Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC

Blood samples for analysis of fasting total serum bile acids were drawn at specified timepoints. Participants were to fast (water intake only) for at least 4 hours prior to the collection of samples for serum bile acids. Exceptions were made for infants <12 months of age if unable to fast for the full 4 hours. Baseline for Cohort 1 placebo/odevixibat and Cohort 2 groups was defined as the average of last 2 values before the first dose of study treatment in the study. Baseline for Cohort 1 odevixibat/odevixibat group was defined as average of last 2 values before the first dose of study treatment in study A4250-005 (NCT03566238).

A positive pruritus assessment was defined as a scratching score of <=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant.

A positive pruritus assessment was defined as a scratching score of <=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant.

Blood samples for analysis of fasting total serum bile acids were drawn at specified timepoints. Participants were to fast (water intake only) for at least 4 hours prior to the collection of samples for serum bile acids. Exceptions were made for infants <12 months of age if unable to fast for the full 4 hours. Baseline for Cohort 1 placebo/odevixibat, and Cohort 2 groups was defined as the average of last 2 values before the first dose of study treatment in the study. Baseline for Cohort 1 odevixibat/odevixibat group was defined as average of last 2 values before the first dose of study treatment in study A4250-005 (NCT03566238).

A positive pruritus assessment was defined as a scratching score of <=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant.

A positive pruritus assessment was defined as a scratching score of <=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant. AM score represents night-time itching/scratching and sleep disturbance.

A positive pruritus assessment was defined as a scratching score of <=1 or at least a 1-point drop from baseline on the Albireo ObsRO instrument. The proportion of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant. PM score represents daytime itching/scratching and tiredness.

A responder is defined as a participant who reports a decrease in pruritus score from unrounded baseline equivalent to or greater than the threshold of meaningful change estimated from the blinded psychometric analysis. The averaged pruritus score was used to calculate the percentage of participants achieving meaningful reduction at specified Week against the thresholds value of 1.00 based on bi-weekly scores at specified Week obtained from blinded psychometric analysis across all anchors support a threshold of 1.0 point for AM, PM and AM and PM scratching scores. ObsRO instrument was used to assess severity of observed scratching twice a day (AM and PM) with score from 0 to 4 where 0 is no scratching and 4 is worst possible scratching.

A responder is defined as a participant who reports a decrease in pruritus score from unrounded baseline equivalent to or greater than the threshold of meaningful change estimated from the blinded psychometric analysis. The averaged pruritus score was used to calculate the percentage of participants achieving meaningful reduction at specified Week against the thresholds value of 1.00 based on monthly scores at specified Week obtained from blinded psychometric analysis across all anchors support a threshold of 1.0 point for AM, PM and AM and PM scratching scores. ObsRO instrument was used to assess severity of observed scratching twice a day (AM and PM) with score from 0 to 4 where 0 is no scratching and 4 is worst possible scratching.

The percentage of participants who achieved positive pruritus assessment for more than 50% of the time for Weeks 0-72 is reported. A positive pruritus assessment is defined as a scratching score of <=1 or at least a 1-point decrease from baseline on the Albireo ObsRO instrument based on rounded baseline and was calculated based on reported eDiary data. At each assessment, the AM score was compared to the baseline AM average, and the PM score was compared to the baseline PM average. All assessments after intercurrent events (premature treatment discontinuation, death, or initiation of rescue treatments such as biliary diversion surgery or liver transplantation) or follow-up assessments (>= last dose day + 15 days) were excluded from analysis.

Participants who underwent biliary diversion surgery and or liver transplantation data has been reported.

Growth factors like height was measured by the standardized assessments outlined in the US food and drug administration (FDA) guidance document. Height was measured using certified stadiometer. Change in growth parameters was assessed using linear growth (height) compared to standard growth curve (Z-score) calculated by using the software or methods from the centers for disease control (CDC) website for participants with age >=2 years old and from the world health organization (WHO) website for participants with age <2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to first dose of study treatment. A Z-score indicates how many standard deviation's (SD) a participant's measurement (like height), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below average a measurement was.

Growth factors like weight was measured by the standardized assessments outlined in the US FDA guidance document. Weight was measured using certified weight scale. Change in growth parameters was assessed using linear growth (weight) compared to standard growth curve (Z-score), calculated by using the software or methods from the CDC website for participants with age >=2 years old and from the WHO website for participants with age <2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to the first dose of study treatment. The Z-score indicates how many SDs a participant's measurement (like weight), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below the average a measurement was.

Growth factors like BMI was measured by the standardized assessments outlined in the US FDA guidance document. BMI was calculated by weight (kg) / height (m)^2. Change in growth parameters was assessed using linear growth (BMI) compared to standard growth curve (Z-score), calculated by using the software or methods from the CDC website for participants with age >=2 years old and from the WHO website for participants with age <2 years old. Participants whose accurate age was not available, Z-score was not calculated. Baseline is the last available assessment prior to the first dose of study treatment. The Z-score indicates how many SDs a participant's measurement (like BMI), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below the average a measurement was.

Data for the number of participants with use of UDCA and rifampicin are reported.

The PELD score was calculated for children under 12 years of age, ranged across negative to positive values. The calculation of the PELD score was done by converting the laboratory parameters: total bilirubin in milligram/deciliter (mg/dL), albumin in gram (g)/dL, and creatinine in mg/dL laboratory parameters were converted to units. PELD score was calculated as 4.80*ln (total bilirubin)+18.57*ln [international normalized ratio (INR)] - 6.87*ln (albumin) + 4.36 (if participant <1 year: scores for participants listed for liver transplantation before the participant's first birthday continued to include the value assigned for age (<1 year) until the participant reached the age of 24 months) + 6.67 (if the participant has growth failure [<-2 standard deviation]). The laboratory values <1.0 were set to 1.0 for the calculation of the PELD score. Lower scores represent less severe hepatic disease. Baseline is the last available assessment prior to the first dose of study treatment.

The MELD score was calculated for children 12 years of age or older ranges from 6 to 40. The calculation of the MELD score was done by converting the laboratory parameters in the following units: total bilirubin in mg/dL, albumin in g/dL, and creatinine in mg/dL laboratory parameters were converted to units. MELD score for children 12 years of age or older ranges from 6 to 40 was calculated as 9.57*ln (creatinine) + 3.78*ln (total bilirubin) + 11.2 *ln (INR) + 6.43. Laboratory values <1.0 were set to 1.0 and serum creatinine values >4.0 mg/dL were set to 4.0 for calculation of the MELD score. Lower scores represent less severe hepatic disease. Baseline is the last available assessment prior to the first dose of study treatment.

AST to APRI score was calculated as [(AST in units per liter {U/L})/ (AST upper limit of normal {ULN} in U/L)] * 100/ (platelets in 10^9/L). The APRI score is a way to assess fibrosis of the liver. The lower the APRI score (< 0.5), the greater the negative predictive value and ability to rule out cirrhosis; the higher the value (> 1.5) the greater the positive predictive value and ability to rule in cirrhosis. Lower values indicate less severe hepatic fibrosis. Baseline is the last available assessment prior to the first dose of study treatment.

Fib-4 score was calculated as (age * AST in U/L)/ (platelets in 10^9/L *√ ( alanine aminotransferase [ALT] in U/L). The FIB-4 score estimates the amount of scarring in the liver. A FIB-4 score <1.45 has a negative predictive value of 90% for advanced fibrosis (Ishak fibrosis score 4-6 which includes early bridging fibrosis to cirrhosis). In contrast, a FIB-4 > 3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. Lower values indicate less severe hepatic fibrosis. Baseline is the last available assessment prior to the first dose of study treatment.