Ravicti Drug Information

Clinical 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. 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 51 Sodium phenylbutyrate 71 46 24-Hour AUC (micromol∙h/L) RAVICTI 866 673 Sodium phenylbutyrate 977 653 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 values in adults in Study 2 were within normal limits during long-term treatment with RAVICTI (range: 6 to 30 micromol/L). Of 51 adult patients participating in the 12-month, open-label treatment with RAVICTI, 7 patients (14%) reported a total of 10 hyperammonemic crises. The fasting ammonia measured during Study 2 is displayed in Figure 3. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L. Figure 3: Ammonia Levels in Adult Patients with UCDs in Long-Term Treatment Study 2 Open-Label, Long-Term Study in Adults An open-label long-term, study (Study 5) was conducted to assess ammonia control in adult patients with UCDs.

The study enrolled patients with UCDs who had completed the safety extensions of Study 1, Study 3 or Study 4 (Study 2, 3E and 4E, respectively). A total of 43 adult patients between the ages of 19 and 61 years were in the study. The median length of study participation was 1.9 years (range: 0 to 4.5 years). Venous ammonia levels were monitored at a minimum of every 6 months. Mean fasting ammonia values in adult patients in Study 5 were within normal limits during long-term (24 months) treatment with RAVICTI (range: 24.2 to 31.4 micromol/L). Of the 43 adult patients participating in the open-label treatment with RAVICTI, 9 patients (21%) reported a total of 21 hyperammonemic crises.

Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L. Figure 2 Figure 3

Clinical Studies in Pediatric Patients 2 Years to 17 Years of Age

with UCDs The efficacy of RAVICTI in pediatric patients 2 years to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to RAVICTI switchover studies (Studies 3 and 4). Study 3 was 7 days in duration and Study 4 was 10 days in duration. These studies compared ammonia levels of patients on RAVICTI to ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs. Four patients less than 2 years of age were excluded from this analysis due to insufficient data.

The dose of RAVICTI was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate that patients were taking when they entered the trial. Sodium phenylbutyrate or RAVICTI were administered in divided doses with meals. Patients adhered to a low-protein diet throughout the study.

After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments. UCD subtypes included OTC (n = 12), ASL (n = 8), and ASS deficiency (n = 2), and patients received a mean RAVICTI dose of 8 mL/m 2 /day (8.8 g/m 2 /day), with doses ranging from 1.4 to 13.1 mL/m 2 /day (1.5 to 14.4 g/m 2 /day). Doses in these patients were based on previous dosing of sodium phenylbutyrate. The 24-hour AUCs for ammonia (AUC 0-24h ) in 11 pediatric patients 6 years to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments.

In pediatric patients 6 years to 17 years of age, the ammonia AUC 0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on RAVICTI vs sodium phenylbutyrate, respectively. In patients between 2 years and 5 years of age with UCDs, the ammonia AUC 0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on RAVICTI versus sodium phenylbutyrate, respectively. The mean ammonia levels over 24 hours in open-label, short-term Studies 3 and 4 at common time points are displayed in Figure 4. 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 4: Ammonia Levels in Pediatric Patients 2 Years to 17 Years of Age with UCDs in Short-Term Treatment Studies 3 and 4 Open-Label, Uncontrolled, Extension Studies in Pediatric Patients 2 Years to 17 Years of Age Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises over a 12-month period.

In two studies (Study 2, which also enrolled adults, and an extension of Study 3, referred to here as Study 3E), a total of 26 pediatric patients ages 6 years to 17 years were enrolled and all but 1 had been converted from sodium phenylbutyrate to RAVICTI. Mean fasting venous ammonia levels were within normal limits (range: 17 to 23 micromol/L) during long-term treatment with RAVICTI. Of the 26 pediatric patients 6 years to 17 years of age participating in these two trials, 5 patients (19%) reported a total of 5 hyperammonemic crises. The fasting ammonia levels measured during these two extension studies in patients 6 years to 17 years are displayed in Figure 5. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L. Figure 5: Ammonia Levels in Pediatric Patients 2 Years to 17 Years of Age with UCDs in Long-Term Treatment Studies 2 and 3E In an extension of Study 4 (referred to as Study 4E), after a median time on study of 4.5 months (range: 1 to 5.7 months), 2 of 16 pediatric patients ages 2 years to 5 years had experienced three hyperammonemic crises. Open-Label, Long-Term Study in Pediatric Patients 1-Year to 17 Years of Age An open-label, long-term study (Study 5) was conducted to assess ammonia levels in pediatric patients with UCD. The study enrolled patients with UCDs who had completed Studies 2, 3E and 4E. A total of 45 pediatric patients ages 1-year to 17 years were included in the study.

The median length of treatment was 1.7 years (range: 0.2 to 4.6 years). Venous ammonia levels were monitored at a minimum every 6 months. Mean ammonia values in pediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with RAVICTI (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with RAVICTI, 11 patients (24%) reported a total of 22 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L. Figure 4 Figure 5

Clinical Studies in Pediatric Patients Less Than 2 Years of Age with

UCDs The efficacy of RAVICTI in pediatric patients less than 2 years of age with UCDs was evaluated in uncontrolled, open-label studies (Studies 4/4E, 5 and 6). A total of 17 pediatric patients with UCDs aged 2 months to less than 2 years participated in Studies 4/4E, 5 and 6. Study 6 enrolled 16 pediatric patients less than 2 months of age. Uncontrolled, Open-Label Studies in Pediatric Patients Aged 2 Months to Less than 2 Years of Age (Studies 4/4E, 5) A total of 7 patients with UCDs aged 2 months to less than 2 years participated in Studies 4/4E and 5. In these studies, there were 7, 6, 6, 6 and 3 pediatric patients who completed 1, 6, 9, 12 and 18 months, respectively (mean and median exposure of 15 and 17 months, respectively). Patients were converted from sodium phenylbutyrate to RAVICTI. The dosage of RAVICTI was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the study. Patients received a mean RAVICTI dose of 7.5 mL/m 2 /day (8.2 g/m 2 /day), with doses ranging from 3.3 to 12.3 mL/m 2 /day (3.7 to 13.5 g/m 2 /day). Patients were dosed three times per day (n = 3) or four times per day (n = 4). Venous ammonia levels were monitored on Days 1, 3, and 10 in Study 4 and at week 1 in Study 4E. Two patients had elevated ammonia values on Day 1 of treatment (122 micromol/L and 111 micromol/L, respectively) and neither had associated signs and symptoms of hyperammonemia.

At Day 10/week 1, six of the 7 patients had normal ammonia levels (less than 100 micromol/L) while the remaining patient had an elevated ammonia value on Day 10 (168 micromol/L) and was asymptomatic. During the extension period, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability.

The mean ammonia levels in pediatric patients at month 1, 3, 6, 9 and 12 were 58, 49, 34, 65, and 31 micromol/L during treatment with RAVICTI, respectively. Three patients reported a total of 3 hyperammonemic crises defined as having signs and symptoms consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, combativeness, and/or somnolence) associated with high ammonia levels (greater than 100 micromol/L) and requiring medical intervention. Hyperammonemic crises were precipitated by gastroenteritis, vomiting, infection or no precipitating event (one patient). There were 4 patients who had one ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis.

Uncontrolled, Open-Label Study in Pediatric Patients Less Than 2 Years of Age (Study 6) Study 6 was an uncontrolled, open-label study in pediatric patients less than 2 years of age. The primary efficacy endpoint was successful transition to RAVICTI within a period of 4 days followed by 3 days of observation for a total of 7 days, where successful transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia level less than 100 micromol/L. Ammonia levels were monitored for up to 4 days during transition and on Day 7. Pediatric Patients 2 Months to Less than 2 Years of Age A total of 10 pediatric patients with UCDs aged 2 months to less than 2 years participated in Study 6, of which 6 patients converted from sodium phenylbutyrate to RAVICTI and 1 patient converted from sodium phenyl butyrate and sodium benzoate. The dosage of RAVICTI was calculated to deliver the same amount of PBA as the sodium phenylbutyrate dosage the patients were taking when they entered the trial.

Two patients were treatment-naïve and received RAVICTI dosage of 7.5 mL/m 2 /day and 9.4 mL/m 2 /day, respectively. One additional patient was gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while RAVICTI was initiated. The dosage of RAVICTI after transition was 8.5 mL/m 2 /day.

There were 9, 7, 7, 4, 1 and 4 pediatric patients who completed 1, 3, 6, 12, 18 and 24 months, respectively (mean and median exposure of 9 and 9 months, respectively). Patients received a mean RAVICTI dose of 8 mL/m 2 /day (8.8 g/m 2 /day), with doses ranging from 4.8 to 11.5 mL/m 2 /day (5.3 to 12.6 g/m 2 /day). Patients were dosed three times a day (n = 6), four times a day (n = 2), or five or more times a day (n = 2). Nine patients successfully transitioned as defined by the primary endpoint. One additional patient developed hyperammonemia on Day 3 of dosing and experienced surgical complications (bowel perforation and peritonitis) following jejunal tube placement on Day 4. This patient developed hyperammonemic crisis on Day 6, and subsequently died of sepsis from peritonitis unrelated to drug. Although two patients had Day 7 ammonia values of 150 micromol/L and 111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.

During the extension phase, venous ammonia levels were monitored monthly. Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. The mean normalized ammonia levels in pediatric patients at months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18 and 24 were 67, 53, 78, 93, 78, 67, 38, 38, 36, 48 and 53 micromol/L during treatment with RAVICTI, respectively.

Three patients reported a total of 7 hyperammonemic crises as defined in Study 4/4E and 5. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract infection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events). There was one additional patient who had one ammonia level that exceeded 100 micromol/L which was not associated with a hyperammonemic crisis. Pediatric Patients Less than 2 Months of Age A total of 16 pediatric patients less than 2 months of age participated in Study 6. Median age at enrollment was 0.5 months (range: 0.1 to 2 months). Eight patients had OTC deficiency, 7 patients had ASS deficiency, and 1 patient had ASL deficiency. Ten of the 16 patients transitioned from sodium phenylbutyrate to RAVICTI within 3 days of treatment and their initial dosage of RAVICTI was calculated to deliver the same amount of phenylbutyrate as the sodium phenylbutyrate dosage administered prior to RAVICTI dosing.

Three of the 16 patients were treatment-naïve and started RAVICTI at dosages of 9, 9.4, and 9.6 mL/m 2 /day. The remaining 3 of the 16 patients transitioned from intravenous sodium benzoate and sodium phenylacetate to RAVICTI within 3 days of treatment and their initial dosages of RAVICTI were 10.4, 10.9, and 10.9 mL/m 2 /day. Of the 16 patients, 16, 14, 12, 6, and 3 patients were treated for 1, 3, 6, 12, and 18 months, respectively.

After the initial 7-day transition period, patients received a mean RAVICTI dosage of 8 mL/m 2 /day (8.8 g/m 2 /day), with doses ranging from 3.1 to 12.7 mL/m 2 /day (3.4 to 14 g/m 2 /day). The frequency of dosing varied throughout the study. The majority of patients were dosed three times per day with feeding. No patients discontinued during the 7-day transition phase.

Ammonia values across different laboratories were normalized (transformed) to a common normal pediatric range of 28 to 57 micromol/L for comparability. During the safety extension phase (months 1-24), venous ammonia levels were monitored monthly for the first 6 months of treatment and every 3 months thereafter until the patients terminated or completed the study. During the safety extension phase, 1 patient discontinued from the study due to an adverse event (increased hepatic enzymes), 2 patients were withdrawn from the study by their parent/guardian, and 4 patients discontinued from the study early to undergo a liver transplant (protocol-defined discontinuation criterion). The normalized ammonia levels in pediatric patients with available values (which varied by month of treatment) in Study 6 in patients less than 2 months of age are shown in Table 4. Table 4: Ammonia normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay) Levels in Pediatric Patients Less than 2 Months of Age with UCDs in Study 6 Month N (patients with available ammonia level) Normalized Ammonia (micromol/L) normal range: 28 to 57 micromol/L. Mean (SD) Median (Min, Max) 1 15 71 60 2 11 58 50 3 14 53 46 4 11 94 64 5 10 52 57 6 9 49 42 9 8 56 45 12 6 35 36 15 4 52 52 18 3 64 63 24 9 63 72 Five patients (all less than 1 month of age) experienced a total of 7 hyperammonemic crises defined as in Study 4/4E and 5. Hyperammonemic crises were precipitated by upper respiratory tract infection (2 events), change in diet (1 event), or had no identified precipitating event (4 events).