Summary Basis of Decision for Ravicti

 

Clinical Pharmacology

Urea cycle disorders (UCDs) are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from ammonia. Absence of these enzymes or transporters results in the accumulation of toxic levels of ammonia in the blood and brain of affected patients. Phenylacetic acid (PAA), a metabolite of Ravicti, is the active moiety of Ravicti. Phenylacetic acid conjugates with glutamine via acetylation in the liver and kidneys to form phenylacetylglutamine (PAGN) which provides an alternate vehicle for waste nitrogen excretion.

The clinical pharmacology included reports on human pharmacodynamic and pharmacokinetic studies.

Inconsistencies were noted in the drug interaction studies, and only summary results for the clinical drug interaction study (HPN-100-019) were provided in the NDS as the clinical study report for this drug interaction study was not final at the time of filing. These summary results appeared to contradict results from two in vitro drug interaction studies (CFU004 and 005) which were submitted for review. Final data from the clinical drug interaction study were required to draw conclusions on drug interactions with Ravicti and to inform the product label. The absence of this key drug interaction study resulted in the submission receiving a Notice of Deficiency (NOD).

The sponsor addressed the issue appropriately in the response to the NOD and the final clinical study report for HPN-100-019 was submitted for review. The study results showed that Ravicti may be a weak inducer of the CYP3A4 enzyme and coadministration of Ravicti with drugs that are metabolized by CYP3A4 may result in lower plasma concentrations of the coadministered drug. While the study suggests that the drug effect may be reduced, it must also be noted that in some instances the metabolite also has pharmacological activity, in which case the overall drug effects may be increased. Results of the clinical study were of value for providing appropriate information for the Ravicti Product Monograph.

Overall, the clinical pharmacological data support the use of Ravicti for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Ravicti in controlling ammonia in patients with UCDs was evaluated in 114 UCD patients across four short-term (1 to 2 weeks) switch-over controlled studies (Studies 003, 006, 005 and 012) and three long-term 12-month studies (Studies 005-extension, 007, 012-extension). The short-term studies enrolled 85 UCD patients (59 adult and 26 pediatric) and the long-term studies enrolled 100 UCD patients (51 adults and 49 pediatric). Most patients in the short-term studies also participated in the long-term studies.

Study 003 was a Phase II, open-label, fixed-sequence, switch-over study that compared the efficacy of Ravicti to sodium phenylbutyrate (NaPBA) in 10 adult UCD patients who were being treated with NaPBA for control of their UCD. Patients were enrolled and received NaPBA for 1 week and then switched to Ravicti for 1 week. Each patient received NaPBA or Ravicti three times a day (tid) with meals. The dose of Ravicti was calculated to deliver the same amount of PBA as the dose of NaPBA. After 1 week of dosing with each treatment, all patients underwent 24 hours of ammonia measurements, as well as blood and urine pharmacokinetic (PK) testing. Dietary protein was controlled throughout the study.

The pivotal study was Study 006, a Phase III, randomized, double-blind, active-controlled, cross-over study conducted to assess the non-inferiority of Ravicti to NaPBA by evaluating blood ammonia in 45 adult UCD patients who were being treated with NaPBA for control of their UCD. Each patient was randomized 1:1 to one of two treatment groups to receive either (A) NaPBA + a Ravicti placebo for 2 weeks and then an NaPBA placebo + Ravicti for the next 2 weeks; or (B) Ravicti + an NaPBA placebo for 2 weeks and then a Ravicti placebo + NaPBA for the next 2 weeks. Each patient received NaPBA or Ravicti tid with meals. The dose of Ravicti was calculated to deliver the same amount of PBA as the NaPBA dose. After 2 weeks of dosing, by which time patients had reached steady-state on each treatment, all patients underwent 24 hours of ammonia measurements and PK testing. Dietary protein was controlled throughout the study. Upon completion of Study 006, patients were allowed to enrol into a separate long-term (12-month) open-label study (Study 007).

Study 005 and Study 012 were Phase II, open-label, fixed-sequence, switch-over studies to compare Ravicti to NaPBA in the control of blood ammonia in 11 and 15 pediatric UCD patients, respectively. In each study, patients who were being treated with NaPBA received NaPBA for 1 week and then switched to Ravicti for 1 week. Each patient received NaPBA or Ravicti tid with meals. The dose of Ravicti was calculated to deliver the same amount of PBA as the dose of NaPBA.Three times or four times daily feeding and administration of Ravicti was recommended; however, flexibility was allowed based on the patient's prior NaPBA dosing regimen and/or feeding habits. After 1 week of dosing with each treatment, all patients underwent 24 hours of ammonia measurements as well as blood and urine PK testing. Dietary protein was controlled throughout the study. Upon completion of the switch-over part of each study, patients were allowed to continue receiving treatment and new additional patients were allowed to enrol to receive Ravicti for 12 months in an open-label safety extension.

Study 007 was a Phase III, long-term (12-month), uncontrolled, open-label study conducted to assess monthly ammonia control and hyperammonemic crisis over a 12-month period in three studies (Study 007 which also enrolled adults, extension of Study 005, and extension Study 012). A total of 49 children ages 2 month to 17 years were enrolled, and all but 1 had been converted from NaPBA to Ravicti.

The assessment of blood ammonia was central to the evaluation of efficacy and safety in UCD patients, as it is the signature biochemical abnormality common to these disorders and is believed to be a surrogate for outcomes. Therefore, systemic exposure of 24-hour blood ammonia levels (area under the curve [AUC_0-24]) for Ravicti versus (vs.) NaPBA was selected as the primary efficacy endpoint. In all studies, ammonia AUC_0-24 was compared during PBA equivalent, steady-state dosing of each drug. In the pivotal efficacy study, blood ammonia AUC_0-24 comparison was made on Days 14 and 28; while in the supportive short-term studies the blood ammonia AUC_0-24 comparison between Ravicti vs. NaPBA was performed after dosing with either drug for up to 7 days.

Short Term Efficacy in Adult UCD Patients

The pivotal study (Study 006) succeeded in showing non-inferiority of Ravicti to NaPBA. Ravicti, when given at a PBA molar equivalent dose, was non-inferior to NaPBA in controlling blood ammonia assessed as 24-hour AUC in 44 adults with UCD. There was a non-significant trend toward lower blood ammonia values AUC_0-24 (~11%) during treatment with Ravicti compared with NaPBA (865.85 ± 660.529 vs. 976.63 ± 865.352 μmol*h/L, respectively).

In the pooled analysis of the short-term studies in adults, the mean daily ammonia level was 34 µmol/L vs. 40 µmol/L for patients on NaPBA. The maximum PAA and PAGN concentrations achieved during treatment with Ravicti were 38.5 µg/mL and 78.6 µg/mL, respectively vs. 91.5 µg/mL and 86.3 µg/mL with NaPBA, respectively.

Long Term Efficacy in Adult UCD Patients

Study 007 was a Phase III, open-label study, conducted with the objective of evaluating long-term safety and efficacy of Ravicti use in patients with UCDs. The study showed Ravicti to be efficacious in long-term ammonia control. Months 1-12 mean values ranged from 20.7 to 31.3 μmol/L, and except at Month 11 (mean value of 31.3 μmol/L), the mean ammonia value was lower than the baseline mean value (27.6 μmol/L). The maximum ammonia values observed at each visit ranged from 60.0 μmol/L (Month 2) to 209.9 μmol/L (Month 11). At baseline, 31% of patients had an elevated ammonia value. The percentage of patients with an elevated ammonia value was lower at each scheduled time point (ranging from 14% at Month 2 to 25% at Month 11).

In long-term studies, the median (25-75 percentiles) levels of PBA, PAA and PAGN obtained from 195 samples in 51 adult patients were 0.5 (0.5-2.78) µg/mL, 1.12 (0.5-4.17) µg/mL, and 14.28 (4.64-28.15) µg/mL, respectively. Of 51 adult patients participating in the 12-month, open-label treatment with Ravicti, 7 patients (14%) reported a total of 10 hyperammonemic crises vs. 15 crises in 9 (18%) patients in the preceding 12 months prior to study entry, in patients receiving NaPBA.

Short Term Efficacy in Pediatric UCD Patients

In the pooled analysis of the short-term studies in children (Studies 005 and 012), the mean daily ammonia level was 24 µmol/L for patients treated with Ravicti vs. 35 µmol/L for patients treated with NaPBA (p = 0.007; paired t-test). Glutamine level was 661 μmol/L vs. 710 μmol/L on sodium phenylbutyrate during treatment with Ravicti (number of patients [n] = 26). Four patients <2 years of age were excluded for this analysis due to insufficient data. The maximum PAA and PAGN concentrations achieved during treatment with Ravicti were 87.3 µg/mL and 93.9 µg/mL, vs. 50.2 µg/mL and 74.6 µg/mL on NaPBA, respectively.

Long Term Efficacy in Pediatric Patients

Study 005 with its long-term safety extension evaluated the efficacy of Ravicti in controlling blood ammonia levels in pediatric patients ages 6-17 years with UCDs. Ammonia was well-controlled throughout the study, with similar results in the 6- to 11-year and 12- to 17-year age groups. Mean ammonia levels for the safety population were similar throughout the study and were always below the standardized upper limit of normal of 35 μmol/L among the participating study sites. Results were similar for the two age groups.

Three of 17 patients (18%) had a total of 3 hyperammonemic crises during the 12-month safety extension, which was fewer than the number of patients (5 [29%]) who had reported a total of 8 hyperammonemic crises in the 12 months prior to the study. No precipitating factor was reported for any of these crises. Two of these crises while taking Ravicti occurred during Month 5 of treatment and the third during Month 7, and all were reported as adverse events (AEs) unrelated to study drug.

Study 012 assessed the efficacy of Ravicti in pediatric UCD patients aged 29 days to <6 years of age during treatment for up to 12 months. This open-label study consisted of two parts: a 10-day switch-over period and a long-term treatment phase with Ravicti for up to 12 months. Overall, the study showed Ravicti to provide ammonia control that was at least as good as that provided by NaPBA for all age groups. Most parents of the patients preferred Ravicti over NaPBA due to ease of administration.

The mean ammonia AUC_0-24 level was lower with Ravicti than with NaPBA (median difference between treatments of -37.84 μmol*h/L). Mean ammonia levels were lower on Day 10 with Ravicti than on Day 1 with NaPBA at all timepoints, as were mean daily average ammonia and peak ammonia levels (daily average: 25 μmol/L; peak: 39 μmol/L with Ravicti vs. 37 μmol/L and 53 μmol/L with NaPBA). While these differences were not statistically significant, they indicate that Ravicti provides ammonia control to the same extent as NaPBA.

Mean systemic exposure (AUC_0-24) of PBA following Ravicti administration was similar to that observed with NaPBA (255 vs. 483 μg*h/mL, respectively) and was generally similar in the age subgroups (<2 years and 2 to <6 years). Mean overall systemic exposure (AUC_0-24) was also similar for PAA and PAGN during treatment with the two drugs. In contrast to PBA, PAA and to a lesser extent PAGN exposure was generally higher among pediatric patients under 2 years of age than in the overall population, but again similar for the two drugs.

From the long-term studies (Study 007, extension of Study 005, and extension Study 012), the median (25-75 percentiles) levels of PBA, PAA and PAGN obtained from 250 samples in 49 pediatric patients were 2.07 (0.5-8.7) µg/mL, 2.95 (0.5-31.19) µg/mL, and 21.18 (7.14-52.56) µg/mL, respectively. Of the 49 pediatric patients treated with Ravicti for up to 12 months, 12 patients (24.5%) reported a total of 17 hyperammonemic crises vs. 38 crises in 21 (42.9%) patients in the preceding 12 months prior to study entry, in patients receiving NaPBA.

Overall Analysis of Efficacy

The primary efficacy endpoint, non-inferiority of Ravicti to NaPBA in controlling blood ammonia levels in patients with UCDs, was achieved in the short-term and long-term studies. Ravicti was also shown to be efficacious in long-term ammonia control, normalization of mean ammonia values and lowering of both the mean ammonia values and the percentage of patients with elevated ammonia values during the study compared to baseline. In addition, the percentage of patients with hyperammonemic crises and the average number of crises per patient were lower over the 12-month study duration than in the 12 months preceding the study

Health Canada authorized the proposed indication that was filed with the New Drug Submission.

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

Clinical Safety

The clinical safety of Ravicti was assessed in the pivotal, Phase III, randomized, double-blind, cross-over, controlled Study 006 (described in the Clinical Efficacy section).

The safety profile for both Ravicti and NaPBA was satisfactory and no serious or unexpected adverse events were observed. Most AEs were mild in intensity and manageable for both Ravicti and NaPBA treatment. One hyperammonemic crisis occurred during NaPBA treatment, and one patient discontinued NaPBA treatment because of high blood ammonia levels (123 μmol/L) and headache on Day 1 of the study.

Treatment-emergent adverse events (TEAEs) were reported in 23 of 45 (51.1%) patients while receiving NaPBA and in 27 of 44 (61.4%) patients while receiving Ravicti. Most TEAEs were considered by the investigator to be mild in intensity. Symptoms suggestive of lower gastrointestinal (GI) disorders (for example [e.g.] diarrhea and flatulence) were reported more frequently with Ravicti treatment, whereas symptoms suggestive of upper GI disorders (e.g., abdominal discomfort, dyspepsia, nausea, and oral discomfort) were reported more frequently with NaPBA treatment. These events were generally mild, not serious, and did not result in patients withdrawing from the study. Dizziness was reported by more patients treated with NaPBA than Ravicti (8.9% vs. 0).

An analysis of UCD symptoms typically associated with UCD or its treatment showed that fatigue, nausea, decreased appetite/food aversion, and increased appetite occurred less frequently with Ravicti compared with NaPBA treatment.

Due to the low number of patients in the study (intent-to-treat population = 46), it was difficult to make any reliable safety conclusions. To improve on the safety analysis an integrated summary of safety was conducted, using results from several studies.

An assessment of adverse drug reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) across four short-term active-controlled studies and three long-term (12 month) uncontrolled clinical studies.

The most common adverse drug reactions (≥5%) among all patients taking Ravicti in the clinical studies included diarrhea, flatulence, headache, decreased appetite, vomiting, nausea, fatigue, and skin odor. In the short-term studies (number of patients [n] = 80), the adverse drug reactions of diarrhea, flatulence, and headache were each reported in 8.8% of the patients. In the long-term studies (n = 100), vomiting, decreased appetite, and skin odor were reported in 7.0%, 7.0%, and 6.0% of the patients, respectively.

Treatment-related AEs reported in ≥2% of the patients included: abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper, constipation, diarrhea, dyspepsia, flatulence, gastroesophageal reflux disease, nausea, oral discomfort, retching, vomiting, fatigue, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased anion gap, decreased lymphocyte count, decreased Vitamin D, decreased/increased appetite, dizziness, headache, tremors, food aversion, metrorrhagia, acne, and abnormal skin odor.

There were no life-threatening or fatal AEs. None of the serious AEs were determined by the sponsor to be treatment-related.

No UCD patients died while participating in Ravicti clinical studies. Five non-UCD hepatically impaired patients died while participating in the studies. Their causes of death were attributed to renal failure (n = 2), hepatic insufficiency (n = 1) and esophageal/GI hemorrhage (n = 2).

Pediatric UCD patients treated with Ravicti for up to 1 year continued to exhibit growth that was similar to the normal population.

Adverse drug reactions that resulted in clinical intervention in UCD patients who participated in clinical studies were mostly GI reactions (flatulence, nausea, vomiting, abdominal distention) or neurological reactions (dysgeusia, lethargy, speech disorder, paresthesia, tremors).

Plasma values of PBA, PAA and PAGN during 12 months of dosing from the entire clinical programme were very similar to those observed during the short-term switchover studies, with no tendency toward accumulation of metabolites over time. Median PAA values in both pediatric and adult patients were at least 50-fold below the lower end of the range reportedly associated with reversible neurological AEs, however, there was some concern that PAA levels in pediatric patients, particularly those of younger age, were higher than in adults.

In the pediatric data, a total of 7 patients aged 2 months to 2 years were studied. While the drug's overall effect in this group was similar to that in older patients, some metabolic differences were noted, including higher PAA levels, and it was determined that Ravicti was not sufficiently studied to determine Ravicti's safety and recommend use in this patient population. Since children under 2 months of age may have immature pancreatic exocrine function that could impair Ravicti hydrolysis, the statement that Ravicti has not been studied in patients <2 months of age was revised to state that the use of Ravicti in this age group is contraindicated.

An electrocardiogram assessment study demonstrated a dose- and concentration-dependent increase in heart rate over the therapeutic dose range, with increases of up to 10 beats/min. QTcF interval shortening was also observed, with a maximum mean difference from placebo of -7.2 ms which is not known to have pro arrhythmic consequences.

Overall, the safety data support the approval of Ravicti for the specified indication. The safety profile of Ravicti is acceptable for it to be used in the chronic management of adult and pediatric patients ≥2 years of age with UCDs who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Appropriate warnings and precautions are in place in the approved Ravicti Product Monograph to address the identified safety concerns.

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