Ocaliva (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic potential of obeticholic acid was assessed in carcinogenicity studies of up to 2 years in duration in mice and rats. In mice, there were no drug-related neoplastic findings at doses up to 25 mg/kg/day obeticholic acid, a dose that produced systemic exposures approximately 12-times those in humans at the MRHD of 10 mg. In rats, obeticholic acid was administered at doses of 2, 7, and 20 mg/kg/day. At 20 mg/kg/day (approximately 12-times the human exposure at the MRHD), obeticholic acid caused an increase in the incidence of benign granulosa cell tumors in the ovaries and benign granular cell tumors in the cervix and vagina of female rats. There were no drug-related neoplastic findings in male rats.

Obeticholic acid was not genotoxic in the Ames test, a human peripheral blood lymphocyte chromosomal aberration test, and a mouse micronucleus test. The glycine conjugate of obeticholic acid was also not genotoxic in an Ames test and human peripheral blood lymphocyte chromosome aberration test. The taurine conjugate of obeticholic acid was not genotoxic in an Ames test, and was negative in a human peripheral blood lymphocyte chromosomal aberration test in the presence of metabolic activation; the findings of the chromosomal aberration assay in the absence of metabolic activation were inconclusive.

Obeticholic acid, administered at oral doses of 5, 25, and 50 mg/kg/day to male rats for 28 days before mating and throughout the mating period, and to female rats from 14 days before mating through mating and until gestation day 7, did not alter male or female fertility or early embryonic development at any dose (the 50 mg/kg/day dose is approximately 13-times the human exposure at the MRHD).

14 CLINICAL STUDIES

The recommended starting dosage of OCALIVA is 5 mg orally once daily for 3 months with titration to 10 mg once daily based upon tolerability and response [see Dosage and Administration (2.2)]. Initiation of therapy with a starting dosage OCALIVA 10 mg once daily is not recommended due to an increased risk of pruritus [see Adverse Reactions (6.1)].

Trial 1 was a randomized, double-blind, placebo-controlled, 12-month clinical trial which evaluated the safety and efficacy of OCALIVA in 216 patients with PBC who were taking 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 trial if the ALP was 1.67-times upper limit of normal (ULN) or greater and/or if total bilirubin was greater than 1-times ULN but less than 2-times ULN. Patients were excluded from the trial 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 receive either OCALIVA 10 mg once daily for the entire 12 months of the trial, (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 ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction) (n=70); or placebo (n=73). OCALIVA or placebo was administered in combination with UDCA in 93% of patients during the trial 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.

The study population 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 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. Distribution of patients by Rotterdam disease stage criteria at baseline is shown in Table 2. Cirrhosis was present at baseline in 4 patients (5%) in the OCALIVA 10 mg arm, 7 patients (10%) in the OCALIVA titration arm, and 9 patients (12%) in the placebo arm.

Table 2: Rotterdam Disease Stage Criteria at Baseline in Trial 1 by Treatment Arm with or without UDCA *
Disease Stage OCALIVA 10 mg(N=73) OCALIVA Titration(N=70) Placebo(N=73)
Percentages are based on non-missing values for each time point.
*
In the trial, there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.
Early: normal total bilirubin and normal albumin (values less than or equal to ULN and greater than or equal to the lower limit of normal (LLN), respectively), Moderately advanced: abnormal total bilirubin or abnormal albumin, Advanced: abnormal total bilirubin and abnormal albumin. Total bilirubin ULN: 1.1 mg/dL (females) and 1.5 mg/dL (males). Albumin LLN: 35 g/L (females and males).
Early, n (%) 66 (90) 64 (91) 65 (89)
Moderately Advanced, n (%) 7 (10) 6 (9) 8 (11)
Advanced, n (%) 0 (0) 0 (0) 0 (0)

Table 3 shows the percentage of patients by treatment arm in Trial 1 who achieved a response to the primary composite endpoint at Month 12, and to the individual components of the primary endpoint (i.e., ALP less than 1.67-times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%). A total of 33 patients in the OCALIVA titration arm, who did not achieve a response at 6 months and tolerated OCALIVA, had their dosage increased from 5 mg once daily to 10 mg once daily. Of these 33 patients, 13 (39%) achieved the primary composite endpoint at 12 months.

Table 3: Percentage of Adult Patients with PBC Achieving the Primary Composite Endpoint at Month 12 in Trial 1 by Treatment Arm with or without UDCA *
OCALIVA10 mg(N=73) OCALIVATitration (N=70) Placebo (N=73)
*
In the trial, there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.
Patients randomized to OCALIVA titration received OCALIVA 5 mg for the initial 6-month period. At Month 6, patients who were tolerating OCALIVA, but had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction were eligible for titration from 5 mg once daily to 10 mg once daily for the final 6 months of the trial.
Percentage of patients achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin less than or equal to the ULN, and an ALP decrease of at least 15%. Missing values were considered a non-response. The exact test was used to calculate the 95% CIs.
§
p<0.0001 for OCALIVA titration and OCALIVA 10 mg arms versus placebo. P-values are obtained using the Cochran–Mantel–Haenszel General Association test stratified by intolerance to UDCA and pretreatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN.
Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=ITT population]); percentage of patients with Month 12 values are 86%, 91%, and 96% for the OCALIVA 10 mg, OCALIVA titration and placebo arms, respectively.
#
The mean baseline total bilirubin value was 0.65 mg/dL, and was less than or equal to the ULN in 92% of the enrolled patients.
Primary Composite Endpoint
Responder rate, (%)§ 48 46 10
[95% CI] [36, 60] [34, 58] [4, 19]
Components of Primary Endpoint
ALP less than 1.67-times ULN, n (%) 40 (55) 33 (47) 12 (16)
Decrease in ALP of at least 15%, n (%) 57 (78) 54 (77) 21 (29)
Total bilirubin less than or equal to ULN #, n (%) 60 (82) 62 (89) 57 (78)

Mean Reduction in ALP

Figure 1 shows the mean reductions in ALP in OCALIVA-treated patients compared to placebo. Reductions were observed as early as Week 2, plateaued by Month 3 and were maintained through Month 12 for patients who were maintained on the same dosage throughout 12 months. Although Trial 1 studied titration at 6 months, these data are supportive of titration of OCALIVA after 3 months [see Dosage and Administration (2.2)]. For patients in the OCALIVA titration arm whose OCALIVA dosage was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at Month 12 in the majority of patients [see Clinical Pharmacology (12.2)].

Figure 1: Mean ALP over 12 Months in Trial 1 by Treatment Arm with or without UDCAa

Figure 1
(click image for full-size original)
a In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.
b Patients randomized to OCALIVA titration received OCALIVA 5 mg once daily for the initial 6-month period. At Month 6, patients who were tolerating OCALIVA, but had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction were eligible for titration from 5 mg once daily to 10 mg once daily for the final 6 months of the trial.

Mean Reduction in GGT

The mean (95% CI) reduction in gamma-glutamyl transferase (GGT) was 178 (137, 219) U/L in the OCALIVA 10 mg arm, 138 (102, 174) U/L in the OCALIVA titration arm, and 8 (-32, 48) U/L in the placebo arm.

OCALIVA Monotherapy

Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to OCALIVA as monotherapy (24 patients received OCALIVA 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from Trial 1 and from a randomized, double-blind, placebo-controlled, 3-month clinical trial. At Month 3, 9 (38%) OCALIVA-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in OCALIVA-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

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