Procysbi Drug Information

Clinical 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 the two groups, respectively. In new patients, serum creatinine was essentially unchanged over the period of follow-up (about half of the patients were followed for 24 months) and phosphocysteamine and cysteamine hydrochloride had similar effects.

The long-term follow-up group also had essentially no change in renal function (almost 80% were followed at least 2 years). In four studies of patients with untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Both new patients and patients in the long-term follow-up group maintained height (although they did not catch up from baseline). There was no apparent difference in height maintenance between the two doses.

Clinical Trials with

PROCYSBI Multi-Center, Open-Label, Randomized Clinical Trial in Patients Receiving Immediate-Release Cysteamine Bitartrate A clinical trial comparing immediate-release cysteamine bitartrate and PROCYSBI was conducted in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis (Study RP103-03; NCT01000961). Patient age ranged from 6 to 26 years (mean age 12 years) and 56% were male. Patients with WBC cystine concentrations greater than 2 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) and estimated glomerular filtration rate (eGFR corrected for body surface area) less than 30 mL/minute/1.73 m 2 at the time of screening were excluded from the trial. Prior to randomization, patients were to be on a stable dose of immediate-release cysteamine bitartrate administered every six hours.

PROCYSBI dose adjustments of up to approximately 100% of the total daily dose of immediate-release cysteamine bitartrate were allowed by trial criteria. The average total daily dose of PROCYSBI for patients completing the clinical trial was approximately 91% of the average total daily dose of immediate-release cysteamine bitartrate for patients at trial entry. This trial demonstrated that at steady-state, PROCYSBI administered every 12 hours was non-inferior to immediate-release cysteamine bitartrate administered every 6 hours with respect to the depletion of WBC cystine concentrations (Table 5). Using a linear mixed effects statistical analysis model, the least-square-mean value of WBC cystine was 0.52 ± 0.06 nmol ½ cystine/mg protein after 12 hours under PROCYSBI and 0.44 ± 0.06 nmol ½ cystine/mg protein after 6 hours under immediate-release cysteamine; a difference of 0.08 ± 0.03 nmol ½ cystine/mg protein (95.8% Confidence Interval = 0.01 to 0.15). Table 5: Comparison of WBC cystine concentrations in open-label, randomized, cross-over clinical trial participants, who were on a stable dose of immediate-release cysteamine prior to randomization, with WBC cystine less than 2 nmol ½ cystine/mg protein throughout the trial Per–Protocol (PP) Population (N=39) Immediate-release cysteamine bitartrate PROCYSBI WBC cystine concentration in nmol ½ cystine/mg protein (LS Mean ± SE) 0.44 ± 0.06 0.52 ± 0.06 Difference in Treatment effect (LS mean ± SE) 0.08 ± 0.03 Multi-Center, Single-Arm, Open-Label, Long-Term Extension Clinical Trial of PROCYSBI Forty of the 41 patients completing the randomized trial continued treatment with PROCYSBI in an open-label extension trial, for a total treatment duration ranging from 1 month to 6.7 years in the study (Study RP103-03-04; NCT01197378). Thirty-six of the 40 patients continued treatment with PROCYSBI for at least 24 months and 20 patients continued treatment for longer than 60 months in the extension trial, and maintained their mean WBC cystine concentrations below 1 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) over this time period.

Thirteen pediatric patients, aged 2 to 6 years, were also enrolled in the extension trial and treated with PROCYSBI. All of them were on treatment with immediate-release cysteamine bitartrate at the time of enrollment. All 13 patients received at least 18 months of treatment with PROCYSBI, and their mean ± SD WBC cystine concentration (measured using the mixed leukocyte assay) decreased from 1.41 ± 1.03 nmol ½ cystine/mg protein at baseline to 1.22 ± 1.40 nmol ½ cystine/mg protein after 18 months of treatment. Seven of these pediatric patients were able to achieve a WBC cystine concentration (measured using the mixed leukocyte assay) of less than 1.0 nmol ½ cystine/mg protein after 18 months of treatment; their mean ± SD dose of PROCYSBI increased from 0.81 ± 0.25 grams/m 2 per day at baseline to 0.90 ± 0.25 grams/m 2 per day after 18 months of treatment.

During extended treatment with PROCYSBI, mean estimates of renal function, as measured by the eGFR, were maintained. Multi-Center, Open-Label, Clinical Trial in Cysteamine Naïve Patients Less than 6 Years of Age A clinical trial of PROCYSBI (Study RP103-08; NCT01744782) was conducted in 17 patients with a documented diagnosis of nephropathic cystinosis who were naïve to cysteamine treatment (15 patients between the ages of 1 and 5 years, one 9-year old and one 22-year old). The PROCYSBI starting dose was ¼ the maintenance dose of 1 gram/m 2 /day (actual dosing was based on weight bands using the available capsule strengths, as shown in (Table 1) and the dosage was gradually increased by 10% every 2 weeks. Dosage adjustment was allowed throughout the trial and was based on subject-specific factors (e.g., weight, tolerability) and WBC cystine concentrations.

WBC cystine concentrations were obtained 30 minutes after the morning dose collected bi-monthly until the patient's WBC cystine concentration (using the mixed leukocyte assay) was < 1 nmol ½ cystine/mg protein. Treatment duration was at least 12 months. Fourteen of the 15 patients between 1 year and less than 6 years of age completed 12 months of treatment, and 10 patients completed 18 months of treatment.

Thirteen of the 14 patients achieved their highest total daily dosage of PROCYSBI following the 9-month visit (9-month visit for 8 subjects, 12-month visit for 4 subjects, and 18-month visit for 1 subject). Some patients did not have WBC cystine samples collected at each visit or results were not reportable due to laboratory errors. Thus, the numbers of patients with available WBC cystine data varied across the time points analyzed. In patients with missing samples, dose escalation was continued if the patient's last reported WBC cystine concentration was > 1 nmol ½ cystine/mg protein.

In patients 1 year to less than 6 years, the mean (±SD) WBC cystine concentration on Day 1, 30 minutes following the first dose, was 3.17±2.95 nmol ½ cystine/mg protein (n=15 patients). At 12 months (13 patients with samples), the mean WBC cystine concentration was 0.80 ± 0.60 nmol ½ cystine/mg protein at 30 minutes post dose. At 18 months (9 patients with samples) the mean WBC cystine concentration was 0.74 ± 0.64 nmol ½ cystine/mg protein at 30 minutes post dose. In patients 1 year to less than 6 years, the mean (±SD) weight percentiles at Day 1 (n=14), 12 months (n=13) and 18 months (n=10) were 3.5 ± 11.1, 11.9 ± 18.3, and 30.1 ± 28.2, respectively, and patient weight z-scores were -4.0 ± 2.1, -2.2 ± 1.7, and -1.3 ± 2.0, respectively.

In the same patients, similar trends were observed for height.