Disease Prevalence and Incidence

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 and eye.^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 the severity of the CTNS gene mutation:³ infantile nephropathic form, juvenile nephropathic form, and adult nonnephropathic form. The infantile nephropathic form is the most serious form and the most prevalent, implicated in 95% of cases.^1,3 Symptoms of this form generally present before the age of 12 months, with evidence of proximal tubular damage with or without corneal cystine crystal deposits.⁷ There is further organ involvement as the disease progresses.⁷ Juvenile nephropathic cystinosis carries similar symptoms to infantile cystinosis, except its onset is delayed to within the first decade of life, and it carries a slower progression rate.³ The adult non-nephropathic form of cystinosis is exclusively ocular, with photophobia due to corneal crystals.¹ Patients very often identify this disease as having a serious impact on their school and work life, and also admit that it takes a toll on the entire family. Many parents of children with cystinosis have reported that it requires 24/7 vigilance, with the combination of regular clinic and allied health professional visits.

The prevalence of cystinosis is approximately 1 in 100 000 to 1 in 200 000 births globally, regardless of ethnic origin.⁸ A higher incidence rate has been observed in selected populations with detected founder mutation in the province of Brittany, France (1 in 26,000 live births) as well as in Saguenay–Lac-Saint-Jean, Quebec (1 in 62,500 live births).^3,9

Upon findings of renal tubular Fanconi’s syndrome, nephropathic cystinosis should be investigated among other inherited causes.⁴ It is subsequently confirmed by findings of: corneal cystine crystals on slit lamp examination, increased cystine content of leukocytes, and CTNS mutations.⁴ Other indicators that can identify disease progression include impaired growth, anorexia, reduction in glomerular filtration rate leading to chronic kidney disease, hypothyroidism, metabolic bone disease, swallowing difficulties, delayed gastric emptying and intestinal dysmotility, hypocholesterolemia, and neurocognitive alterations in attention, planning, and motor processing speed.^1,4,8

Standards of Therapy

In nephropathic cystinosis, lysosomal cystine accumulation damages different tissues at different rates, perhaps by enhancing apoptosis.⁸ Therefore, management of nephropathic cystinosis currently consists of both symptomatic treatment and specific treatment with cysteamine.

The aim of symptomatic treatment is to maintain fluid and electrolyte balance, encourage good nutrition, and prevent rickets. Due to impaired sweating in these patients, heat exhaustion is a concern. The loss of excessive water and salts in the urine can lead to dehydration as well as progression to acidosis.⁸ As a result, patients are often provided with supplementary doses of potassium, sodium, and phosphate, in accordance with serum values. Other symptoms such as poor appetite, vomiting, and oral motor dysfunction can be circumvented by the use of a nasogastric or gastronomy tube.⁴ For impairment in growth velocity, patients with nephropathic cystinosis can be administered growth hormone to improve and maintain velocity.¹⁰

For all nephropathic cystinosis patients, early and diligent cystine-depleting therapy with oral cysteamine is recommended to preserve renal glomerular function. Administration of cysteamine has been found to prevent further deterioration of renal function and development of renal complications, as well as extrarenal complications.^11–13 As a result, cysteamine is recommended to be administered at the time of diagnosis of cystinosis, and continued lifelong.⁴

Drug

Delayed-release cysteamine (Procysbi) capsules are a beaded, enteric-coated, delayed-release formulation of the bitartrate salt of cysteamine (also called cysteamine bitartrate or mercaptamine bitartrate), which reacts with lysosomes to convert intracellular cystine to cysteine, which is able to exit the lysosome.^5,14 This reduces accumulation of lysosomal cystine as a result of the defective transport of this molecule in cystinosis patients.^3,5,14 This formulation is encapsulated in hard gelatin, and to be administered orally.⁵ Capsules can be opened and the contents either sprinkled on food or dispersed in liquids, and the medication can also be administered via gastrostomy, nasogastric, or gastrostomy-jejunostomy tube.¹⁵

The enteric-coated capsule dissolves rapidly in the stomach, however the microspheronized beads within the capsule do not dissolve until they reach the small intestine, which is intended to reduce gastrointestinal adverse effects and improve bioabsorption.¹⁵ This formulation results in stable plasma cysteamine levels over 12 hours, which enables twice-daily dosing, and eliminates the need for nighttime administration.¹⁵

The immediate-release form of cysteamine (Cystagon) had been the primary cystine-depleting therapy accessible in Canada for the treatment of the nephropathic cystinosis. Cystagon was accessed only through Health Canada’s Special Access Programme; it did not have a Health Canada Notice of Compliance for the treatment of nephropathic cystinosis. Phosphocysteamine (a phosphorothioester that was developed to be more tolerable and to have fewer adverse effects than cysteamine) was also only accessible through the Special Access Programme. However, according to the clinical expert consulted for this review, phosphocysteamine had the same dosing regimen as immediate-release cysteamine and was used less frequently than Cystagon. Both immediate-release products became inaccessible during the course of the CDR review after Procysbi became available on the market in Canada.