrolment approximately 1 year after the first patient in cohort 1 was rolled over to PEDFIC 2, the median exposure was |||| weeks.

Overall, adherence with daily dosing of odevixibat was high, with a median overall adherence of ||||| || |||||||||| |||| ||| |||||| ||| ||||| || |||||||||| |||| ||| |||| |||||| ||||. The rate of adherence was similar across study groups in cohort 1 and cohort 2.

Table 20: Baseline Characteristics in the PEDFIC 2 Study (Full Analysis Set)

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; BRIC = benign recurrent intrahepatic cholestasis; GGT = gamma-glutamyl transferase; PFIC = progressive familial intrahepatic cholestasis; SD = standard deviation; SE = standard error; UDCA = ursodeoxycholic acid.

^aFor patients in cohort 1, the dose indicated is the dose administered during their participation in the PEDFIC 1 study.

^bExcluding || patients with BRIC who were enrolled in cohort 2.

^cCohort 2 (excluding patients with BRIC) + placebo refers to patients enrolled in cohort 2 plus the patients who were assigned to placebo during their participation in the PEDFIC 1 study.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Concomitant Medications and Co-Interventions

All patients took at least 1 concomitant medication during the treatment period. Most patients received concomitant medications for the treatment of pruritus and for vitamin supplementation. Generally, the types and use of these medications were similar across the study groups, with the exception that a |||||| |||||||||| || |||| || ||||||||| ||||| |||||||| |||||||| ||| ||| || |||||||||| ||||||||| |||| || ||||| ||||||||||| || ||||| ||| ||||| |||||||||||||| |||||||||||| |||| || |||| compared with patients who received odevixibat in the PEDFIC 1 study.

|||| |||||||| ||||||||| ||||||||| |||| |||||||||| |||||| ||| ||||||||| ||||||.

Efficacy

Serum Bile Acid

Median changes (range) in sBAs levels from the PEDFIC 2 study at baseline to week 22 and 24 were ||| |||||||| |||||| ||||||| || |||||||| ||| ||||||||||| || |||||||||| || |||||| || ||| |||| ||||||| ||||| ||||||| || |||||||| ||| ||| |||||||| ||| ||||||||||| ||| |||||||| ||| ||| |||||||| ||||||| || |||||| || |||||| ||||||| ||||||| || |||| ||||| ||||||||| ||| ||||| || ||||||||| |||| |||||||||| ||| |||||||||| ||| |||| |||||||| |||||| ||||||| ||| ||| |||||||| || |||||||| |||| |||||||| |||||| ||||||.

Median changes (range) in sBAs levels from the PEDFIC 2 study at baseline to week 70 and 72 were ||| ||||||| |||||| ||||||| || |||||||| ||| ||||||||||| || |||||||||| || |||||| || ||| ||||| |||||||| |||||| ||||||| || |||||||| ||| ||| |||||||| ||| ||||||||||| ||| |||||||| ||| ||| |||||||| ||||||| || |||||| || |||||| ||||||| ||||||| || |||| ||||| ||||||||| ||| ||||| || ||||||||| |||| |||||||||| ||| |||||||||| ||| |||| |||||||| |||||| ||||||| ||| |||.

Table 21: Patient Disposition in the PEDFIC 2 Study

BRIC = benign recurrent intrahepatic cholestasis.

Note: Cohort 1 patients entered from the PEDFIC 1 study and therefore did not undergo screening. ||||||| ||||| ||| ||| ||||| ||| |||||||||||| ||||||||| || ||| || |||| ||||||||| |||||| ||| |||| ||||| ||||||| || ||| ||||| || || |||.

^aFor patients in cohort 1, the dose indicated is the dose administered during their participation in the PEDFIC 1 study.

^bCohort 2 enrolled 2 patients with BRIC; they are currently ongoing in the 72-week treatment period.

^cCohort 2 (excluding patients with BRIC) plus placebo refers to the patients enrolled in cohort 2 plus the patients who were assigned to placebo during their participation in the PEDFIC 1 study.

^dContinuing on treatment and in the study as of the data cut-off date of July 31, 2022.

^e||||||| ||||| ||| ||||||||| ||| ||||||| ||||||||| ||||||| ||||||| ||| ||||||| || |||||||| || ||||||| ||||||| ||||| ||| |||| ||| ||| ||||||||||||||| ||||| ||| ||||||||| ||| ||||||| ||||||||| ||||||| ||||||| ||| ||||||| ||||||||| ||||| ||| ||||||||| ||| ||||||| ||||||||| ||||||| ||||||| ||| ||||||| ||||||||| ||||| ||| ||||||||| ||| ||||||| ||||||||| ||||||| ||||||| ||| ||||||| ||||||||| ||||| ||| ||||||||| ||| ||||||| ||||||||| ||||||| ||||||| ||| ||||||| ||.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Figure 4: [Redacted]

Table 22: Exposure to Study Drug in the PEDFIC 2 Study (Full Analysis Set)

BRIC = benign recurrent intrahepatic cholestasis; SD = standard deviation.

^aFor patients in cohort 1, the dose indicated is the dose administered during their participation in the PEDFIC 1 study.

^bExcluding | patients enrolled with BRIC.

^cCohort 2 (excluding patients with BRIC) + placebo refers to patients enrolled in cohort 2 plus the patients who were assigned to placebo during their participation in the PEDFIC 1 study.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Table 23: Summary of Change in Serum Bile Acids After 24 Weeks and 72 Weeks of Treatment (Full Analysis Set)

BRIC = benign recurrent intrahepatic cholestasis; SE = standard error.

^aFor patients in cohort 1, the dose indicated is the dose administered during their participation in the PEDFIC 1 study.

^bCohort 2 (excluding patients with BRIC) + placebo refers to patients enrolled in cohort 2 plus patients who were assigned to placebo during their participation in the PEDFIC 1 study.

^cBaseline for the PEDFIC 2 study; end of treatment for the PEDFIC 1 study.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Pruritus Assessments

The effect of treatment with odevixibat 120 mcg/kg/day on pruritus severity over 72 weeks in all study groups in cohort 1 and in cohort 2 is summarized in Table 24 and Figure 5.

Among patients who had received active treatment in the PEDFIC 1 study and those who were treatment-naive at study entry, the median (range) proportion of positive pruritus assessments was ||||| ||| |||||| ||||| || ||||| || ||||||||| ||| ||||| ||| |||||| ||||| || ||||| || ||| |||||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| ||| |||||||| ||| ||| |||||||| || |||||||||| || ||||||||| |||||||||||| || ||| |||||||||| || ||||| ||||||||| ||||| ||| |||||| ||||| || |||||| ||||| ||| |||||||| ||||||||| |||||||||| |||| ||||||| || |||||| ||| |||||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| || ||| ||||||| ||||| ||| ||||| |||||| |||||| |||| ||| ||||||| ||||||||| |||||| ||| ||||| |||||| |||||| |||| ||| ||||||| ||||||||| ||||||| || |||||| || ||| |||||| ||||||| |||||||||| || |||||||| |||||||| ||||||||||| || ||| ||||||| ||||| ||| ||||| |||| ||| ||||||| ||||||||| |||||| ||| ||||| |||||| |||||| |||| ||| ||||||.

Data were consistent when the analysis was performed based on morning and evening scores separately.

Table 24: Summary of Proportion of Positive Pruritus Assessments at the Patient Level (Combined Morning and Evening PRUCISION ObsRO Scores) Over the 24-Week Treatment Period (Full Analysis Set)

BRIC = benign recurrent intrahepatic cholestasis; ObsRO = observer-reported outcome; SE = standard error.

^aFor patients in cohort 1, the dose indicated is the dose administered during their participation in the PEDFIC 1 study.

^bCohort 2 (excluding patients with BRIC) + placebo refers to patients enrolled in cohort 2 plus patients who were assigned to placebo during their participation in the PEDFIC 1 study.

Source: PEDFIC 2 interim Clinical Study Report (2022).²⁵

Figure 5: [Redacted]

Sleep Parameters

Treatment with odevixibat to improve patient’s sleep based on observer-reported information was consistent with what was observed in pruritus. For patients who had previously received odevixibat during the PEDFIC 1 study, mean changes from baseline to weeks 21 to 24 in patients who had received 40 mcg/kg/day versus those who had received 120 mcg/kg/day in the PEDFIC 1 study was || ||| ||||| ||| |||||| || ||||||||||| ||| ||||||||| ||||| ||||||||| ||| ||| |||||||| ||||||| || ||||| ||||||||| ||| ||||||||||||||| |||| ||||||| |||| |||||||| || ||||| ||||| |||| || ||| || ||| |||||| || ||||||||||.

Growth Parameters

Changes in height and weight scores were noted during treatment with odevixibat 120 mcg/kg/day (Figure 6 and Figure 7).

For patients in cohort 1 who had previously received odevixibat in the PEDFIC 1 study, the mean (SE) change from baseline to week 24 in height z score was |||| ||||||||| |||| ||||||| ||| ||| |||||||| ||| |||||||||| |||||| ||||||||| ||| ||||||| ||| ||| |||||||| || |||||||||| |||||| |||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || |||||||||||| |||| ||||| |||||||| ||| ||||| |||||||| ||| |||||||| ||| ||| |||||||| |||||||||| || |||||||||| ||| ||| ||||||||||| ||||||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || ||||||||| |||| ||||| |||||||| ||| ||||| ||||||||| ||| ||||| ||||||| ||||||||||||.

For patients in cohort 1 who had received placebo in the PEDFIC 1 study and in patients in cohort 2, the mean (SE) changes in height z score were ||||| ||||||||| ||| ||||| ||||||||| ||||||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || |||||||||||| |||| ||||| |||||||| ||| ||||| |||||||| ||| |||||||| ||| ||| |||||||||| |||||||| ||||||| || |||||||| ||| |||||||| || |||||| || ||||||||||||| ||| |||| |||| ||||||| |||| |||||||| || ||||||||| |||| ||||| |||||||| ||| ||||| ||||||||| ||||||||||||.

For patients in cohort 1 who had previously received odevixibat in the PEDFIC 1 study, the mean (SE) change from baseline to week 72 in height z score was ||||| ||||||||| |||| ||||||| ||| ||| |||||||| ||| |||||||||| |||||| ||||||||| ||| ||||||| ||| ||| |||||||| || |||||||||| |||||| |||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || ||||||||||| |||| ||||| |||||||| ||| ||||| |||||||| ||| |||||||| ||| ||| |||||||| |||||||||| || |||||||||| ||| ||| ||||||||||| ||||||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || ||||||||| |||| ||||| |||||||| ||| ||||| ||||||||| ||| ||||| ||||||| ||||||||||||.

For patients in cohort 1 who had received placebo in the PEDFIC 1 study and in patients in cohort 2, mean (SE) changes in height z score were ||||| |||||||| ||| ||||| ||||||||| ||||||||||||| |||| |||| ||||||| |||| |||||||| || |||| || || |||||||||||| |||| ||||| |||||||| ||| ||||| |||||||| ||| |||||||| ||| ||| |||||||||| |||||||| ||||||| || ||||||||| ||| |||||||| || |||||| || ||||||||||||| ||| |||| |||| ||||||| |||| |||||||| || |||||||| |||| ||||| |||||||| ||| ||||| ||||||||| ||||||||||||.

Figure 6: [Redacted]

Figure 7: [Redacted]

Surgical Intervention

|||||||| |||||||| || |||| ||||| ||||||||| |||||||| |||||||||||| |||||||||||||||| ||| ||||||||| ||||||| ||||||||| ||||||| ||| || |||||||| ||| ||||||||| ||||| ||||||||||||||| ||||||||| ||||| |||||||||| ||| ||| ||||| ||||||| |||||| |||||||||| || ||||| || |||||||||||||||||| ||| ||||| ||||||| ||||||| ||||| || ||| || ||||||||||| ||| ||||| ||||||| ||||||| ||||| || ||| ||| |||| || ||| || |||||||| ||| ||||| ||||||| ||||| |||||||||| ||| || |||| ||||||||| ||||||.

Laboratory Parameters

For patients in cohort 1 who had received placebo, mean change from baseline to week 24 was ||||| |||||| || ||||| |||||||||| ||| ||||||||||||||| |||| |||||| ||| ||||| |||||| || ||||| |||||||||.

Health-Related Quality of Life

A summary of the total score for the PedsQL Parent Report and Family Impact Module is presented in Table 25.

For patients who had previously received odevixibat in the PEDFIC 1 study, mean (SE) change of total scores on the PedsQL Parent Report from baseline to week 24 in the PEDFIC 2 study for patients who had received 40 mcg/kg/day and 120 mcg/kg/day were |||| ||||||| ||| |||| |||||||| ||||||||||||.

For patients in cohort 1 who received odevixibat in the PEDFIC 1 study, the mean (SE) changes from baseline to week 24 were |||| ||||||| ||| |||| ||||||| ||| |||||||| ||| ||| |||||||||| |||||||| ||| || |||||||||| ||| ||| |||||||||| ||||| ||||||||||||| ||| |||||||| || ||||||||| |||||||| |||||||| ||| |||| |||| |||||| ||| ||||| ||||||| ||| ||| |||||||||||||| ||| ||||| ||| |||| |||| |||||| ||| ||||| |||||||.

Table 25: Summary of Change From Baseline to Week 24 and Week 72 in PedsQL Total Score (Full Analysis Set)