New ophthalmic solution for cystinosis

Cystinosis is a multi-organ, progressive and debilitating life-threatening genetic disorder caused by the intracellular accumulation of the amino acid cystine as a result of defects in cystinosin, a protein responsible for lysosomal efflux. The disease may affect the renal, endocrine, neurological, and muscular organ systems and manifests early in life in the most severe cases. Treatment consists of supportive symptomatic therapy accompanied by lifelong oral administration of the aminothiol cysteamine (also known as mercaptamine), an enzyme that converts cystine to free cysteine and cysteine-cysteamine mixed disulphide structures inside the lysosomes, which are then transported out of the organelles via regular export systems for lysine.

Once in the cytoplasm, these complexes are reduced by glutathione into cysteine and cysteamine, which re-enters the lysosomes to react with cystine once again. Cysteamine administration, when initiated early in childhood, delays the progression of the renal pathology and the need for kidney transplantation, and also prevents or slows down the development of extra-renal manifestations.^1,2

In addition to the systemic manifestations, cystine crystals build up in the corneas of all cystinosis patients and can produce eye pain, recurrent corneal abrasion and calcification, decrease in visual acuity, photophobia and blepharospasm. However, systemic cystine-depletion therapy does not clear the amino acid’s deposits in the eye due to the limited vascularisation of the cornea, and topical administration is required to reverse the formation of crystals in the anterior eye and to prevent late ophthalmic complications such as peripheral corneal neovascularisation, retinopathy, glaucoma and blindness, which may in some cases require corneal transplantation.^1–3

Historically, aqueous solutions of cysteamine hydrochloride for ocular administration have been prepared ex tempore at hospital compounding pharmacies, and the absence of standardised protocols and procedures can result in substantial variations from site to site in the concentration of the active ingredient, and hence in effectiveness, as well as in chemical stability, which greatly shortens the shelf-life of the medication.

Conversion of cystine and action of cysteamine (mercaptamine)

These compounded formulations have to be applied frequently during the day, from six times a day up to every hour the patient is awake and, as a consequence, there is necessarily an overnight treatment gap. The inconvenience of multiple daily applications also strongly contributes to the burden of the disease and suboptimal adherence to treatment, potentially causing further structural damage in the long term.⁴

Despite these limitations of formulations supplied by hospitals in regard to pharmacological properties and dosing, there are still few commercially available options worldwide. Cystaran™ (cysteamine hydrochloride), developed by Sigma-Tau Pharmaceuticals in collaboration with the National Institutes of Health (NIH), is the only ophthalmic solution for the treatment of ocular cystinosis in the US, but the medicinal product only received regulatory approval in 2012 owing to stability issues with its active ingredient.⁵

Cystaran™ has a shelf-life of one week and requires hourly dosing as the average hospital-compounded eye drops, and therefore does not represent a substantial technical advance in terms of formulation (see Table 1). Side effects resulting from its use include headaches, sensitivity to light, eye redness and pain/irritation, as well as visual field defects.⁶

Several attempts have been made over the years to improve cysteamine eye drop formulations in regard to optical penetration and stability, with varying degrees of success. In 2015, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency refused to recommend one of these formulations, Dropcys, to receive marketing authorisation in the EU owing to insufficient clinical data supporting efficacy and long-term safety and a lack of stability assessments of the solution upon reconstitution (see Table 1).⁷

Recent studies have, however, demonstrated the benefits of viscosity-modified, controlled-release synthetic hydrogel formulations of cysteamine containing polymers such as sodium hyaluronate, hydroxyethyl cellulose and carbomer 934.^8,9 In January 2017, the European commission granted Marketing Authorisation to Cystadrops® (cysteamine hydrochloride), a gel-based formulation of cysteamine developed by Orphan Europe, to reduce the corneal accumulation of cystine crystals in patients with ocular cystinosis aged two years old or older. This medicine will be available as a 3.8 mg/g cysteamine solution and presents significant advantages relative to compounded formulations (see Table 1).¹⁰

In parallel to these significant formulation advances, investigations of alternative treatments and ocular delivery systems are currently ongoing. As an example, a synergistic nanowafer system with extended stability at room temperature that administers cysteamine once a day showed promising results in a cystinosin-deficient mouse model of cystinosis at lower doses, compared to topical eye drops administered twice a day (see Table 1).¹¹

Hospital ophthalmic cysteamine hydrochloride formulations are usually simple water-based solutions or may be available in the form of a lyophilised powder that must be reconstituted before use. They are usually prepared for specific patients and have short shelf-lives owing to the inherent pH-dependent instability of the active ingredient in aqueous solutions, where it is easily subjected to oxidation to disulphide, and sensitivity to heating and light.

Additionally, they require a high number of applications, which creates obstacles to compliance among adults, and in particular among children and adolescents. Other current limitations of these compounded eye drops include a short contact time of the active ingredient with the eye, low tissue penetration, and rapid elimination caused by blinking and the natural eye drainage to the nasolacrimal duct.^4,8 

By contrast, the new Cystadrops^® gel formulation is transparent and bioadhesive and presents increased viscosity, allowing for a longer contact with the surface of the eye. These favourable rheological properties can have significant impact on treatment adherence through a decrease in the number of instillations needed; in fact, Cystadrops^® is administered four times daily versus hourly during waking hours for other formulations.

Moreover, this medicinal product shows improved stability (up to seven days) and can be stored at room temperature for easier usage, whereas other formulations need to be refrigerated (see Table 1). Finally, a more neutral pH value of the hydrogel formulation also reduces the stinging, itching, lacrimation and discomfort experienced during applications.^4,8

The relatively rapid action of cysteamine hydrochloride eye drops in the relief of ocular pain and photophobia is well documented. A solution at a concentration of 0.11% showed to be superior to placebo in reducing cystine deposit formation in early studies conducted at the NIH in the US. Subsequent studies provided evidence of increased efficacy, while maintaining an acceptable tolerability profile, for a more concentrated solution (0.55%) administered at least six times per day, and up to every hour during the day, but no effects on crystal formation were seen with a dosing schedule of four times a day.

An improved formulation containing benzalkonium chloride was developed in order to improve microbiological stability, but this preservative should be avoided in patients showing hypersensitivity to this substance and in those using soft contact lenses or presenting corneal ulcerations.⁴

The efficacy of Cystadrops^® has been evaluated in two clinical studies conducted in Europe. In an open-label, dose-response, Phase I/II study (the Cystadrops OCT-1 study), which involved eight patients with nephropathic cystinosis, a fixed-dose regimen of a standard 10% cysteamine hydrochloride solution, prepared in the pharmacy of a central hospital, was administered three to five times daily before initiation of treatment with the new Cystadrops^® formulation, according to an adaptive dosing regimen based on the number of cystine deposits.

Initially, the reduction in the corneal cystine crystal density was comparable to that seen for the active comparator, but the cysteine-depleting effect of Cystadrops^® was sustained for a period of four minutes at a dosing frequency of three instillations per day. Improvements in symptoms of photophobia were also observed, and treatment compliance was higher than 95%.¹² A pivotal, open-label, Phase III study (the CHOC study) then evaluated the superiority of Cystadrops^® versus a pharmacy hospital formulation in reducing cystine crystals (data to be published).¹³ It would be interesting to see if the results from head-to-head studies of Cystadrops^® can further support the superior optical outcomes seen in the pivotal registration trial.

There is an inherent risk of microbiological contamination when preparing compounded formulations, even under aseptic conditions, and the need for facilities certified for good manufacturing practices adds to the complexity of the compounding process. The production of the eye drops onsite involves dissolving the cysteamine powder in water suitable for injection and sterilising the resulting solution by microfiltration while avoiding exposure to light. Specific procedural requirements and restrictions may limit the time available for the adequate preparation of the solutions due to limitations in dedicated staff members.⁴

In the Cystadrops OCT-1 study, the most frequently observed side effects were stinging, blurred vision and burning sensation immediately after instillation. Eye pain at instillation mostly subsided over time, reaching tolerable levels after four minutes. No serious adverse events were reported in this trial.¹² Other side effects associated with the medicinal product reported to the European regulatory authority were ocular hyperaemia, eye pruritus and irritation, and increased lacrimation.¹⁰

Although cystinosis with renal involvement constitutes the most serious form of the disease, its optical features lead to significant loss of quality of life for both paediatric and adult patients. Considering the dramatically improved prognosis and increase in life expectancy for these patients when treatment with systemic cysteamine is initiated early, the management of ocular long-term complications assumes a more relevant position in the overall treatment plan of cystinosis.

Conventional hospital pharmacy-compounded eye drop formulations present limitations in efficacy and stability when compared with marketed eye drops, but these are not widely available at the moment. It must be also noted that these formulations do not completely eliminate crystal deposit formation and are still associated with detrimental ocular side effects to some extent.

Cystadrops^® undoubtedly represents an advancement in this scarce landscape of ophthalmic formulations for cystinosis, and the development of new and improved formulations and drug delivery systems requiring less frequent dosing but retaining maximum benefit, together with a better understanding of the pathophysiological mechanism of the disease, will positively contribute to the broadening of the therapeutic portfolio for these patients.

1. Elmonem MA et al. Cystinosis: a review. Orphanet J Rare Dis 2016;11:47.
2. Kalatzis V et al. Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter EMBO J 2001;20:5940–9.
3. Cystinosis Research Network. https://cystinosis.org/images/family-support/resources/CRN_Standards_12pgloRes.pdf (accessed December 2016).
4. Radojkovic B. Cysteamine eye drops in the treatment of cystinosis – an Australian perspective J Pharm Pract Res 2015;45:440–5.
5. Sigma-Tau Press Release. Sigma-Tau Pharmaceuticals Inc receives FDA approval of Cystaran™ (cysteamine ophthalmic solution) 0.44% for treatment of corneal cystine crystals in cystinosis patients. www.sigmatau.com/news/Cystaran.asp (accessed December 2016).
6. Cystaran Prescribing Information. Sigma-Tau Pharmaceuticals. 2012. www.cystaran.com/Cystaran_PI.pdf (accessed December 2016).
7. European Medicines Agency. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004038/WC500210937.pdf (accessed December 2016).
8. Buchan B et al. Gel formulations for treatment of the ophthalmic complications in cystinosis. Int J Pharm 2010;392:192–7.
9. McKenzie B et al. Preformulation of cysteamine gels for treatment of the ophthalmic complications in cystinosis. Int J Pharm 2016;515(1-2):575–82.
10. European Medicines Agency. www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003769/WC500214160.pdf (accessed December 2016).
11. Marcano DC et al. Synergistic cysteamine delivery nanowafer as an efficacious treatment modality for corneal cystinosis. Mol Pharm 2016;13:3468–77.
12. Labbe A et al. A new gel formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis: The Cystadrops OCT-1 study Mol Gen Metab 2014;111:314–20.
13. EU Clinical Trials Register. www clinicaltrialsregister.eu/ctr-search/trial/2009-012564-13/FR.