PROCYSBI^® Digital Modules

Hello and welcome to the PROCYSBI^® Learning Capsules. My name is Sarah Lafond and I'm a pediatric nurse case manager with Nephrology.

Today's presentation is intended to give you a brief overview of PROCYSBI^® cysteamine delayed-release capsules, a treatment indicated for nephropathic cystinosis.

The objectives of today's presentation are to first understand how to identify, manage and treat patients with nephropathic cystinosis. Secondly, to assess the clinical profile and efficacy of PROCYSBI^® and lastly, to review the dosage and administration of PROCYSBI^®. This session will be divided into three learning capsules, followed by a summary of what we have learned and important safety information about PROCYSBI^®. We will begin with an overview of cystinosis.

Capsule 1: Cystinosis Overview

Cystinosis is a rare multisystemic genetic disorder. It is caused by the autosomal recessive inheritance of the CTNS gene. The CTNS gene provides instructions to produce cystinosin, which transports the amino acid cystine out of the lysosomes. Without cystinosin, cystine builds up and forms crystals in the lysosomes throughout the body.

The build up of cystine crystals leads to damage in the different tissues and organs, including the brain, eyes, muscles, liver, pancreas, and kidneys. There are 3 types of cystinosis: (1) Intermediate Cystinosis, (2) Non-nephropathic cystinosis, and (3) Nephropathic Cystinosis, which is the most common and severe type. This will be the focus of today's session.

Renal Fanconi syndrome, which is a rare disorder characterized by kidney dysfunction, is usually the first noticeable sign of nephropathic cystinosis and becomes apparent around 4 to 6 months of age. Symptoms of Renal Fanconi syndrome include dehydration, vomiting, constipation, failure to thrive, delayed growth and/or rickets, polyuria, polydipsia, and proximal tubular dysfunction.

It is important that children showing symptoms of Renal Fanconi syndrome are assessed for nephropathic cystinosis.

Diagnosis of nephropathic cystinosis should be made as soon as possible so that the treatment can be initiated early.

Diagnosis can be confirmed with a measurement of leukocyte cystine levels, a slit lamp exam displaying corneal cystine crystals, which are likely to show after the first year of life, or genetic testing for the CTNS gene. Note that it is important to diagnose and quickly determine an appropriate treatment regimen as early cysteamine therapy dramatically improves the overall prognosis of nephropathic cystinosis.

The management of nephropathic cystinosis includes cystine-depleting treatment with cysteamine therapy, treatment of extrarenal complications such as hypothyroidism or diabetes, and appropriate nutrition. Note that oral systemic cysteamine therapy does not remove cystine from the eyes and thus cysteamine eye drops may be required for the treatment of ocular cystine crystals. Renal function can be preserved, and the onset of end-stage renal disease can be delayed with strict adherence to cysteamine. A dosing delay of just 2 to 3 hours can cause considerable cystine accumulation. Thus, continuous disease management is crucial to ensure the best possible outcomes for people living with nephropathic cystinosis.

On the contrary, the absence of cysteamine treatment will lead to a poor prognosis of nephropathic cystinosis. At about 10 to 12 years of age, end-stage renal disease manifests as a result of decreased renal function. About a decade later, extrarenal complications such as hypothyroidism, diabetes and muscle atrophy begin to surface. Unfortunately, even with a successful renal transplantation, patients may not survive past the age of 30 years, thus, reinforcing that ongoing disease management is essential to ensure the best possible outcomes for those with nephropathic cystinosis. Let's move on to the second capsule where I will share a scientific overview of PROCYSBI^®.

Capsule 2: Scientific Overview

PROCYSBI^® is indicated for the treatment of nephropathic cystinosis. The safety and efficacy of PROCYSBI^® in patients less than 1 year and 65 years of age and older have not been established. PROCYSBI^® works by decreasing the build up of cystine in the cells. The process involves converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can leave the lysosome.

A pharmacokinetic investigation found that PROCYSBI^® provided delayed gradual absorption of cysteamine. The comparison for absorption and excretion with a single dose of PROCYSBI^® versus immediate-release cysteamine bitartrate at steady state are shown here. The time to maximum absorption and half life were much longer with PROCYSBI^® than immediate-release cysteamine bitartrate. The extended half-life of PROCYSBI^® and the delayed time to peak concentration are due to the delayed and gradual absorption of the microbeads. Taking PROCYSBI^® twice a day maintains white blood cells cystine levels < 1 nmol half cystine per mg of protein.

In a short-term, multi-centre, open-label, cross-over trial, PROCYSBI^® was compared head-to-head with immediate-release cysteamine bitartrate for the control of white blood cell cystine concentrations. Patients were randomized to receive either PROCYSBI^® or immediate-release cysteamine bitartrate. The trial demonstrated that PROCYSBI^® was noninferior to immediate-release cysteamine bitartrate with regards to decreasing white blood cell cystine levels.

In an extension study, white blood cell cystine concentrations were assessed in the long-term. 40 of the 41 patients from the previously mentioned short-term study continued to the single-arm, open-label extension trial for about 3 years. The study included non-naïve PROCYSBI^® patients from the short-term study, as well as pediatric patients who were less than or equal to 6 years of age. The mean white blood cell cystine levels for non-naïve patients remained below 1.0 nmol ½ cystine/mg protein, the target white blood cell cystine concentration. Now let's move on to the third capsule, where I will share a practical overview of PROCYSBI^®.

Capsule 3: Practical Overview

PROCYSBI^® is taken twice a day every 12 hours, allowing dosing flexibility and maintenance of therapeutic white blood cell cystine levels.

It is crucial that treatment with PROCYSBI^® begin immediately after the diagnosis of nephropathic cystinosis. The dosing of PROCYSBI^® is dependent on white blood cell cystine concentrations as well as how well the patient can tolerate the medication. The dose should not exceed 1.95 g/m² per day. Ensure to be mindful of your patient's medication history, as a titration for cysteamine-naïve patients is different from patients switching from immediate-release cysteamine bitartrate. Lastly, for those patients that take medications that increase gastric pH, frequently monitor white blood cell cystine levels as dose adjustments of PROCYSBI^® may be needed.

For those patients who are switching from immediate-release cysteamine bitartrate and who have issues with gastrointestinal tolerability, it is recommended that PROCYSBI^® is started at 75% of the dose of immediate-release cysteamine bitartrate. However, ensure to monitor white blood cell cystine levels closely as this may reduce the effectiveness of PROCYSBI^®.

PROCYSBI^® can be administered in three different ways for the convenience and tolerability of your patients. It can be swallowed whole with water or fruit juice, except grapefruit juice. Do not crush or chew the capsules. For pediatric patients who are at risk of aspiration or may have difficulty swallowing, PROCYSBI^® can be opened and the capsule contents can be mixed with applesauce. Lastly, PROCYSBI^® can also be administered through a gastrostomy tube 14 French or larger. In this method, the contents of the capsule can be open and mixed with half a cup of strained applesauce.

Here are some key factors to consider when teaching your patients how to take PROCYSBI^®. Food should not be eaten for at least 2 hours before or for at least 30 minutes after taking PROCYSBI^®. If this is not possible, PROCYSBI^® should be taken with food and the amount should be limited to half a cup within one hour before taking PROCYSBI^® and up until 30 minutes after taking PROCYSBI^®. If PROCYSBI^® is taken with drugs that raise gastric pH, the white blood cell cystine levels should be monitored often as dose adjustments to PROCYSBI^® may be necessary. PROCYSBI^® should be taken in a consistent manner with regards to food. Alcoholic beverages should not be consumed during treatment with PROCYSBI^®. And lastly, foods high in fat or protein should be avoided close to dosing with PROCYSBI^®.

Summary

To summarize the most important points we covered today, cystinosis is a rare, multisystemic disease that can affect multiple organs and tissues. Early cysteamine therapy is crucial for the prognosis of people with nephropathic cystinosis. PROCYSBI^® is the first and only delayed-release capsule for the treatment of nephropathic cystinosis. And, when administered twice daily 12 hours apart, it provides continuous cystine control.

If gastrointestinal tolerability is a known concern, PROCYSBI^® should be initiated at 75% of the dose of the immediate-release cysteamine bitartrate. PROCYSBI^® has the flexibility of being swallowed whole with fruit juice or water, mixed with applesauce, or taken through a gastrostomy tube. Food should not be eaten for at least 2 hours before or for at least 30 minutes after administration. And lastly, PROCYSBI^® demonstrated control in white blood cell cystine levels in both short and long-term clinical trials. Please listen to the important safety information for PROCYSBI^® and consult the Product Monograph for complete safety information. Thank you.

Important Safety Information

Important safety information. Indications and clinical use: PROCYSBI^® (cysteamine delayed-release capsules) is indicated for the treatment of nephropathic cystinosis. Safety and efficacy in patients less than 1 or greater than and equal to 65 years of age have not been established. Contraindications: Hypersensitivity to cysteamine bitartrate, any form of cysteamine, penicillamine, any ingredient in the formulation or any component in the container. Other relevant warnings and precautions: Risk of Ehlers-Danlos-like syndrome. Gastrointestinal (GI): Risk of ulceration and bleeding, fibrosing colonopathy. Routinely monitor white blood cell (WBC) cystine levels to assess treatment effect. Closer WBC cystine level monitoring recommended in: Hepatic impairment, concomitant use with drugs that increase gastric pH.

Reversible leukopenia: Monitor WBC counts. Alkaline phosphate: Monitor for elevated levels. Central nervous system (CNS): Monitor and evaluate if symptoms develop. Benign intracranial hypertension (pseudotumor cerebi [PTC]): Monitor for signs and symptoms. Does not prevent eye deposition of cystine crystals. Dosing in renal insufficiency. Risk of serious skin rashes. Use in pregnant women (potential risk to a fetus). Breastfeeding not recommended. For more information: Please consult the Product Monograph for important information relating to adverse reactions, drug interactions, and dosing and administration which have not been discussed in this piece.

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