The effects of transitioning from immediate release to extended release cysteamine therapy in Norwegian patients with nephropathic cystinosis: a retrospective study.

BACKGROUND: Nephropathic cystinosis is a rare lysosomal storage disorder in which accumulation of cystine and formation of crystals particularly impair kidney function and gradually lead to multi-organ dysfunction. Lifelong therapy with the aminothiol cysteamine can delay the development of kidney failure and the need for transplant. The purpose of our long-term study was to explore the effects of transitioning from immediate release (IR) to extended release (ER) formulation in Norwegian patients in routine clinical care. METHODS: We retrospectively analysed data on efficacy and safety in 10 paediatric and adult patients. Data were obtained from up to 6 years before and 6 years after transitioning from IR- to ER-cysteamine. RESULTS: Mean white blood cell (WBC) cystine levels remained comparable between the different treatment periods (1.19 versus 1.38 nmol hemicystine/mg protein) although most patients under ER-cysteamine underwent dose reductions. For the non-transplanted patients, the mean estimated glomerular filtration rate (eGFR) change/year was more pronounced during ER-treatment (- 3.39 versus - 6.80 ml/min/1.73 m2/year) possibly influenced by individual events, such as tubulointerstitial nephritis and colitis. Growth measured by Z-height score tended to develop positively. Four of seven patients reported improvement of halitosis, one reported unchanged and two reported worsened symptoms. Most adverse drug reactions (ADRs) were of mild severity. One patient developed two serious ADRs and switched back to IR-formulation. CONCLUSIONS: The results from this long-term retrospective study indicate that switching from IR- to ER-cysteamine was feasible and well tolerated under routine clinical practice. ER-cysteamine allowed satisfactory disease control over the long period considered. A higher resolution version of the Graphical abstract is available as Supplementary information.

Switching from immediate- to extended-release cysteamine in patients with nephropathic cystinosis: from clinical trials to clinical practice.

Background: The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Methods: We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12 months, switched to ER cysteamine, and received it for at least 6 months before inclusion. Results: Data were collected from nine patients (four children, five adults) 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Conclusions: Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population.

The Clinical Manifestations and Disease Burden of Cystinosis in Saudi Arabia: A Single-Tertiary Center Experience.

BACKGROUND: There is a lack of regional and local evidence that describes the nature of cystinosis, a multiorgan accumulation of cystine, and its extent of organ damage. Therefore, this study aimed to determine the outcomes of cystinosis in patients who were followed up at a large tertiary care hospital. METHODS: Medical records of patients with cystinosis were retrospectively reviewed. Patients' baseline demographics, lab values, medications, comorbidities, and complications were collected and described. Univariable and multivariable logistics regression models were constructed to control for confounders and build prediction models. RESULTS: In our cohort of 39 patients, the mean age was 13.8±9.9 years. Approximately 56.4% of the patients had stunted growth, and the mortality rate was 25.6%. Regarding complications, the majority of patients developed myopathy (79.5%), end-stage renal disease (ESRD) (74.4%), and hypothyroidism (71.8%). Age (odds ratio=1.14, 95% confidence interval (95% CI): 1.012, 1.285) and stunted growth (odds ratio=6.62, 95% CI: 1.024, 42.835) were found to be predictors of renal replacement therapy and renal transplantation, respectively (p<0.047). CONCLUSION: This study on cystinosis patients reveals a high incidence of renal complications, with a significant mortality rate and common complications such as myopathy and ESRD. Age was found to be an independent risk factor for renal replacement therapy, while stunted growth predicted the need for transplantation. These findings underscore the urgency for early diagnosis, comprehensive treatment, and careful monitoring in managing cystinosis effectively.

Long-term clinical benefits of delayed-release cysteamine bitartrate capsules in patients with nephropathic cystinosis (response to "A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis").

The aim of this letter to the editor is to summarize the results from three clinical trial programs evaluating delayed-release cysteamine bitartrate (DR-CYS), which demonstrated the long-term clinical benefits in patients with nephropathic cystinosis when dosed every 12 h. The authors of "A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis" presented recommendations altering the dosage and dosing scheme from what has been previously approved by the FDA for DR-CYS. In this letter to the editor, we critique the authors' aforementioned article as it is a retrospective analysis of a small number of patients and does not follow the dosing recommendation by the FDA for equivalent dosing of DR-CYS to immediate-release cysteamine bitartrate (IR-CYS). In addition, the article does not include study data to properly support the authors' suggestion of increased dosing effects and benefits. We present a summary of the results from the DR-CYS clinical trial program and evidence of the rigor from which the clinical data for DR-CYS were generated and recommendation for usage as prescribed.

Enteric-Coated Cysteamine Bitartrate in Cystinosis Patients.

Cystinosis is a severe inherited metabolic storage disease caused by the lysosomal accumulation of cystine. Lifelong therapy with the drug cysteamine bitartrate is necessary. Cysteamine cleaves intralysosomal cystine, and thereafter, it can exit from the organelle. The need for frequent dosing every 6 h and the high prevalence of gastrointestinal side effects lead to poor therapy adherence. The purpose of our study was to improve cysteamine treatment by comparing the efficacy of two cysteamine formulas. This is highly relevant for the long-term outcome of cystinosis patients. The cystine and cysteamine levels of 17 patients taking immediate-release cysteamine (IR-cysteamine/Cystagon®) and 6 patients taking encapsulated delayed-release cysteamine (EC-cysteamine) were analyzed. The EC-cysteamine levels showed a near-ideal pharmacokinetic profile indicative of delayed release (longer Tmax and Tmin), and the corresponding cystine levels showed few fluctuations. In addition, the Cmax of IR-cysteamine was greater, which was responsible for unbearable side effects (e.g., nausea, vomiting, halitosis, lethargy). Treatment with EC-cysteamine improves the quality of life of cystinosis patients because the frequency of intake can be reduced to 2-3 times daily and it has a more favorable pharmacokinetic profile than IR-cysteamine. In particular, cystinosis patients with no access to the only approved delayed-release cysteamine Procysbi® could benefit from a cost-effective alternative.

Cysteamine bitartrate delayed-release capsules control leukocyte cystine levels and promote statural growth and kidney health in an open-label study of treatment-naïve patients <6 years of age with nephropathic cystinosis.

Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease that is characterized by accumulation of cysteine and formation of crystals within cells of different organs and tissues causing systemic manifestations in childhood that include poor linear growth, ocular involvement, hypothyroidism, and progressive kidney disease. This study was a long-term, prospective open-label evaluation of twice-daily delayed release (DR) cysteamine capsules in cystinosis patients <6 years of age who were naïve to any form of cysteamine treatment. Fifteen treatment-naïve patients <6 years old (mean age 2.2 ± 1.0 years, 53% male, 73% White) were enrolled and treated with DR-cysteamine capsules for up to 18 months. Patients had clinically meaningful decreases in WBC cysteine concentration during treatment (3.2 ± 3.0 nmol ½ cystine/mg protein at Day 1 to 0.8 ± 0.8 nmol ½ cystine/mg protein at study exit), and anthropometric data improvements were consistently observed in height, weight and body surface area. Additionally, estimated glomerular filtration rate increased from 55.93 ± 22.43 ml/min/1.73 m2 at baseline to 63.79 ± 21.44 ml/min/1.73 m2 at study exit. Pharmacokinetic/Pharmacodynamic results support the use of the same starting, escalation, and maintenance doses according to body surface for children aged <6 years that are currently recommended in adults and older children. All patients experienced ≥1 adverse event(s) with vomiting (80%) and upper respiratory tract infection (53%) most frequently reported. Based on our study, patients <6 years of age with nephropathic cystinosis without prior treatment can safely and effectively initiate treatment with DR-cysteamine, a delayed-release form of cysteamine bitartrate that can be given every 12 h.

A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis.

BACKGROUND: Nephropathic cystinosis is a rare and severe metabolic disease leading to an accumulation of cystine in lysosomes which especially harms kidney function. A lifelong therapy with the aminothiol cysteamine can delay the development of end-stage renal disease and the necessity of kidney transplantation. The purpose of our study was to compare the effectiveness of immediate-release and delayed-release cysteamine on cystine and cysteamine levels as well as assessing the onset of adverse effects. METHODS: We retrospectively analysed cystine and cysteamine levels of 17 patients after a single dose of immediate-release cysteamine (Cystagon®, Mylan Pharmaceuticals, Canonsburg, PA and Recordati Pharma GmbH) as well as a single dose of delayed-release cysteamine (Procysbi®; Horizon Pharma USA and Chiesi Farmaceutici S.p.A., Parma, Italy) respectively. Data were collected during a period of three years in the context of optimizing the individual treatment regimens. The dose of DR-cysteamine was reduced to 70% of the equivalent dose of IR-cysteamine. The efficacy of both formulas in depleting white blood cells' cystine levels and their side effects were compared. RESULTS: Immediate (IR)- and delayed-release (DR) cysteamine effectively decreased intracellular cystine levels under the target value of 0.5 nmol cystine/mg protein, while fewer side effects occurred under DR-cysteamine. Mean maximum levels of cysteamine were reached after 60 min with IR-cysteamine and after 180 min with DR-cysteamine. CONCLUSION: A therapy with DR-cysteamine is as effective as IR-cysteamine while less side effects were reported. Our data show that DR-cysteamine should be dosed higher than 70% of the equivalent dose of IR-cysteamine in order to decrease cystine levels over an extended period of time. Moreover, our data suggest increasing the dosing scheme of Procysbi® to three times daily, to prevent a rapid decrease and achieve a steadier decline in cystine levels. Due to the more convenient dosing scheme, DR-cysteamine might ameliorate therapy adherence and improve patients' quality of life.

A systematic literature review of cysteamine bitartrate in the treatment of nephropathic cystinosis.

OBJECTIVES: To summarize available clinical evidence for cysteamine bitartrate preparations in the treatment of nephropathic cystinosis as identified through a systematic literature review (SLR). METHODS: We searched MEDLINE, MEDLINE In-Process and Embase using Ovid with a predefined search strategy through 19 January 2016. All publicly available clinical reports on the use of delayed-release (DR) cysteamine bitartrate (Procysbi 1 ) or immediate-release (IR) cysteamine bitartrate (Cystagon 2 ) in patients with cystinosis were included. RESULTS: We identified a total of 103 publications and 10 trial records. Of these, 9 studies describe DR cysteamine bitartrate (n = 267 patients), 42 describe IR cysteamine bitartrate (n = 1,427 patients) and in 53 studies the exact preparation was not specified (n = 906 patients). The vast majority of the studies used a non-randomized study design, with randomized clinical trials (RCTs) being scarce (1 study comparing DR and IR formulation) and case reports (n = 49) being the most common study design representing 47% of the total. CONCLUSION: A substantial evidence base for cysteamine bitartrate in the treatment of nephropathic cystinosis was identified. However, the majority of the evidence was of relatively low quality, with evidence levels of 3 or 4.