PROCYSBI Cysteamine bitartrate 75 mg Granule, Delayed Release — NDC 75987-140-13 (Billing 75987-0140-13)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

12.2Pharmacodynamics Normal individuals and persons heterozygous for cystinosis have WBC cystine concentrations of less than 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively, when measured using the mixed leukocyte assay. 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 cysteamine 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. The cystine concentration in WBC lysate was measured with LC/MS/MS and total protein content in human WBC lysate was measured using the bicinchoninic acid (BCA) assay. A correction factor was applied to the total protein content for the difference in results from the Lowry method.

The cystine concentration in nmol ½ cystine/mg protein was calculated by multiplying nmol cystine/mg protein by 2 [see Dosage and Administration (2.5) ].

12.3Pharmacokinetics The pharmacokinetics of cysteamine with administration of PROCYSBI were evaluated in 43 patients age ranged from 6 to 26 years (mean age 12 years) with cystinosis and with an estimated glomerular filtration rate of greater than 30 mL/minutes/1.73 m2. Table 4 shows the mean pharmacokinetic parameters for PROCYSBI and immediate-release cysteamine bitartrate at steady state. The mean (± SD) dose for PROCYSBI was 656 ± 144 mg/m2 (given every 12 hours) and for immediate-release cysteamine bitartrate was 404 ± 88 mg/m2 (given every 6 hours).

Table 4: Pharmacokinetic parameters for cysteamine at steady state* after administration of PROCYSBI or immediate-release cysteamine bitartrate Immediate-release cysteamine bitartrate given every 6 hours PROCYSBI given every 12 hours C max (mg/L) 2.7 ± 1.4 3.6 ±

1.8AUC 0-6h (min*mg/L) 351 ± 153 NA AUC 0-12h (min*mg/L) NA 726 ± 339 AUC inf (min*mg/L) 380 ± 157 785 ± 358 T max (min) 73 ± 31 188 ± 88 t½ (min) 90 ± 24 253 ± 403 CL/F (L/min) 1.4 ± 0.8 1.2 ±

0.8Vd/F (L) 198 ± 159 382 ± 404 Absorption The pharmacokinetics of cysteamine with administration of PROCYSBI are consistent with a delayed-release formulation; the mean T max for cysteamine was 188 minutes with PROCYSBI compared with 73 minutes for immediate-release cysteamine bitartrate. The mean plasma cysteamine peak and AUC were similar when a single PROCYSBI dose of 600 mg was administered with 240 mL orange juice or with 240 mL water. The systemic exposure to cysteamine was similar when PROCYSBI was administered with orange juice as a whole capsule and sprinkled in applesauce in the fasted state.

In a food effect study conducted in healthy subjects (n=20), administration of a meal 30 minutes following PROCYSBI administration (intact capsules) decreased C max by 34% and AUC 0-t by 32% compared to administration of a meal 2 hours post-dose [see Dosage and Administration (2.6) ] . Distribution Cysteamine was moderately bound to human plasma proteins, predominantly to albumin, with mean protein binding of about 52%. Plasma protein binding was independent of concentration over the concentration range achieved clinically with the recommended doses.

The volume of distribution (Vd/F) was 382 L for PROCYSBI compared with 198 L for immediate-release cysteamine bitartrate. Elimination After each dose of PROCYSBI the cysteamine concentration in the blood continues to decline for approximately 30 minutes and the WBC cystine concentration increases accordingly . The apparent clearance (Cl/F) of cysteamine was similar between PROCYSBI (1.2 ±

0.8L/min) and immediate-release cystea… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

12.3Pharmacokinetics The pharmacokinetics of cysteamine with administration of PROCYSBI were evaluated in 43 patients age ranged from 6 to 26 years (mean age 12 years) with cystinosis and with an estimated glomerular filtration rate of greater than 30 mL/minutes/1.73 m2. Table 4 shows the mean pharmacokinetic parameters for PROCYSBI and immediate-release cysteamine bitartrate at steady state. The mean (± SD) dose for PROCYSBI was 656 ± 144 mg/m2 (given every 12 hours) and for immediate-release cysteamine bitartrate was 404 ± 88 mg/m2 (given every 6 hours).

Table 4: Pharmacokinetic parameters for cysteamine at steady state* after administration of PROCYSBI or immediate-release cysteamine bitartrate Immediate-release cysteamine bitartrate given every 6 hours PROCYSBI given every 12 hours C max (mg/L) 2.7 ± 1.4 3.6 ±

1.8AUC 0-6h (min*mg/L) 351 ± 153 NA AUC 0-12h (min*mg/L) NA 726 ± 339 AUC inf (min*mg/L) 380 ± 157 785 ± 358 T max (min) 73 ± 31 188 ± 88 t½ (min) 90 ± 24 253 ± 403 CL/F (L/min) 1.4 ± 0.8 1.2 ±

0.8Vd/F (L) 198 ± 159 382 ± 404 Absorption The pharmacokinetics of cysteamine with administration of PROCYSBI are consistent with a delayed-release formulation; the mean T max for cysteamine was 188 minutes with PROCYSBI compared with 73 minutes for immediate-release cysteamine bitartrate. The mean plasma cysteamine peak and AUC were similar when a single PROCYSBI dose of 600 mg was administered with 240 mL orange juice or with 240 mL water. The systemic exposure to cysteamine was similar when PROCYSBI was administered with orange juice as a whole capsule and sprinkled in applesauce in the fasted state.

In a food effect study conducted in healthy subjects (n=20), administration of a meal 30 minutes following PROCYSBI administration (intact capsules) decreased C max by 34% and AUC 0-t by 32% compared to administration of a meal 2 hours post-dose [see Dosage and Administration (2.6) ] . Distribution Cysteamine was moderately bound to human plasma proteins, predominantly to albumin, with mean protein binding of about 52%. Plasma protein binding was independent of concentration over the concentration range achieved clinically with the recommended doses.

The volume of distribution (Vd/F) was 382 L for PROCYSBI compared with 198 L for immediate-release cysteamine bitartrate. Elimination After each dose of PROCYSBI the cysteamine concentration in the blood continues to decline for approximately 30 minutes and the WBC cystine concentration increases accordingly . The apparent clearance (Cl/F) of cysteamine was similar between PROCYSBI (1.2 ±

0.8L/min) and immediate-release cysteamine bitartrate (1.4 ±

0.8L/min). The half-life was 253 minutes for PROCYSBI and 90 minutes for immediate-release cysteamine bitartrate. Specific Populations Pediatric patients 1 year to less than 6 years of age The pharmacokinetics of cysteamine with administration of PROCYSBI at steady state were evaluated in 11 cysteamine treatment naïve patients between the ages of 1 and 5 years of age with nephropathic cystinosis.

A mean (± SD) C max of 1.26 ± 0.86 mg/L was reached at an average T max of 199 ± 138 minutes and the mean (± SD) dose was 242 ± 93 mg/m 2 . The mean exposure was calculated to be 206 ± 113 minutes*mg/L (AUC last ) and 231 ± 123 minutes*mg/L (AUC inf ). The mean CL ss /F was estimated to be 0.69 ±

0.37L/minutes with an average half-life (t ½ ) of 270 ± 56 minutes. Overall, the pharmacokinetics in patients between the ages of 1 and 5 years of age is comparable with those in older children and adults. Patients with Renal Impairment The pharmacokinetics of cysteamine with administration of a single oral dose of 600 mg PROCYSBI were evaluated in non-cystinosis subjects with renal impairment and healthy subjects with normal renal function (eGFR >90 mL/min/1.73m 2 ) matched for age, body mass index and sex.

The mean AUC inf and mean C max for cysteamine were 8%, and 3% lower, respectively, in subjects with mild renal impairment (eGFR 60 to 89 mL/… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Normal individuals and persons heterozygous for cystinosis have WBC cystine concentrations of less than 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively, when measured using the mixed leukocyte assay. 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 cysteamine 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. The cystine concentration in WBC lysate was measured with LC/MS/MS and total protein content in human WBC lysate was measured using the bicinchoninic acid (BCA) assay. A correction factor was applied to the total protein content for the difference in results from the Lowry method.

The cystine concentration in nmol ½ cystine/mg protein was calculated by multiplying nmol cystine/mg protein by 2 [see Dosage and Administration (2.5) ].

14 CLINICAL STUDIES

14.1Clinical Trials with Immediate-Release Cysteamine Efficacy of immediate-release cysteamine bitartrate was demonstrated in open-label clinical trials of cysteamine hydrochloride and phosphocysteamine. An open-label clinical trial of cysteamine hydrochloride was conducted in 94 pediatric patients (mainly from the United States) with nephropathic cystinosis. Patients were treated with increasing doses of cysteamine hydrochloride (mean dose 54 mg/kg per day) to attain WBC cystine concentrations of less than 2 nmol ½ cystine/mg protein 5 to 6 hours post-dose.

The clinical outcomes were compared with a historical control group of 17 pediatric patients who had been in the placebo group of a randomized placebo-controlled trial of ascorbic acid. Cysteamine-treated patients had been diagnosed at a mean age of 22 months and had a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and had a mean age of about 52 months old at trial entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).

The average median WBC cystine concentration during treatment was 1.7 ± 0.2 nmol ½ cystine/mg protein. There were 70 cysteamine-treated patients with a baseline serum creatinine of less than 2 mg/dL who were followed for at least 1 year, and 17 placebo patients. Twelve of the 94 cysteamine-treated patients required early dialysis or renal transplant.

Median follow-up of cysteamine patients was over 32 months, and 20% were followed more than 5 years. Median follow-up of the placebo group was 20 months; only 1 patient was followed more than 24 months. Glomerular function among cysteamine-treated patients was maintained over time.

Placebo-treated patients experienced a gradual rise in serum creatinine. Renal tubular function was not affected by treatment. Calculated creatinine clearances were evaluated for two groups of pediatric patients, one with poor WBC cystine depletion (defined as median WBC cystine concentrations greater than 3 nmol ½ cystine/mg protein or WBC cystine concentrations not measured at least 2 times per year) and one with good WBC cystine depletion.

The final mean creatinine clearance of the good depletion group was 20.8 mL/min/1.73 m 2 greater than the mean for the poor-depletion group. Height-for-age measurements of treated patients were compared with height-for-age measurements of 143 patients initially screened for inclusion in the trial. Patients on treatment maintained growth (i.e., did not show increasing growth failure compared with normal scales) although growth velocity did not increase enough to allow patients to catch up to age norms for height.

In another open-label clinical trial, 46 patients who had completed the clinical trial of cysteamine hydrochloride (averaging 6.5 years of treatment) and 93 treatment naïve patients were treated with either cysteamine hydrochloride or phosphocysteamine (patient's choice). Patients had cystinosis diagnosed by elevated WBC cystine (mean 3.63 nmol ½ cystine/mg). Newly enrolled patients and the 46 continuing patients were required to have serum creatinine less than 3 mg/dL and 4 mg/dL, respectively.

Patients were randomized to doses of 1.3 or 1.95 grams/m 2 per day and stratified according to whether the serum creatinine was above 1.2 mg/dL or not. Doses could be raised if WBC cystine concentrations were approximately 2 nmol ½ cystine/mg protein and lowered due to intolerance. The mean age of the newly enrolled patients was about 49 months for the cysteamine group and about 34 months for the phosphocysteamine group.

The mean age of the patients in the long-term follow-up group was about 9 years. Mean doses were 1.27 grams/m 2 per day and 1.87 grams/m 2 per day in the two groups and WBC cystine concentrations averaged 1.72 ± 1.65 nmol ½ cystine/mg protein and 1.86 ± 0.92 nmol ½ cystine/mg protein in the 1.3 grams/m 2 per day and 1.95 grams/m 2 per day in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Cysteamine has not been tested for its carcinogenic potential in long-term animal studies. PROCYSBI was not mutagenic in the Ames test. It produced a negative response in an in-vitro sister chromatid exchange assay in human lymphocytes, but a positive response in a similar assay in hamster ovarian cells.

Repeat breeding reproduction studies were conducted in male and female rats. Cysteamine was found to have no effect on fertility and reproductive performance at an oral dose of 75 mg/kg per day (450 mg/m 2 per day, 0.4 times the recommended human dose based on body surface area). At an oral dose of 375 mg/kg per day (2250 mg/m 2 per day, 1.7 times the recommended human maintenance dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.