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| Drug | Cysteamine delayed-release capsules (Procysbi) |
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| Indication | Treatment of nephropathic cystinosis |
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| Reimbursement Request | As per indication |
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| Dosage Form(s) | Delayed-release 25 mg and 75 mg capsules |
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| NOC Date | 13 June 2017 |
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| Manufacturer | Horizon Pharma Ireland Ltd. |
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Introduction
Cystinosis is a rare autosomal recessive metabolic disease, caused by mutations in the cystinosin, lysosomal cystine transporter (CTNS) gene.1 These mutations cause a defect in cystinosin transport of cystine out of the lysosome, resulting in an accumulation of cystine in all organs with initial manifestation in the kidney.1,2 Renal symptoms include the appearance of severe Fanconi syndrome or tubulopathy that later progresses to chronic kidney disease, where renal replacement therapy of choice is kidney transplantation.1 Ocular symptoms are characterized by cystine crystal deposits in the cornea, which can result in photophobia and reductions in visual acuity.1,3 Other manifestations can include growth retardation, irregular retinal depigmentation, rickets, hepatomegaly, hypothyroidism, insulin-dependent diabetes, muscular weakness, neurocognitive abnormalities, bone fractures, and infertility.1–3 Cystinosis is classified into three different subtypes based on severity of the CTNS gene mutation;3 infantile nephropathic form, juvenile nephropathic form, and adult nonnephropathic. The infantile nephropathic form is the most serious form and the most prevalent, implicated in 95% of cases.1,3
Management of nephropathic cystinosis currently consists of both symptomatic treatment and specific treatment with cysteamine. Therapy with oral cysteamine is used to preserve renal function and reduce extrarenal complications. It is often started at the time of diagnosis of cystinosis and continued lifelong.4
Procysbi (delayed-release cysteamine) is indicated for the treatment of nephropathic cystinosis and is available in 25 mg and 75 mg oral capsules. The recommended maintenance dose for cysteamine-naive patients is 1.30 g/m2 per day, divided into two equal doses given every 12 hours.
The objective of this review is to perform a systematic review of the beneficial and harmful effects of delayed-release cysteamine (Procysbi [RP103]).
Results and Interpretation
Included studies
One study met the inclusion criteria for this review. Study RP103-03 (N = 43) was a randomized, crossover, open-label study evaluating the noninferiority of RP103 (enteric-coated, delayed-release cysteamine) with Cystagon (immediate-release cysteamine). Patients were greater than and equal to 6 years old, had nephropathic cystinosis, and were on a stable dose of Cystagon sufficient to maintain their white blood cell (WBC) cystine level at less than and equal to 2.0 nmol half cystine/mg protein. Randomization was preceded by a two- to three-week run-in period during which all patients received Cystagon every six hours. There were two treatment periods of three weeks each, with no washout period between treatments. The primary outcome of the study was mean peak WBC cystine levels. Noninferiority testing of RP103 compared with Cystagon was based on WBC cystine levels.
There were several weaknesses in the study design. The study was not blinded, and while the justification for not using blinded methodology was reasonable, the lack of blinding could have introduced bias into the assessment of subjective outcomes such as health-related quality of life and adverse events. Furthermore, the reasons for selecting a noninferiority margin of 0.3 nmol half cystine/mg protein did not appear to be based upon the minimal clinically important difference. The minimal clinically important difference for WBC cystine has not been established (Appendix 4b). The impact of a difference smaller than the noninferiority margin on clinical outcomes is not known.
Efficacy
No data were available for some outcomes listed in the review protocol, specifically: patient growth, time to renal transplant, kidney function, growth hormone usage, cognitive function, impact on thyroid function, pulmonary dysfunction, incidence of myopathy, cholesterol levels, retinopathy, vascular/cerebral calcifications, glucose control, and hypergonadotropic hypogonadism.
No patients died during the study. Health-related quality of life (HRQoL) was measured using the PedsQL 4.0 Core Scale. There was no statistical testing performed on the data and there were no obvious differences observed between the two treatments. In the per-protocol population, the least squares mean for WBC cystine at week 3 in the RP103 and Cystagon groups were 0.52 and 0.44 nmol half cystine/mg protein, respectively (mean difference: 0.08; 95.8% confidence interval [CI], 0.012 to 0.15; P < 0.001). In the intent-to-treat (ITT) population, the least squares mean for WBC cystine at week 3 in the RP103 and Cystagon groups were 0.53 and 0.74 nmol half cystine/mg protein, respectively (mean difference: −0.21; 95.8% CI, −0.48 to 0.06; P value not reported). The upper limit of the 95.8% confidence interval was lower than the noninferiority margin of 0.3 nmol half cystine/mg protein in the per-protocol and the ITT analyses. There were no clinically significant differences observed between the two treatments for kidney function, adherence to therapy, or swallowing difficulties, but the study was not designed to detect differences in these outcomes.
Harms
Overall, 58% and 32% of patients reported adverse events during treatment with RP103 and Cystagon, respectively. Gastrointestinal adverse events were the most frequently reported category of adverse event and were reported in 14 patients (33%) during treatment with RP103 and in nine patients (22%) during treatment with Cystagon. Of the more frequently reported adverse events, patients reported nausea (16%), vomiting (19%), and abdominal pain (9%) during treatment with RP103, compared with 7%, 12%, and 0%, during treatment with Cystagon, respectively. The incidence of non-gastrointestinal adverse events in the study was 26% during treatment with RP103 and the incidence was 10% during treatment with Cystagon.
Potential Place in Therapy
The clinical expert consulted for the review noted that, based on its design, included outcomes, and limited statistical comparisons, the RP103-03 study really only addresses the reduction of whole WBC cystine levels. The observed effect with Procysbi relative to Cystagon in the study likely indicates that Procysbi has a clinically meaningful effect in reducing cystine levels, similar to that of Cystagon; however, there remains uncertainty about the relative effects of Procysbi on other outcomes.
Conclusions
Results of a small crossover randomized controlled trial (RCT) indicated that Procysbi (RP103) is noninferior to Cystagon based on WBC cystine levels after three weeks of open-label treatment. A noninferiority boundary of 0.3 nmol half cystine/mg protein was selected, but the minimal clinically important change in WBC cystine is not known. There were no clinically significant differences observed between the two cysteamine formulations for other outcomes such as adherence to therapy, swallowing ability, or quality of life, but the trial was not designed to show differences in these outcomes. The rates of serious adverse events, as well as non-serious gastrointestinal and non-gastrointestinal adverse events, were higher during treatment with Procysbi compared with the rates observed during treatment with Cystagon.
Table 1Summary of Efficacy Results — WBC Cystine Levels
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| Population | Treatment | N | LSM (SE) | Difference of LSM (SE) | 95.8% CI of LSM Difference | P Value |
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| Per-Protocol | Cystagon | 39 | 0.44 (0.06) | 0.08 (0.03) | 0.01 to 0.15 | < 0.0001 |
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| RP103 | 39 | 0.52 (0.06) |
| Intent-to-Treat | Cystagon | 41 | 0.74 (0.14) | −0.21 (0.13) | −0.48 to 0.06 | NR |
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| RP103 | 43 | 0.53 (0.14) |
CI = confidence interval; LSM = least squares mean; NR = not reported; SE = standard error.
Source: FDA Medical Review5 Clinical Study Report.6
Table 2Summary of Harms in Study RP103-03
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| Treatment Period |
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| Parameter | Run-In
N = 43 | RP103
N = 43 | Cystagon
N = 41 | Overall
N = 43 |
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| Patients with ≥ 1 AE, n(%) | 13 (30) | 25 (58) | 13 (32) | 34 (79) |
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| AE with overall incidence ≥ 5% | | | | |
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| Vomiting | 3 (7) | 8 (19) | 5 (12) | 14 (33) |
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| Nausea | 1 (2) | 7 (16) | 3 (7) | 10 (23) |
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| Abdominal pain | 4 (9) | 4 (9) | 0 | 8 (19) |
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| Headache | 2 (5) | 4 (9) | 0 | 5 (12) |
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| Decreased appetite | 0 | 1 (2) | 2 (5) | 3 (7) |
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| Hypokalemia | 0 | 3 (7) | 0 | 3 (7) |
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| Cough | 1 (2) | 2 (5) | 0 | 3 (7) |
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| Rhinorrhea | 3 (7) | 0 | 0 | 3 (7) |
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| Renal impairment | 0 | 2 (5) | 1 (2) | 3 (7) |
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| Patients with ≥ 1 SAE, n(%) | 0 | 6 (14) | 1 (2) | 7 (16) |
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| Abdominal discomfort | 0 | 1 (2) | 0 | 1 (2) |
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| Vomiting | 0 | 1 (2) | 0 | 1 (2) |
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| Hypokalemia | 0 | 1 (2) | 0 | 1 (2) |
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| Hypovolemia | 0 | 0 | 1 (2) | 1 (2) |
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| Gastroenteritis | 0 | 1 (2) | 0 | 1 (2) |
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| Femur fracture | 0 | 1 (2) | 0 | 1 (2) |
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| Knee deformity | 0 | 1 (2) | 0 | 1 (2) |
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| Patients with ≥ 1 AE leading to discontinuation, n(%) | 0 | 1 (2)
(cellulitis) | 0 | 1 (2) |
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AE = adverse event; N = total number of patients; n = number of patients in subgroup; SAE = serious adverse event.
Source: Clinical Study Report.6
