Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy, ATC code: A05AX05 
Mechanism of action

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).
Pharmacodynamic effects

Odevixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase the clearance of bile acids through the colon, reducing the concentration of bile acids in the serum. The extent of reduction of serum bile acids does not correlate with systemic PK.

Trial 3 is a 24-week, randomized, double-blind, placebo-controlled trial conducted in 52 patients with a confirmed diagnosis of ALGS who were administered treatment with BYLVAY 120 mcg/kg once daily. At baseline, serum bile acids were variable ranging from 93 to 510 mcmol/L. Serum bile acid concentrations were reduced from baseline as early as Week 4 of odevixibat treatment and the reduction was generally maintained during treatment over 24 weeks.


Clinical efficacy
PFIC
The efficacy of Bylvay in patients with PFIC was evaluated in two phase 3 trials. Trial 1 was a 24-week, randomised, double-blind, placebo-controlled trial conducted in 62 patients with a confirmed diagnosis of PFIC Type 1 or Type 2. Patients were randomised 1:1:1 to placebo, or 40 or 120 mcg/kg/day odevixibat and stratified by PFIC Type (1 or 2) and age (6 months to 5 years, 6 to 12 years, and 13 to ≤ 18 years). Patients with pathologic variations of the ABCB11 gene that predict complete absence of the BSEP protein and those with ALT > 10 × ULN or bilirubin > 10 × ULN were excluded. 13% of the patients had prior biliary diversion surgery. Patients completing Trial 1 were eligible to enrol in Trial 2, a 72-week open-label extension trial. The primary endpoint in Trial 1 was 
the proportion of patients with at least a 70% reduction in fasting serum bile acid levels or who achieved a level ≤ 70 µmol/L at week 24.

The proportion of positive pruritus assessments at the patient level over the 24-week treatment period based on an observer-reported outcome (ObsRO) instrument was a secondary endpoint. A positive pruritus assessment was a score of ≤ 1 or at least 1-point improvement from baseline. Pruritus assessments were conducted in the morning and evening using a 5-point scale (0-4). Additional secondary endpoints included changes from baseline to end of treatment in growth, sleep parameters (per ObsRO) and ALT.

Median (range) age of patients in Trial 1 was 3.2 (0.5 to 15.9) years; 50% were male and 84% were white. 27% of patients had PFIC Type 1 and 73% had PFIC Type 2. At baseline, 81% of patients were treated with UDCA, 66% with rifampicin, and 89% with UDCA and/or rifampicin. Baseline hepatic impairment per Child-Pugh classification was mild in 66% and moderate in 34% of patients. Baseline mean (SD) eGFR was 164 (30.6) mL/min/1.73 m². Baseline mean (SD) ALT, AST and bilirubin levels were 99 (116.8) U/L, 101 (69.8) U/L, and 3.2 (3.57) mg/dL, respectively. Baseline mean (SD) pruritus score (range: 0-4) and serum bile acids levels were similar in odevixibat-treated patients (2.9 [0.089] and 252.1 [103.0] µmol/L, respectively) and placebo-treated patients (3.0 [0.143] and 247.5 [101.1] µmol/L, respectively).

Table 6 presents the results of the comparison of the key efficacy results in Trial 1 between odevixibat and placebo. These data are displayed graphically over the 24-week treatment period in Figure 1 (serum bile acids) and Figure 2 (scratching scores).

Table 6: Comparison of key efficacy results for odevixibat vs. placebo over the 24-week treatment period in patients with PFIC in trial 1
Odevixibat
Placebo         40 mcg/kg/day 120 mcg/kg/day                 Total
Efficacy endpoint               (N=20)              (N=23)             (N=19)              (N=42) Proportion of patients with reduction in serum bile acids at end of treatment n (%)                              0               10 (43.5)           4 (21.1)           14 (33.3) (95% CI)                     (0.00, 16.84)      (23.19, 65.51)      (6.05, 45.57)      (19.57, 49.55) Difference in proportion
0.44              0.21                0.33 vs. placebo
(0.22, 0.66)      (0.02, 0.46)        (0.09, 0.50)
(95% CI)
One-sided p-valuea                                  0.0015             0.0174              0.0015 Proportion of positive pruritus assessments over the treatment period Proportion                       28.74               58.31              47.69               53.51 Difference in proportion                         28.23 (9.18)       21.71 (9.89)        24.97 (8.24) (SE) vs. placebo (95%                            (9.83, 46.64)      (1.87, 41.54)       (8.45, 41.49) CI)b a
Based on Cochran Mantel Haenszel test stratified by PFIC Type. P-values for the dose groups are adjusted for multiplicity.
b
Based on least squares means from an analysis of covariance model with daytime and night-time baseline pruritus scores as covariates and treatment group and stratification factors (PFIC Type and age category) as fixed effects.


Figure 1: Mean (±SE) change from baseline in serum bile acid concentration (µmol/L) over time


Placebo             Odevixibat 40 mcg/kg/day              Odevixibat 120 mcg/kg/day        Odevixibat All Doses N=20                N=23                                  N=19                             N=42 100
Mean (SE) of Change



50 from Baseline



0
-50
-100
-150
-200
-250
0                       4                8                   12               16       18      20     22       24 Weeks
Number of Patients
Placebo         20                                         20                18                  17                       16              12       11 40 mcg/kg/day                          23                  21                21                  20                       15              14       17
120 mcg/kg/day 19                                          19                16                  16                       11              11       15 All doses                              42                  40                37                  36                       26              25       32 

Figure 2: Mean (±SE) change from baseline in pruritus (scratching) severity score over time 
Placebo             Odevixibat 40 mcg/kg/day             Odevixibat 120 mcg/kg/day        Odevixibat All Doses N=20                N=23                                 N=19                             N=42 0.5
Mean (SE) of Change



0.0 from Baseline



-0.5
-1.0

-1.5

-2.0
0        1   2      3   4    5   6   7   8     9   10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Weeks
Number of Patients
Placebo                                20 20 20 20 20 20 20 20 20 20 20 20 20 18 18 17 17 17 16 15 15 15 15 13 12 40 mcg/kg/day                          23 23 23 23 23 23 23 22 22 23 23 23 23 19 19 19 19 20 19 18 19 19 19 19 17
120 mcg/kg/day 19 19 19 19 19 19 19 19 19 18 18 18 18 16 16 16 16 16 16 16 16 16 16 15 14 All doses                              42 42 42 42 42 42 42 41 41 41 41 41 41 35 35 35 35 36 35 34 35 35 35 34 31 

In line with the results for reduction of pruritus (scratching), odevixibat reduced the percentage of days the patient required soothing, and patients less often required help falling asleep and had fewer days needing to sleep with a caregiver. Treatment with odevixibat also led to improvements from baseline in liver function test results (Table 7). The effect of odevixibat on growth parameters over 24 weeks is also presented.


Table 7: Comparison of efficacy results for growth and hepatic biochemical parameters for odevixibat vs. placebo over the 24-week treatment period in patients with PFIC in trial 1
Odevixibat
Placebo       40 mcg/kg/day 120 mcg/kg/day                 Total
Efficacy endpoint                  (N=20)             (N=23)             (N=19)              (N=42) Alanine aminotransferase (U/L) (mean [SE])
Baseline                        76.9 (12.57)      127.7 (34.57)        89.1 (19.95)      110.2 (20.96) Change to Week 24                3.7 (4.95)        -27.9 (17.97)      -25.3 (22.47)      -26.7 (13.98) Mean difference vs.                                -14.8 (16.63)      -14.9 (17.25)      -14.8 (15.05) placebo (95% CI)a                                  (-48.3, 18.7)      (-49.6, 19.9)       (-45.1, 15.4) Aspartate aminotransferase (U/L) (mean [SE])
Baseline                        90.2 (11.59)      114.2 (17.24)        96.0 (16.13)      106.0 (11.87) Change to Week 24                4.7 (5.84)        -36.7 (12.21)      -27.0 (19.42)      -32.1 (11.02) Total bilirubin (µmol/L) (mean [SE])
Baseline                        53.3 (12.97)       52.2 (10.13)        57.0 (18.05)        54.4 (9.75) Change to Week 24               -9.6 (15.16)        -23.7 (9.23)      -19.3 (13.62)       -21.7 (7.92) Height z-scores (mean [SE])
Baseline                        -2.26 (0.34)        -1.45 (0.27)       -2.09 (0.37)        -1.74 (0.23) Change to Week 24               -0.16 (0.10)        0.05 (0.11)        0.00 (0.16)         0.03 (0.09) Mean difference vs.                                  0.32 (0.16)       0.15 (0.17)         0.24 (0.14) a placebo (95% CI)                                    (0.00, 0.65)      (-0.18, 0.48)       (-0.05, 0.53) Weight z-scores (mean [SE])
Baseline                        -1.52 (0.32)        -0.74 (0.27)       -1.19 (0.35)        -0.94 (0.21) Change to Week 24                0.10 (0.10)        0.29 (0.11)        0.15 (0.12)         0.22 (0.08) Mean difference vs.                                 0.28 (0.14)        0.08 (0.15)         0.18 (0.13) placebo (95% CI)a                                  (-0.01, 0.57)      (-0.22, 0.37)       (-0.08, 0.44) a
Based on least squares means from a mixed model for repeated measures (MMRM) with baseline value as a covariate, and treatment group, visit, treatment-by-visit interaction, treatment-by-baseline interaction and stratification factors (PFIC type and age category) as fixed effects.

Trial 2 is an interim cut of data from an ongoing 72-week open-label extension trial in PFIC patients treated with Bylvay 120 mcg/kg/day. The 79 patients (PFIC1 [22%], PFIC2 [51%], PFIC3 [5%] or PFIC6 [1%]) treated with 120 mcg/kg/day for up to 48 weeks experienced a durable effect on serum bile acids reduction, improvement in pruritus score, ALT, AST and total bilirubin. Across the 79 patients, 45 had assessments on or after 48 weeks of treatment with odevixibat, including 13, 30, 1 and 1 patients with PFIC1, PFIC2, PFIC3, and PFIC6, respectively; 9, 21, 4, and 0 patients, respectively, had not reached 48 weeks of treatment and were ongoing at the data cut-off. Overall, 7 patients with PFIC2 had discontinued prior to 48 weeks of treatment with odevixibat. Improvements in z-scores for height and weight indicate an enhanced growth velocity and the potential for catch-up growth in actively growing children.

ALGS
The efficacy of BYLVAY was evaluated in Trial 3 (NCT04674761), a 24-week, randomized, double- blind, placebo-controlled trial. Trial 3 was conducted in 52 pediatric patients, aged 6 months to 15 years, with a confirmed diagnosis of ALGS and presence of pruritus at baseline. Patients who had decompensated liver disease, who had other concomitant liver disease, whose INR was greater than 1.4, whose ALT was greater than 10-times the upper limit of normal (ULN) at screening, whose total bilirubin was greater than 15-times the ULN at screening, or who had received a liver transplant were excluded from Trial 3.

Patients were randomized to placebo (n=17) or 120 mcg/kg (n=35). Study drug was administered once daily with a meal in the morning. In patients weighing less than 19.5 kg or patients who could not swallow the whole capsule, study drug was sprinkled on soft food and then administered orally.

Median age (range) of the patients in Trial 3 was 6.1 (1.7 to 15.5) years in the BYLVAY group and 4.2 (0.5 to 14.3) years in the placebo group; 5 patients were older than 12 years of age. Of the 52 patients, 52% were male and 83% were white; 92% of patients had the JAG1 mutation and 8% had the NOTCH2 mutation. The mean (standard deviation [SD]) scratching score in the 2 weeks prior to baseline was 2.9 (0.6). Baseline mean (SD) eGFR was 159 (51.4) mL/min/1.73 m2. Baseline median (range) ALT, AST, and total bilirubin were 152 (39-403) U/L, 135 (57-427) U/L, and 2.0 (0.4-11.4) mg/dL, respectively.

Given the patients’ young ages, a single-item observer-reported outcome (ObsRO) was used to measure patients’ scratching severity as observed by their caregiver twice daily (once in the morning and once in the evening). Scratching severity was assessed on a 5-point ordinal response scale, with scores ranging from 0 (no scratching) to 4 (worst possible scratching). Patients were included in Trial 3 if the average scratching score was greater than or equal to 2 (medium scratching) in the 14 days prior to baseline.

Table 8 presents the results of the comparison between BYLVAY and placebo on the change from baseline in average scratching score based on ObsRO assessments to Month 6 (Weeks 21 to 24).
The average scratching score for each patient for each month post-baseline was calculated by: (Step 1) averaging the morning scores and averaging the evening scores within a week; (Step 2) averaging the morning and evening weekly scores to yield a single weekly score; and finally (Step 3) averaging the 4 weekly scores within the month. The baseline average scratching score for each patient was calculated by averaging the weekly scores obtained in Step 2 across the 2 weeks prior to randomization and initiation of blinded treatment. Patients treated with BYLVAY demonstrated greater improvement in pruritus compared with placebo. Figure 2 displays the means (95% confidence interval) of patients’ average scratching scores in each treatment group for each month.

Table 8: Efficacy Results in Patients with ALGS in Trial 3

BYLVA
Placebo                                           Y
(n=17)                                      120 mcg/kg/day
(n=35)
Baseline Average Scratching Score
Mean (SD)                                       3.0 (0.6)                                                                    2.8 (0.5) Change from Baseline in Average Scratching Score to Month 6 (Weeks 21 to 24)a Mean (SE)                                       -0.8 (0.2)                                                                   -1.7 (0.2) Mean Difference vs Placebo (95% CI)                          -0.9 (-1.4, -0.3) p-value                                                           0.002 a
Based on least square means from a mixed-effect model for repeated measures (MMRM) for change from baseline to each month accounting for baseline average scratching score, baseline age stratification (<10, ≥10 years), baseline direct bilirubin, treatment group, time (in months), and treatment-by-time interaction.


Figure 2: Mean* of the Average Scratching Scores for Each Month in Trial 3 


*Figure 2 presents means for baseline and least squares means for Month 1 to 6 Least squares means are based on a mixed model repeated measure (MMRM) analysis accounting for baseline average scratching score, baseline age stratification (<10, ≥10 years), baseline direct bilirubin, treatment group, time (in months), and treatment-by-time interaction.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Odevixibat is minimally absorbed following oral administration; absolute bioavailability data in humans are not available, and estimated relative bioavailability is < 1%. Peak odevixibat plasma concentration (Cmax) is reached within 1 to 5 hours. Simulated Cmax values in a paediatric PFIC patient population for the 40 and 120 mcg/kg/day doses are 0.211 ng/mL and 0.623 ng/mL, respectively, and AUC values were 2.26 ng × h/mL and 5.99 ng × h/mL, respectively. There is minimal accumulation of odevixibat following once-daily dosing.

Effect of food
Systemic exposure of odevixibat does not predict efficacy. Therefore, no dose adjustment for food effects is considered necessary. Concomitant administration of a high-fat meal (800 - 1,000 calories with approximately 50% of total caloric content of the meal from fat) resulted in decreases of approximately 72% and 62% in Cmax and AUC0-24, respectively, compared to administration under fasted conditions. When odevixibat was sprinkled on apple sauce, decreases of approximately 39% and 36% in Cmax and AUC0-24, respectively, were observed compared to administration under fasted conditions. Taking into account the lack of PK/PD relationship and need for sprinkling the odevixibat capsule contents on food for younger children, odevixibat can be administered with food.

Distribution

Odevixibat is more than 99% bound to human plasma proteins. The mean body weight adjusted apparent volumes of distribution (V/F) in paediatric patients for the 40 and 120 mcg/kg/day dose regimens are 40.3 and 43.7 L/kg, respectively.

Biotransformation

Odevixibat is minimally metabolised in humans.
Elimination

Following administration of a single oral dose of 3,000 mcg of radiolabeled odevixibat in healthy adults, the average percent recovery of the administered dose was 82.9% in faeces; less than 0.002% was recovered in the urine. More than 97% of faecal radioactivity was determined to be unchanged odevixibat.

The mean body weight normalised apparent total clearances CL/F in paediatric patients for the 40 and 120 mcg/kg/day dose regimens are 26.4 and 23.0 L/kg/h, respectively, and the mean half-life is approximately 2.5 hours.

Linearity/non-linearity

The Cmax and AUC0-t increase with increasing doses in a dose-proportional manner; however due to the high interindividual variability of approximately 40%, it is not possible to estimate the dose proportionality accurately.

Pharmacokinetic/pharmacodynamic relationship(s)
Consistent with the mechanism and site of action of odevixibat in the gastrointestinal tract no relationship between systemic exposure and clinical effects is observed. Also, no dose-response relationship could be established for the investigated dose range 10-200 mcg/kg/day and the PD parameters C4 and FGF19.

Special populations

No clinically significant differences in the pharmacokinetics of odevixibat were observed based on age, sex or race.

Pediatric patients
In pediatric patients with ALGS who received BYLVAY 120 mcg/kg once daily with food in the morning, the measurable odevixibat concentrations ranged from 0.05 to 3.4 ng/mL.


Hepatic impairment
The majority of patients with PFIC presented with some degree of hepatic impairment because of the disease. Hepatic metabolism of odevixibat is not a major component of the elimination of odevixibat.
Analysis of data from a placebo-controlled study in patients with PFIC Types 1 and 2 did not demonstrate a clinically important impact of mildly impaired hepatic function (Child Pugh A) on the pharmacokinetics of odevixibat. Although, body weight adjusted CL/F values were lower and body weight adjusted V/F values were larger in paediatric patients with PFIC with Child Pugh B compared to healthy subjects, the safety profile was comparable between the patient groups. Patients with severe hepatic impairment (Child-Pugh C) have not been studied.

Renal impairment
There are no clinical data in patients with renal impairment, but the impact of renal impairment is expected to be small due to low systemic exposure and odevixibat is not excreted in urine.

In vitro studies

In in vitro studies, odevixibat did not inhibit CYPs 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations, but was shown to be an inhibitor of CYP3A4/5.


Odevixibat does not inhibit the transporters P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OATP1B1, OATP1B3, OAT1, OAT3), organic cation transporter (OCT2), multidrug and toxin extrusion transporter (MATE1 or MATE2-K).

Odevixibat is not a BCRP substrate.