Summary Basis of Decision for Ocaliva

Clinical Pharmacology

Obeticholic acid, the medicinal ingredient of Ocaliva, is an agonist for farnesoid X receptor (FXR), a nuclear receptor expressed in the liver and intestine. The FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. Activation of FXR decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Ocaliva for the specified indication.

In order to support the approval of the Ocaliva (obeticholic acid) 10 mg tablets proposed for market, a bioequivalence study (Study 747-115) conducted under fasting conditions compared the proposed Ocaliva (obeticholic acid) 10 mg tablets to the obeticholic acid 10 mg tablets administered in the Phase III pivotal clinical study (Study 747-301). The study met the applicable bioequivalence standards for obeticholic acid on log transformed parameters calculated from measured data. In addition, the measured drug content of the lots of the test and reference products used in the study (percent of label claim) were within 5% of each other.

In order to support the dosing recommendations (i.e., with and without food) and statements regarding the effect of food on the pharmacokinetics of obeticholic acid, the sponsor submitted a bioavailability study (Study 747-104) comparing the proposed Ocaliva (obeticholic acid) 10 mg tablets administered under single-dose fasting and high-fat, high-calorie fed conditions. The data from Study 747-104 demonstrated that the bioavailability of obeticholic acid from the proposed Ocaliva (obeticholic acid) 10 mg tablets was not comparable when administered under fasting and high-fat, high-calorie fed conditions.

A waiver was requested from conducting a comparative bioavailability study with the 5 mg strength on the basis of its proportionality to the 10 mg strength tablet that was administered in Studies 747-104 and 747-115. Health Canada considers the 5 mg and 10 mg strengths to be proportional. The data submitted comply with the requirements outlined in Health Canada's policy on Bioequivalence of Proportional Formulations - Solid Oral Dosage Forms (1996).

For further details, please refer to the Ocaliva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Ocaliva was evaluated in a Phase III, randomized, double-blind, placebo-controlled, 12-month study (Study 747-301, POISE). The study included 216 patients with primary biliary cholangitis (PBC) who were taking ursodeoxycholic acid (UDCA) for at least 12 months (on a stable dosage for at least 3 months), or who were unable to tolerate UDCA and did not receive UDCA for at least 3 months. Patients were included in the study if their alkaline phosphatase (ALP) was 1.67-times the upper limit of normal (ULN) or greater and/or if their total bilirubin was greater than 1-times the ULN but less than 2-times the ULN. Patients were excluded from the study if they had other liver disease, presence of clinically significant hepatic decompensation events (i.e., portal hypertension and its complications, cirrhosis with complications, or hepato-renal syndrome), severe pruritus, or Model for End Stage Liver Disease (MELD) score of 15 or greater.

Patients were randomized (1:1:1) to three groups:

• Ocaliva 10 mg once daily for the entire 12 months of the study, (number of patients [n] = 73)
• Ocaliva titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months if the patient was tolerating Ocaliva but had ALP 1.67-times the ULN or greater, and/or total bilirubin greater than the ULN, or less than a 15% ALP reduction) (n = 70)
• Placebo (n = 73)

Ocaliva or placebo was administered in combination with UDCA in 93% of patients during the study and as monotherapy in 7% of patients who were unable to tolerate UDCA.

The primary endpoint was a responder analysis at Month 12, where response was defined as a composite of three criteria: ALP less than 1.67-times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%. The ULN for ALP was defined as 118 U/L for females and 124 U/L for males. The ULN for total bilirubin was defined as 1.1 mg/dL for females and 1.5 mg/dL for males.

Data from two observational studies (Global PBC Study Group and UK-PBC Cohort) were used to provide evidence that elevated ALP and abnormal bilirubin correlate with worsened outcome in PBC patients in terms of transplant-free survival time. The Global PBC Study Group is an international multicentre collaboration between 15 centres in 8 North American and European countries with pooled clinical data from a retrospective database of 6,191 patients with PBC. The UK-PBC Cohort is a database of individual patient data in >5,900 patients with PBC living in the United Kingdom. The results demonstrated that abnormal bilirubin is associated with worse prognosis in patients with PBC versus normal bilirubin. More importantly, the analysis of Global PBC Study Group demonstrated an association between higher ALP and normal bilirubin values and higher hazard of liver transplant and/or death. The main conclusion of the validation of ALP as a biochemical endpoint is that ALP (ALP ≤1.67 times the ULN with at least a 15% decrease from baseline) at 12 months is a good predictor of clinical outcome in patients with early stages of PBC; therefore, the surrogate efficacy endpoint used in the pivotal study can be considered acceptable until more direct evidence from clinical studies on the effect of Ocaliva on hard outcomes such as the increase in transplant-free survival or time to death is available.

The study population in the pivotal study was 91% female and 94% white. The mean age was 56 years (range 29 to 86 years). The mean baseline ALP concentration was 323.2 U/L, corresponding to 2.74-times the ULN. Approximately 29% of the patients had ALP concentration levels greater than 3-times the ULN. The mean baseline total bilirubin concentration was 0.65 mg/dL, and was less than or equal to the ULN in 92% of the enrolled patients. Cirrhosis was present at baseline in 4 patients (5%) in the Ocaliva 10 mg group, 7 patients (10%) in the Ocaliva titration group, and 9 patients (12%) in the placebo group.

The demographic characteristics of the subjects in the pivotal study were reflective of a population with PBC which was mostly represented by White middle age female population; 93% of subjects in the pivotal study were taking UDCA and could be qualified as non-responders to the treatment based on responder criteria.

Ocaliva doses evaluated in this study were either 10 mg for the entire 12-month period or Ocaliva titration in which all patients received 5 mg for the initial 6-month treatment period. At Month 6, patients either remained at 5 mg if the primary endpoint was achieved and/or the subject had tolerability issues or were uptitrated to 10 mg for the remainder of the 12-month period if the patient did not achieve the primary composite endpoint and was able to tolerate Ocaliva.

In the pivotal study, treatment with Ocaliva (titration or 10 mg) resulted in clinically meaningful and statistically significant improvements in ALP levels as early as the second week of treatment. At Month 6, 51% of the patients in the Ocaliva 10 mg group and 34% of the patients in the Ocaliva titration group achieved the composite endpoint compared to 7% in the placebo group.

At Month 12, the percentage of patients who achieved the composite endpoint was 46% and 48% for the Ocaliva titration and 10 mg Ocaliva groups, respectively, compared with 10% in the placebo group. The difference between placebo and each Ocaliva group was statistically significant (p <0.0001). For both Ocaliva treatment groups, the difference in least square (LS) mean (standard error [SE]) absolute reductions from baseline in ALP were statistically significant (p <0.0001) at all timepoints relative to placebo. At Month 12, the LS mean percent decrease from baseline was 33% and 39% for the Ocaliva titration and 10 mg groups, respectively, as compared with decrease of 5% for the placebo group.

At Month 6 and Month 12, >25% and 30% of Ocaliva-treated patients achieved ALP reductions of ≥40%, respectively, compared to 0% and 1% of placebo-treated patients. During the initial 6 months of treatment, the Ocaliva 10 mg group had larger ALP reductions from baseline, compared with the Ocaliva titration group (i.e., 5 mg), supportive of a dose response between Ocaliva 5 mg and 10 mg. The percentage of patients achieving the composite endpoint increased from 35% to 50% for the Ocaliva titration group (Month 6 and Month 12, respectively) and was maintained for the Ocaliva 10 mg group (58% at Month 6, 55% at Month 12). The increase observed from Month 6 to Month 12 in the Ocaliva titration group is attributable to the subgroup of patients who uptitrated to 10 mg following the 6-month visit vs. those who remained on Ocaliva 5 mg.

Decreases in the absolute change from baseline in total bilirubin were observed for both Ocaliva treatment groups, compared with increases for the placebo treatment group. There was also an improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) values compared to baseline in both treatment groups; no improvement compared to baseline was observed in the placebo group. The improvements were seen as early as 2 weeks post-treatment and reached a maximum at the Month 3 timepoint. Therefore, a positive effect of the drug on both markers of cholestatis, ALP and GGT was demonstrated in the pivotal study.

In the subgroup analysis of patients ≥65 years of age, only 5 patients received Ocaliva at a dose ≤5 mg and 21 patients received Ocaliva 10 mg. By Month 12, 40% (4) of patients in the Ocaliva titration group and 29% (5) patients in the Ocaliva 10 mg group achieved the composite endpoint The limited analysis of data in patients ≥65 years of age demonstrated a trend for a better response with a lower Ocaliva dose than with a higher Ocaliva dose (5 mg vs. 10 mg). As the proposed starting dose is 5 mg for any age group, if an adequate response is achieved no further dose increase is necessary; therefore, no dose adjustment is recommended for patients older than 65 years of age.

Durability of the effects of Ocaliva was evaluated in Long Term Safety & Efficacy (LTSE) studies which are currently ongoing but analysis of interim data (2-year follow-up data) demonstrated persistence of effect with the 5-10 mg doses on ALP and total bilirubin level reduction. The treatment effect achieved in the pivotal study (percentage of patients achieving the primary composite endpoint) was sustained over the subsequent 12-month open-label period (62% for Ocaliva titration and 50% for Ocaliva 10 mg at LTSE Month 12).

Overall, the results of the pivotal study support the specified indication for Ocaliva at the proposed dose in PBC patients in early-moderate stages of the disease and who are on UDCA therapy but with inadequate response to therapy. Considering that study results are reliant on surrogate biochemical endpoint, confirmatory evidence of Ocaliva efficacy will be assessed when hard outcome data become available. See question 4. What follow-up measures will the company take?

Ocaliva as Monotherapy

The efficacy of Ocaliva as monotherapy was evaluated in adults with PBC who were unable to tolerate UDCA. In the pivotal Phase III, randomized, double-blind, placebo-controlled, 12-month study (Study 747-301, POISE), a total of 16 (7.4%) of the study population were not taking UDCA at baseline; 5 placebo patients, 5 Ocaliva titration patients, and 6 Ocaliva 10 mg patients. At Month 12, the number of patients on Ocaliva monotherapy included 3 placebo patients, 5 Ocaliva titration patients, and 5 Ocaliva 10 mg patients. Forty percent (40%, 2 patients) in the Ocaliva titration group and 17% (1 patient) in the Ocaliva 10 mg group achieved the primary composite endpoint compared to 0% patients in the placebo group. The minimal effective dose of 5 mg Ocaliva was only evaluated in 5 patients enrolled in the Ocaliva titration group. The efficacy of Ocaliva 5 mg was supported by a small magnitude decrease in ALP (-46.7 [72.9] U/L) compared to the Ocaliva 10 mg group (-157.6 [66.1] U/L) while an increase in ALP was observed in the placebo group.

The results in the pivotal study were consistent with the results of the Phase II Study 747-201 which was specifically designed to assess the efficacy of Ocaliva when used as monotherapy. This study was a multicentre, randomized, double-blind, placebo-controlled, multidose (10 mg and 50 mg of Ocaliva), parallel-group study of Ocaliva monotherapy in patients with a proven or likely diagnosis of PBC. The study included 20 patients who received 10 mg Ocaliva for 3 months. The primary efficacy endpoint was the percent change in serum ALP level from baseline by Week 12 or last observed ALP value on treatment. The results demonstrated a statistically significant decrease in ALP from baseline at Month 3 in the Ocaliva 10 mg group compared to the placebo group. The mean percent change from baseline in ALP was -44.5% and -37.6% for the 10 mg and 50 mg Ocaliva groups, respectively, in comparison to a 0.4% increase in the placebo group. Treatment with Ocaliva 10 mg resulted in a significantly higher percentage (44%) of patients meeting the composite ALP and bilirubin criteria (the efficacy endpoint used in the pivotal study) compared to placebo (5%).

Even though, the efficacy of the drug was demonstrated to be promising at Month 3 based on the results of pooled data (Studies 747-301 and 747-201); the long-term Ocaliva efficacy (beyond 3-months duration) as monotherapy remains to be established as it is based on a very small number of patients (2 in the Ocaliva titration group and 1 in the Ocaliva 10 mg group). The clinical benefit of Ocaliva as monotherapy will be further evaluated in a post-market approval study. See question 4. What follow-up measures will the company take?

Overall Analysis of Efficacy

The submitted studies support the use of Ocaliva for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. The recommended indication is the same as the indication filed with the submission.

Due to the slow progressive nature of PBC, the efficacy of Ocaliva on hard outcomes has not been established at this time. However, the results of the pivotal study demonstrated clinical benefit of Ocaliva on surrogate outcome of PBC progression (ALP and bilirubin; mostly, in terms of ALP reduction). The majority of patients in the study were at early stages of PBC. Concurrently, there is a subpopulation of PBC patients (up to 50%) who are non-responsive or intolerant to UDCA, the only drug approved in Canada for treatment of PBC. Hence, there is an unmet need for this drug in the PBC population.

Overall, a favourable benefit-risk profile of Ocaliva has been demonstrated when considering the surrogate endpoints; however, the efficacy of Ocaliva in terms of hard outcomes remain to be confirmed in future clinical studies. The sponsor is currently conducting two long-term clinical studies to provide confirmatory evidence of Ocaliva safety and efficacy based on hard outcomes such as transplant-free survival. Ocaliva was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Further evaluation will take place upon the submission of the requested studies after they become available.

For more information, refer to the Ocaliva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Ocaliva was evaluated in a total of 432 patients with PBC in three double-blind placebo-controlled Phase II and Phase III clinical studies. Of these patients, 290 were treated with Ocaliva for at least 6 months, 232 were treated for at least 12 months, and 70 were treated for at least 2 years. There were 131 patients who received Ocaliva 10 mg once daily and 70 patients who received Ocaliva 5 mg once daily.

The most common adverse drug reactions (≥5% in any Ocaliva group and at a rate that was at least 3% greater than that observed in the placebo group) were pruritus/skin eruptions, fatigue/tiredness, abdominal pain and discomfort, oropharyngeal pain, arthralgia, procedural pain, edema peripheral, palpitations, eczema, and pyrexia.

In the placebo-controlled studies, more Ocaliva-treated patients experienced severe treatment-emergent adverse events (TEAEs) compared with patients treated with placebo. Pruritus was the most frequently reported adverse event (AE). Sixty-eight percent of Ocaliva-treated patients reported pruritus compared with 40% of placebo-treated patients. The incidence of gastrointestinal disorders was also higher in the Ocaliva-treated group (43% vs. 39%). Adverse events (AEs) classed as Hepatobiliary Disorders were only reported in Ocaliva-treated patients (35% vs. 0% in the placebo group).

The incidence of pruritus increased with increasing dose and was highest at the 50 mg dose (84%) and lowest in patients who were dosed using a 5 mg to 10 mg titration regimen (56%). Severity of pruritus increased with increasing dose, which was demonstrated by a 37% incidence of patients with severe pruritus at the 50 mg dose level in contrast with only 19% in the titration group.

In the pivotal Phase III 12-month study (POISE), patients in the titration Ocaliva group demonstrated a lower incidence of pruritus overall as well as a lower incidence of severe pruritus compared with the Ocaliva 10 mg dose group. The mean time to onset to any event of pruritus, regardless of severity, occurred within approximately 7 weeks in the Ocaliva 10 mg group, after approximately 2 months in the Ocaliva titration group, and within 3 months in the placebo group. The mean time to severe events of pruritus was earlier in the Ocaliva 10 mg group compared with the Ocaliva titration group and placebo group (approximately 46 days, approximately 160 days, and approximately 102 days, respectively). The analysis of the effect of interventions used for pruritus management (i.e., temporary drug interruption, antipruritic medications) demonstrated that all management strategies were similarly successful.

The incidence of fatigue, another symptom of PBC, was also dose-dependent in the pivotal Phase III study. Fatigue occurred at a similar incidence in the Ocaliva and combined placebo treatment groups.

Liver toxicity, expressed in elevated levels of ALT and AST, was observed in healthy volunteers when Ocaliva was administered at doses higher than the recommended dose. At the 250 mg dose, 50% of subjects experienced both ALT and AST elevations, with the highest ALT level slightly more than 5 times the ULN. Both the ALT and AST values declined towards baseline levels after cessation of dosing. In the same study, less marked increases in ALT and AST enzymes were also observed at the Ocaliva 100 mg dose. These results are consistent with the results of animal toxicology studies where liver toxicity of Ocaliva in terms of elevations in liver enzymes was demonstrated.

Overall, 25 hepatic AEs in 14 patients were observed. The incidence was higher in Ocaliva group than in placebo group (5% vs. 1%). The incidence appeared to be dose-related with the highest incidence of hepatic AEs observed in the 50 mg Ocaliva group. Three patients (5%) in the Ocaliva 50 mg group and 1 patient (1%) in the Ocaliva titration group experienced a severe hepatic disorder compared with none in the placebo group. The time to the onset of the severe hepatic event in the Ocaliva titration group was substantially longer compared with that of the Ocaliva 50 mg group (360 days and 23 days, respectively). During the double-blind, placebo-controlled studies, 9 Ocaliva (13%) had a hepatic disorder TEAE that was considered to be related to Ocaliva.

Pharmacokinetic studies demonstrated a higher exposure to the drug and its metabolites in patients with hepatic impairment. This is especially relevant to the patients with moderate to severe hepatic impairment for whom a dose adjustment is recommended. No dose adjustment is necessary in patients with mild hepatic impairment. The benefit of drug administration to patients with advanced PBC should outweigh the risk of additional liver damage associated with drug administration.

Typically, PBC patients develop dyslipidemia during the course of the disease which may or may not to be associated with an increased risk of cardiovascular disorders. The safety data available to date do not suggest an increased risk of cardiovascular disorders in patients treated with Ocaliva. The incidence of cardiovascular disorders was similar between placebo and Ocaliva treatment groups. However, the uncertainty about risk of cardiovascular disorders associated with continuous long-term administration of Ocaliva remains. The cardiovascular risk from long-term Ocaliva use will be evaluated during post-market studies.

The safety profile of Ocaliva administered as monotherapy was compared with Ocaliva administered concomitantly with UDCA. The incidence of pruritus was higher in patients not taking UDCA compared with those taking UDCA concomitantly (81% vs. 66% in the Ocaliva + UDCA group). Hepatic disorders occurred more frequently in patients treated concomitantly with UDCA vs. those treated with OCA as monotherapy (5% vs. 2%). The incidence of fatigue was lower in patients taking Ocaliva as monotherapy than that in patients who received concomitant UDCA (4% vs. 16% in patients treated with Ocaliva + UDCA) while the incidence of fatigue in the placebo group demonstrated a similar rate of fatigue as those treated with and without UDCA (14% and 13%, respectively).

Overall, the safety profile of Ocaliva is acceptable and manageable for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. The long-term safety will be further studied in ongoing safety studies. The risk of liver toxicity is sufficiently described in the Ocaliva Product Monograph along with mitigation strategies (dose adjustment in patients with moderate-severe hepatic impairment). Ocaliva was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow up to confirm the clinical benefit. Further evaluation will take place upon the submission of the requested studies after they become available.

For more information, refer to the Ocaliva Product Monograph, approved by Health Canada and available through the Drug Product Database.