Ravicti glycerol phenylbutyrate 1.1 g/mL Liquid — NDC 75987-050-06 (Billing 75987-0050-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3 , NH 4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. RAVICTI is a triglyceride containing 3 molecules of PBA.

PAA, the major metabolite of PBA, is the active moiety of RAVICTI. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Figure 1: RAVICTI Mechanism of Action Figure 1

12.2Pharmacodynamics Pharmacological Effects In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia levels was comparable at steady state during the switchover period between RAVICTI and sodium phenylbutyrate [see Clinical Studies (14) ] . Cardiac Electrophysiology The effect of multiple doses of RAVICTI 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects.

The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for RAVICTI, was below 10 ms.

12.3Pharmacokinetics Absorption RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by lipases. PBA derived from RAVICTI is further converted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m 2 of RAVICTI, peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of RAVICTI, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C max ) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively.

In healthy subjects, intact glycerol phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out. In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner.

Following 4 mL of RAVICTI 3 times a day for 3 days, the mean C max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of RAVICTI three times a day for 3 days, mean C max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively. In adult patients with UCDs receiving multiple doses of RAVICTI, maximum plasma concentrations at steady state (C max,ss ) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day.

Intact glycerol phenylbutyrate was not detectable in plasma in patients with UCDs. In clinical studies of RAVICTI in patients with UCDs, the peak observed PAA concentrations by age group are shown in Table 2. Table 2: Peak PAA Concentrations in Patients with UCDs Treated with RAVICTI in Clinical Trials Age Range RAVICTI Dose Mean Peak PAA Concentration micrograms/mL (SD) Median Peak PAA Concentration (Range) Less than 2 months (n = 16) 3.1 to 12.7 mL/m 2 /day (3.4 to 14 g/m 2 /day) 257 (162) 205 (96 to 707) 2 months to less than 2 years (n = 17) 3.3 to 12.3 mL/m 2 /day (3.7 to 13.5 g/m 2 /day) 142 (299) 35 (1 to 1215) 2 years to 17 years (n = 53) 1.4 to 13.7 mL/m 2 /day (1.5 to 15.1 g/m 2 /day) 70 (79) 50 (1 to 410) Adults (n = 43) 0.6 to 14 mL/m 2 /day (0.7 t… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia (NH 3 , NH 4 + ). Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. RAVICTI is a triglyceride containing 3 molecules of PBA.

PAA, the major metabolite of PBA, is the active moiety of RAVICTI. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys (Figure 1). On a molar basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste nitrogen excretion.

Figure 1: RAVICTI Mechanism of Action Figure 1

12.3Pharmacokinetics Absorption RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in the gastrointestinal tract by lipases. PBA derived from RAVICTI is further converted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 mL/m 2 of RAVICTI, peak plasma levels of PBA, PAA, and PAGN occurred at 2 hours, 4 hours, and 4 hours, respectively. Upon single-dose administration of RAVICTI, plasma concentrations of PBA were quantifiable in 15 of 22 participants at the first sample time postdose (0.25 hours). Mean maximum concentration (C max ) for PBA, PAA, and PAGN was 37.0 micrograms/mL, 14.9 micrograms/mL, and 30.2 micrograms/mL, respectively.

In healthy subjects, intact glycerol phenylbutyrate was detected in plasma. While the study was inconclusive, the incomplete hydrolysis of glycerol phenylbutyrate cannot be ruled out. In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose-dependent manner.

Following 4 mL of RAVICTI 3 times a day for 3 days, the mean C max and AUC were 66 micrograms/mL and 930 micrograms∙h/mL for PBA and 28 micrograms/mL and 942 micrograms∙h/mL for PAA, respectively. In the same study, following 6 mL of RAVICTI three times a day for 3 days, mean C max and AUC were 100 micrograms/mL and 1400 micrograms∙h/mL for PBA and 65 µg/mL and 2064 micrograms∙h/mL for PAA, respectively. In adult patients with UCDs receiving multiple doses of RAVICTI, maximum plasma concentrations at steady state (C max,ss ) of PBA, PAA, and PAGN occurred at 8 hours, 12 hours, and 10 hours, respectively, after the first dose in the day.

Intact glycerol phenylbutyrate was not detectable in plasma in patients with UCDs. In clinical studies of RAVICTI in patients with UCDs, the peak observed PAA concentrations by age group are shown in Table 2. Table 2: Peak PAA Concentrations in Patients with UCDs Treated with RAVICTI in Clinical Trials Age Range RAVICTI Dose Mean Peak PAA Concentration micrograms/mL (SD) Median Peak PAA Concentration (Range) Less than 2 months (n = 16) 3.1 to 12.7 mL/m 2 /day (3.4 to 14 g/m 2 /day) 257 (162) 205 (96 to 707) 2 months to less than 2 years (n = 17) 3.3 to 12.3 mL/m 2 /day (3.7 to 13.5 g/m 2 /day) 142 (299) 35 (1 to 1215) 2 years to 17 years (n = 53) 1.4 to 13.7 mL/m 2 /day (1.5 to 15.1 g/m 2 /day) 70 (79) 50 (1 to 410) Adults (n = 43) 0.6 to 14 mL/m 2 /day (0.7 to 15.4 g/m 2 /day) 39 (40) 25 (1.6 to 178) Distribution In vitro , the extent of plasma protein binding for 14 C-labeled metabolites was 81% to 98% for PBA (over 1 to 250 micrograms/mL), and 37% to 66% for PAA (over 5 to 500 micrograms/mL).

The protein binding for PAGN was 7% to 12% and no concentration effects were noted. Elimination Metabolism Upon oral administration, pancreatic lipases hydrolyze RAVICTI (i.e., glycerol phenylbutyrate), and release PBA. PBA undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney through the enzyme phenylacetyl-CoA: L-glutamine-N-acetyltransferase to form PAGN.

PAGN is subsequently eliminated in the urine. Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic impairment. In healthy subjects, after administration of 4 mL, 6 mL, and 9 mL 3 times daily for 3 days, the ratio of mean AUC 0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively.

In a separate study, in patients with hepatic impairment (Child-Pugh B and C), the ratios of mean C max values for PAA to PAGN among all patients dosed with 6 mL and 9 mL twice daily were 3 and 3.7. In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was in the following decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase-related protein 2. Further, glycerol phenylbutyrate was hydrolyzed in vitro by esterases in human plasma.

In these… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Pharmacological Effects In clinical studies, total 24-hour area under the plasma concentration-time curve (AUC) of ammonia levels was comparable at steady state during the switchover period between RAVICTI and sodium phenylbutyrate [see Clinical Studies (14) ] . Cardiac Electrophysiology The effect of multiple doses of RAVICTI 13.2 g/day and 19.8 g/day (approximately 69% and 104% of the maximum recommended daily dosage) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57 healthy subjects.

The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for RAVICTI, was below 10 ms.

14 CLINICAL STUDIES

14.1Clinical Studies in Adult Patients with UCDs Active-Controlled, 4-Week, Noninferiority Study (Study 1) A randomized, double-blind, active-controlled, crossover, noninferiority study (Study 1) compared RAVICTI to sodium phenylbutyrate by evaluating ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrollment for control of their UCD. Patients were required to have a confirmed diagnosis of UCD involving deficiencies of CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing.

Patients had to have no clinical evidence of hyperammonemia at enrollment and were not allowed to receive drugs known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g., corticosteroids), or significantly affect renal clearance (e.g., probenecid). The primary endpoint was the 24-hour AUC (a measure of exposure to ammonia over 24 hours) for venous ammonia on days 14 and 28 when the drugs were expected to be at steady state. Statistical noninferiority would be established if the upper limit of the 2-sided 95% CI for the ratio of the geometric means (RAVICTI/sodium phenylbutyrate) for the endpoint was 1.25 or less.

Forty-five patients were randomized 1:1 to 1 of 2 treatment arms to receive either – Sodium phenylbutyrate for 2 weeks → RAVICTI for 2 weeks; or – RAVICTI for 2 weeks → sodium phenylbutyrate for 2 weeks. Sodium phenylbutyrate or RAVICTI were administered three times daily with meals. The dose of RAVICTI was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dose the patients were taking when they entered the study.

Forty-four patients received at least 1 dose of RAVICTI in the study. Patients adhered to a low-protein diet and received amino acid supplements throughout the study. After 2 weeks of dosing, by which time patients had reached steady state on each treatment, all patients had 24 hours of ammonia measurements.

Demographic characteristics of the 45 patients enrolled in Study 1 were as follows: mean age at enrollment was 33 years (range: 18 to 75 years); 69% were female; 33% had adult-onset disease; 89% had OTC deficiency; 7% had ASS deficiency; 4% had CPS deficiency. RAVICTI was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUC for ammonia. Forty-four patients were evaluated in this analysis.

Mean 24-hour AUCs for ammonia during steady-state dosing were 866 micromol∙h/L and 977 micromol∙h/L with RAVICTI and sodium phenylbutyrate, respectively. The ratio of geometric means was 0.91 [95% CI 0.8, 1.04]. The mean ammonia levels over 24-hours after 2 weeks of dosing (on Day 14 and 28) in the double-blind short-term study (Study 1) are displayed in Figure 2 below.

The mean and median maximum ammonia levels (C max ) over 24 hours and 24-hour AUC for ammonia are summarized in Table 3. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L: Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay) Figure 2: Ammonia Levels in Adult Patients with UCDs in Short-Term Treatment Study 1 Table 3: Ammonia Levels in Adult Patients with UCDs in Short-Term Treatment Study 1 Timepoint Ammonia (n = 44) Mean (SD) Median (min, max) Daily C max (micromol/L) RAVICTI 61 (46) 51 (12, 245) Sodium phenylbutyrate 71 (67) 46 (14, 303) 24-Hour AUC (micromol∙h/L) RAVICTI 866 (661) 673 (206, 3351) Sodium phenylbutyrate 977 (865) 653 (302, 4666) Open-Label, Uncontrolled, Extension Study in Adults A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period.

A total of 51 adults were in the study and all but 6 had been converted from sodium phenylbutyrate to RAVICTI. Venous ammonia levels were monitored monthly. Mean fasting ammonia… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year study in Sprague-Dawley rats, glycerol phenylbutyrate caused a statistically significant increase in the incidence of pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma at a dose of 650 mg/kg/day in males (4.7 times the dose of 6.9 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA) and 900 mg/kg/day in females (8.4 times the dose of 6.9 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA).

The incidence of the following tumors was also increased in female rats at a dose of 900 mg/kg/day: thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal cortical combined adenoma or carcinoma, uterine endometrial stromal polyp, and combined polyp or sarcoma. The dose of 650 mg/kg/day in male rats is 3 times the dose of 7.5 mL/m 2 /day in pediatric patients, based on combined AUCs for PBA and PAA. The dose of 900 mg/kg/day in female rats is 5.5 times the dose of 7.5 mL/m 2 /day in pediatric patients, based on combined AUCs for PBA and PAA.

In a 26-week study in transgenic (Tg.rasH2) mice, glycerol phenylbutyrate was not tumorigenic at doses up to 1000 mg/kg/day. Mutagenesis Glycerol phenylbutyrate was not genotoxic in the Ames test, the in vitro chromosomal aberration test in human peripheral blood lymphocytes, or the in vivo rat micronucleus test. The metabolites PBA, PAA, PAGN, and phenylacetylglycine were not genotoxic in the Ames test or in vitro chromosome aberration test in Chinese hamster ovary cells.

Impairment of Fertility Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats at oral doses up to 900 mg/kg/day. At doses of 1200 mg/kg/day (approximately 7 times the dose of 6.9 mL/m 2 /day in adult patients, based on combined AUCs for PBA and PAA), maternal toxicity was observed and the number of nonviable embryos was increased.