Efficacy

RP103 met the predefined criteria for noninferiority relative to Cystagon in a study that included patients who had been stabilized on Cystagon prior to randomization. The claim of noninferiority was based on WBC cystine level. WBC cystine is the only available biomarker for monitoring effectiveness of cystine-depleting treatment (see Appendix 4b). Newly diagnosed nephropathic cystinosis patients often have WBC cystine levels in the range of 3 to 10 nmol half cystine/mg protein, while controlled individuals generally have levels between 0.2 and 0.5 nmol half cystine/mg protein. In the RP103-03 study, the investigators selected a noninferiority margin of 0.3 nmol half cystine/mg protein. While the relationship between cystine levels and renal function has been described, the minimal clinically important change in WBC cystine has not been clearly established and therefore it is not known if the selected noninferiority margin is a good approximation of the minimal clinically important difference (Appendix 4b).

There were very few differences observed in the other outcomes measured in study RP103-03. There were very few statistical comparisons performed in this study for clinical outcomes. There were no large numerical differences in quality of life (PedsQL 4.0), adherence to therapy, or swallowing outcomes between the two cysteamine products. Data on survival and renal function were collected, but were uninformative because of the small size and short duration of the study.

There were several outcomes measured in the RP103-03 study that were also identified by patient groups as important, such as quality of life, survival, time to kidney transplant, or adherence to therapy. The study was very short and was not designed to test differences between the cysteamine products for these outcomes.

Drug levels were monitored during the RP103-03 study, and while pharmacokinetic parameters were not an outcome of interest in this review, research has shown that one hour after the ingestion of immediate-release cysteamine plasma levels of cysteamine reach a maximum, while WBC cystine levels drop to minimum levels.²⁰ This is followed by a gradual decline in cysteamine levels and a gradual increase in WBC cystine levels. Six hours after ingestion, both cysteamine and WBC cystine levels reach their original values. This has underscored the importance of adherence to this treatment every six hours, including the need for a nighttime dose to be administered.²⁰

Harms

The proportion of patients reporting adverse events in study RP103-03 was higher during treatment with RP103, compared with the period in which patients received Cystagon. The rates of gastrointestinal events were higher during treatment with RP103 (33%) than during treatment with Cystagon (22%). The investigators suggested that this may be explained by the lower usage of PPIs during treatment with RP103. This explanation may be valid and it illustrates the risk of gastrointestinal adverse events when RP103 is taken according to the product labelling.¹⁵ The Canadian product monograph for Procysbi cautions against concomitant use of PPIs or other drugs that increase gastric pH because of variability with cysteamine absorption with Procysbi.

Non-gastrointestinal adverse events were also higher during treatment with RP103 (26%) compared with treatment with Cystagon (10%).

RP103-03 was a very short study. Signals of increase in harms were observed for gastrointestinal and non-gastrointestinal adverse effects. Relative risk of harm requires further study in future clinical trials. One open-label, non-comparative extension study (RP103-04) was conducted following the RP103-03 study. It included 40 patients from study RP103-03 and 19 additional patients, including 13 children under the age of seven and followed them for up to six months (Appendix 5). There is an open-label, non-comparative study (RP103-07) that has been completed and not yet published, but its preliminary findings were available. This study enrolled 41 patients, excluding patients less than 12 years of age (mean age 24.5 years), and followed them for up to 48 months. The non-comparative design and study withdrawal rates limit the extension studies’ ability to provide new information regarding the relative efficacy and harms of Procysbi. The extension studies were able to demonstrate that treatment with RP103 over a longer time period can maintain WBC cystine within the target range (1 nmol half cystine/mg protein), however the non-comparative study failed to maintain a WBC cystine within this target range during RP103 treatment. Adverse events and serious adverse events were common and included diarrhea, vomiting, abdominal pain, and nausea.

Other considerations

According to the clinical expert, cysteamine in the form of Cystagon is the most relevant comparator for Procysbi (RP103) in the Canadian context. Cystagon was available through Health Canada’s Special Access Programme. Some provinces, such as Ontario, offer coverage to some patients. There is one other similar product available through the special access program, phosphocysteamine. Both immediate-release products became inaccessible during the course of the CDR review after Procysbi became available on the market in Canada.

Potential place in therapy¹

Currently nephropathic cystinosis is treated with a variety of supporting medications, but the disease-modifying agent is cysteamine. The agent is not marketed in Canada and is only available through special access request through Heath Canada. The clinical expert involved in the review stated that the administration of immediate-release cysteamine (either as phosphocysteamine or cysteamine) is fraught with several limitations: the medications require four-times-a-day strict dosing to enable stable levels leading to reduction of whole WBC cystine levels; the cysteamine metabolism is associated with higher peak levels, which is thought to contribute to the excretion of the drug into the skin and contribute to the sulphurous odour that impacts the social functioning of those affected; nonadherence to this medication occurs at a high frequency and is a considerable issue, not only due to the difficulty of administering a middle of the night dose, but because of the sulphurous odour in sweat and saliva; and 4) the prevalence of gastrointestinal side effects associated with this medication may limit achieving a therapeutic dose necessary to reduce whole WBC levels of cystine. Identification of a medication that allows for twice-daily administration with stable drug levels is expected to have beneficial effects on the side effect profile and adherence, and ultimately may facilitate easier attainment of reductions of whole WBC cystine levels to within therapeutic targets. The quality of life of the families caring for a patient with cystinosis is similarly likely to be positively impacted through improved sleep and simplification of the medical therapeutic regimen.

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 on other outcomes.

Nephropathic cystinosis patients are easily identified in Canada as there are at least two reference laboratories that are able to conduct the whole WBC cystine assay necessary for diagnosis.