Summary Basis of Decision for Procysbi

Clinical Pharmacology

Cysteamine (the medicinal ingredient in Procysbi) is an aminothiol that participates in a thiol-disulfide interchange reaction within lysosomes, converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

Pharmacodynamics

Using the mixed leukocyte assay, normal individuals and persons heterozygous for cystinosis have white blood cell (WBC) cystine levels of less than 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively. Untreated patients with nephropathic cystinosis have elevations of WBC cystine concentration above 2 nmol ½ cystine/mg protein. After the administration of a single dose of Procysbi, peak concentrations of WBC cystine were observed at 3 hours post-dose. The nadir of WBC cystine closely followed the peak concentrations at 3.5 hours post-dose, and returned to baseline WBC concentrations at 12 hours-post dose.

No thorough QT study or human ether-a-go-go gene (hERG) assay was performed for Procysbi. The absence of these data was considered acceptable for this rare, life-threatening condition with no other treatment approved in Canada given that the active ingredient, cysteamine bitartrate, has been available as an immediate-release (IR) formulation since 1994 in the United States and available in Canada since 2000 through the Special Access Program (SAP). During its international market history, there has not been a signal to suggest an association with QT/QTc interval prolongation, torsades de pointes, or sudden cardiac death.

Pharmacokinetics

In patients with nephropathic cystinosis, the pharmacokinetics of Procysbi is consistent with those of a delayed-release formulation. Additionally, administration of a meal 30 minutes following Procysbi administration (intact capsules) decreased the maximum plasma concentration (C_max) by 34% and plasma concentration-time curve from zero to time infinity (AUC_0-t) by 32%. Food intake two hours after Procysbi administration did not affect the absorption of Procysbi in healthy subjects. Cysteamine was moderately bound to human plasma proteins (52%), predominantly to albumin with a volume of distribution (Vd/F) of 382 L. In vitro cysteamine bitartrate is likely to be metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 in human liver microsomes. Cysteamine bitartrate is a substrate of P-glycoprotein (P-gp) and organic cation transporter 2 (OCT2). Around 0.3% to 1.7% of unchanged cysteamine is eliminated in the urine predominantly as sulphate.

Intrinsic factors such as the influence of race, gender, age (≥65 years and <2 years), and genetic polymorphism on the pharmacokinetics of Procysbi have not been evaluated in clinical studies.

No dosage adjustment of Procysbi is required in patients with mild and moderate renal impairment based on the lack of correlation between exposures or maximal concentrations and estimated glomerular filtration rate (eGFR; >30 ml/min) in nephropathic cystinosis patients. The effects of hepatic impairment, severe renal impairment and end stage renal disease on the pharmacokinetics of Procysbi have not been evaluated.

Drug-Drug Interactions

There is some potential for drug interactions based on the induction of CYP1A2 and CYP3A4 (and possibly CYP2B6) by cysteamine bitartrate, based on in vitro data. Also, drugs that increase the gastric pH (e.g., protein pump inhibitors, medications containing bicarbonate or carbonate) may alter the pharmacokinetics of Procysbi via premature release of cysteamine. This may result in a weaker reduction of WBC cystine concentration. Bicarbonates or carbonates are recommended to be administered at least one hour before or one hour after Procysbi administration to avoid earlier cysteamine release.

Co-administration of omeprazole did not alter the pharmacokinetics of Procysbi. However, this is not sufficient to draw any inferences regarding the effect of the broader category of drugs that may increase gastric pH on the pharmacokinetics of cysteamine.

Consumption of alcohol with Procysbi may increase the rate of cysteamine release and must be avoided.

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

Clinical Efficacy

The clinical efficacy of Procysbi for nephropathic cystinosis was principally supported based on one short-term pivotal study (RP103-03) and one long-term supportive study (RP103-04).

Study RP103-03

Study RP103-03 was a 9-week, open-label, multicentre, randomized, crossover study which evaluated non-inferiority of Procysbi to immediate-release (IR) cysteamine (Cystagon). Forty-three (43) patients with nephropathic cystinosis (aged 6 to 26 years) were randomized to one of two treatment regimens following a 3-week run-in period:

• Procysbi first for 3 weeks then switched to IR cysteamine for 3 weeks, or;
• Immediate-release cysteamine for 3 weeks then switched to Procysbi for 3 weeks.

Subjects entering this study were required to be on a stable dose of IR cysteamine considered by the investigator as sufficient to maintain their WBC cystine level at ≤2.0 nmol ½ cystine/mg protein. White blood cell cystine levels were measured using the mixed leukocyte assay. Patients with WBC cystine concentrations greater than 2 nmol ½ cystine/mg protein and eGFR (corrected for body surface area) less than 30 mL/minute/1.73 m² at the time of screening were excluded from the study.

Procysbi dose adjustments of up to approximately 100% of the total daily dose of IR cysteamine were allowed by study criteria. The average total daily dose of Procysbi for patients completing the clinical trial was approximately 82% of the average total daily dose of IR cysteamine for patients at study entry. There were 24/43 (56%) patients who had their dose of Procysbi up-titrated by the end of the 3 week treatment period.

The primary endpoint of the study was a non-inferiority comparison of Procysbi to IR cysteamine in terms of control of WBC cystine levels.

The primary results from the short-term pivotal RP103-03 study demonstrated that at steady-state, Procysbi administered every 12 hours (over a 3 week period) was non-inferior to IR cysteamine administered every 6 hours (over a 3 week period) with respect to the depletion of WBC cystine concentrations. In fact, the mean peak WBC cystine level was 0.44 nmol ½ cystine/mg protein for the IR cysteamine period, compared to an average peak value of 0.52 nmol ½ cystine/mg protein with Procysbi (mean difference of 0.08 nmol ½ cystine/mg protein, with a 95.8% confidence interval (CI) of -0.01 to 0.17). The upper limit of the 95.8% CI of the difference between Procysbi and IR cysteamine was less than the prespecified non-inferiority margin of 0.3 nmol ½ cystine/mg protein, thus satisfying the non-inferiority criteria.

Study RP103-04

Study RP103-04 is an ongoing, open-label, multicentre, long-term (up to 3.75 years of efficacy data) study conducted in nephropathic cystinosis patients which seeks to assess the tolerability and steady-state pharmacokinetic and pharmacodynamic effects of Procysbi in pediatric and adult cystinosis subjects. In this study, there are three subpopulations enrolled:

• The original cohort of subjects with cystinosis who had completed Study RP103-03 (and therefore had already been treated with Procysbi for approximately three weeks);
• New patients who were ≤ 6 years of age; and,
• New patients who had received a kidney transplant.

A total of 59 subjects (40 subjects; ≤ 6 Years: 13 subjects, Kidney Transplant: 6 subjects) received study drug.

The results from the RP103-04 study showed that WBC cystine levels were generally maintained below 1 nmol ½ cystine/mg protein at each time point for patients in the subpopulation of patients from RP103-03. In the subpopulation of patients ≤6 years of age, WBC cystine levels did not decrease to <1 nmol ½ cystine/mg protein until after 2.5 years of treatment (when data were available for only half of enrolled subjects). The greater difficulty with reducing WBC cystine levels in this subpopulation may reflect the lower doses of cysteamine used (starting dose was 70% relative to the IR cysteamine dose and mean dose over the study was 75% of the IR cysteamine dose prior to study enrollment), as well as the higher baseline WBC cystine levels (1.41 nmol ½ cystine/mg protein), compared to the subpopulation from RP103-03 (1.10 nmol ½ cystine/mg protein). In the subpopulation of renal transplant patients, WBC cystine levels were >2 nmol ½ cystine/mg protein at baseline (2.40 nmol ½ cystine/mg protein) and decreased over the study but were only <1 nmol ½ cystine/mg protein at two time points (only 3 patients had available data from 2 years onwards). Higher baseline WBC cystine levels, advanced disease and older (mean age: 21.7 years) patient population may have contributed to higher WBC cystine levels in this subpopulation.

Additional Efficacy Endpoints Pertaining to Study RP103-03 and Study RP103-04

Additional efficacy endpoints studied in the two clinical studies were mainly descriptive in nature. When comparing mean plasma cysteamine concentrations within each subpopulation over time, the mean concentrations at 0.5 hours post dose were generally higher in the RP103-03 study subpopulation, compared to the other subpopulations. There were no clear patterns with respect to quality of life findings. Further, there were no patterns with respect to difficulty swallowing among patients in the study and most patients had minimal or no pain at baseline and throughout the study.

Baseline eGFR was 66.04, 74.13, and 71.68 mL/min/1.73 m² in RP103-03, ≤6 years of age, and transplant subpopulations, respectively. At several time points, patients in the RP103-03 subpopulation experienced borderline moderately reduced kidney function. At most time points, patients in the ≤6 years and renal transplant subpopulations remained mildly impaired. A decrease to moderately impaired renal function was noted during the first 1.5 years for renal transplant patients.

While efficacy was established with respect to decreased WBC cystine levels, no conclusions could be reached regarding disease outcomes such as delay in renal impairment, difficulty swallowing, or quality of life parameters based on the limited data available.

Given that nephropathic cystinosis is a life-threatening condition for which there are no approved treatments available in Canada, it was considered relevant to permit use in patients <2 and ≥65 years of age. Immediate-release cysteamine has been approved without age restrictions for over 20 years and thus provides some support for safe and effective use of cysteamine in general for these age subpopulations.

In patients switching from IR cysteamine, Health Canada recommended the starting total daily dose of Procysbi to be equivalent to the previous total daily dose of IR cysteamine. This recommended dosing regimen is in contrast to that evaluated in the clinical studies and proposed by the sponsor. The sponsor recommended a reduced starting dose of 75% of the IR cysteamine dose based on potential gastrointestinal tolerability issues that may arise from switching formulations. Health Canada did not accept this given the absence of data to suggest improved tolerability with a reduced starting dose. In addition, the analysis conducted by the Food and Drug Administration (FDA) suggesting: a) that the doses evaluated in the pivotal study were closer to equivalent than originally estimated and b) that there would be a potential loss in efficacy with the proposed regimen. However, it was agreed that, with closer monitoring of WBC cystine, physicians may consider initiation of Procysbi at 75% of the IR cysteamine dose in individuals for whom gastrointestinal tolerability is a known concern.

Indication

The New Drug Submission for Procysbi was filed by the sponsor with the following indication:

• Procysbi (cysteamine bitartrate delayed-release capsules) is indicated for the treatment of nephropathic cystinosis. Cysteamine reduces cystine accumulation in some cells (e.g., leukocytes, kidney, muscle and liver cells) of nephropathic cystinosis patients and, when treatment is started early, it delays the progression of renal failure.
  
  Treatment with Procysbi should be started immediately after diagnosis of nephropathic cystinosis has been confirmed.
  
  Procysbi treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Procysbi (cysteamine delayed-release capsules) is indicated for the treatment of nephropathic cystinosis.
  
  Procysbi treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis.

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

Clinical Safety

The safety profile of Procysbi was primarily based upon safety data from one short-term pivotal study (RP103-03) and one long-term supportive study (RP103-04) previously described in the Clinical Efficacy section. In Study RP103-03, the maximum individual exposure to Procysbi was 21 days. In RP103-04, the mean exposure to Procysbi was approximately 3.0 years at the time of the clinical cut-off for this New Drug Submission.

In the RP103-03 study, the initial starting daily dose of Procysbi was 70-80% of the run-in cysteamine IR daily dose. Treatment with Procysbi, compared with IR cysteamine, resulted in a higher incidence of adverse events (58.1% vs. 31.7%, respectively) and treatment-related adverse events (25.6% vs. 14.6%, respectively). These observations were confounded by the protocol-mandated withholding of gastric acid reducing medications (including protein pump inhibitors) for patients treated with Procysbi, but not IR cysteamine. For both treatment groups, gastrointestinal disorders were the most frequently reported treatment-related adverse events, which included nausea (11.6%) vomiting, (11.6% each), and abdominal pain (7.0%).

The majority of these reported adverse events were mild to moderate in intensity. Serious adverse events were more common with Procysbi, but only one serious adverse event of abdominal discomfort was considered drug-related. The single patient withdrawal due to an adverse event during Procysbi treatment was considered not related to study drug. No deaths were reported in this study.

The treatment-related adverse events observed in Study RP103-04 were consistent with those reported in Study RP103-03. The most common treatment-related adverse events were gastrointestinal (52.5%), comprised of vomiting (33.9%), nausea (15.3%), abdominal pain (13.6%), breath odor (13.6%), and diarrhea (8.5%). Neutropenia, pancytopenia, and renal failure were observed in one patient each. No deaths were reported in this study. Furthermore, no clinically relevant mean changes from baseline in hematology or laboratory parameters were observed during the study.

Special Populations

The effects of severe renal impairment and end stage renal disease on the pharmacokinetics of Procysbi have not been evaluated. Some forms of cysteamine are less well tolerated (i.e., leading to more adverse events) when patients are on dialysis. Closer monitoring of WBC cystine levels is recommended in patients with severe or end stage renal disease.

Procysbi has not been studied in patients with hepatic impairment. Closer monitoring of the WBC cystine levels is recommended in these patients.

There are no available data on Procysbi use in pregnant women. Cysteamine (administered as cysteamine bitartrate) was teratogenic and fetotoxic in rats at doses less than the recommended human maintenance dose. Patients should be advised of the potential risk to a fetus and the importance of ensuring adequate contraception while taking Procysbi.

There is no information on the presence of cysteamine in human milk, or its effects on the breastfed infant. Cysteamine is present in the milk of lactating rats. Growth retardation and a decrease in survival occurred in neonatal rats nursed by mothers receiving cysteamine. Given the potential for serious adverse reactions in breastfed infants from cysteamine, breastfeeding is not recommended.

Conclusion

Overall, the results of the safety evaluation of Procysbi indicate that both short- and long-term treatment is reasonably well tolerated, given its expected clinical benefit. No unexpected safety concerns have been identified to date, given the well-known safety profile of IR cysteamine. Adverse events were predominantly associated with the gastrointestinal system. Gastrointestinal adverse events of vomiting and diarrhea are important safety considerations to monitor, given that patients with advanced cystinosis develop underlying renal Fanconi syndrome, characterized by polyuria, hypokalemia, hypocalcemia, and hypophosphatemia. Thus, recurrent vomiting and diarrhea has the potential to exacerbate perturbation of fluid and electrolyte balance.

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