Thomas Morrow, MD

Few people spend their days thinking about their lysosomes. These amazing intracellular structures are miniature digestive organs that contain enzymes that constantly break down waste material as well as viruses and bacteria. They rely on a complex system of enzymes to degrade the material into some basic building blocks and then to transport the components to other areas of the cell. About 50 different diseases have been discovered that are the result of defects in these specialized proteins. The resulting disorders read like a who’s who of the most expensive diseases, including Gaucher’s disease, Hunter’s disease, Hurler’s disease, and Pompe disease.

Another lysosomal storage disease, nephritic cystinosis, is caused by accumulation of the amino acid cystine. Eventually leading to kidney failure, blindness, weak bones, muscle weakness, pulmonary dysfunction, and eventually death, nephrotic cystinosis is slightly more common in males (ratio 1.4 to one) and disproportionately affects blond, blue-eyed children of European descent who carry the autosomal recessive genetic mutation to the cystinosin, a protein encoded by the lysosomal cystine transporter gene (CTNS) on chromosome 17 p13. The gene is over 26,000 base pairs long.

Over 80 mutations of this gene, leading to decreased activity or total inactivity of the CTNS gene, have been identified. Without the transport protein, cystine levels build up 50 to 100 times the normal level and form crystals that in turn slowly kill individual cells in most major organs. As with most genetic diseases, the level of dysfunction varies depending on the site of the mutation on the gene. The most common is a deletion of a large part of the gene; it accounts for about 50% of those affected by cystinosis, and results in complete loss of cystinosin.

Untreated, the accumulation of crystals causes renal tubular destruction (nephritic cystinosis) and in its worst form presents in patients between ages 6 and 9 months as poor growth and rickets along with polyuria, polydipsia (excessive thirst), and dehydration. The crystals, readily observed by age 16 months, accumulate in the cornea and can be seen on slit lamp exam. Death occurs by age 10 if the patient is not treated.

Scientists created a way to use cysteine bitartrate, in the chemical class called aminothiol, to force a metabolic transformation of cystine into cysteine and cysteine-cysteamine mixed disulfide compounds. This reaction occurs within the lysosomes. Both cysteine and cysteine-cysteamine mixed disulfide can exit the lysosome in patients with cystinosis. Thus, cystine is slowly transported away and levels can remain low as long as the substrate, cysteamine bitartrate, is available.


Cystagon (cysteamine bitartrate), an oral immediate-release therapy, was approved in 1994 by the FDA. If it used as directed, most late complications of cystinosis can be delayed or perhaps avoided. One reference suggested that those affected can live to at least 50 years. But Cystagon must be taken every six hours and can cause a repulsive body odor, can cause nausea and vomiting, and increases gastric acid production.

Recently the FDA approved a new drug with the same active ingredient, cysteamine bitartrate, but in an enteric coated delayed-release formulation named Procysbi. Indicated for management of nephritic cystinosis in persons ages 6 years and older, Procysbi is available as a capsule in 25-mg and 75-mg strengths that can be administered 12 hours apart instead of every six hours. The advantage is obvious — patients maintain a normal sleep interval and avoid the need for a mid-day dose.

Procysbi was studied in 6 clinical trials. Three studied only healthy volunteers. The other three were performed on 72 patients with proven nephropathic cystinosis. Because there was a similar drug available, the trial design leading to FDA approval involved a head-to-head study against the immediate-release drug. The pivotal trial comparing Procysbi with immediate-release cysteamine was Trial 3.

Trial 3 was randomized and “demonstrated that at steady state, Procsbi administered every 12 hours was non-inferior to immediate-release cysteamine bitartrate administered every six hours.” The primary endpoint for this study was “depletion of WBC [white blood cell] cystine levels,” a common and clinically meaningful measurement for patients suffering from this disease.

Remember that cystinosis is rare, so the pool of patients available for clinical trials is small. Because of this, the FDA label for this drug includes a review of previous trials involving the immediate-release form of cysteamine bitartrate as well as the new trials involving the delayed-release form.

Healthy volunteers reported diarrhea, nausea, abdominal pain/discomfort, headache, vomiting, and abnormal urine odor. The most commonly reported adverse reactions in patients with nephritic cystinosis were vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor, and rash.

There were no unexpected serious adverse events, but “a higher incidence of adverse reactions was reported in patients during the Procysbi treatment period compared with the immediate-release cysteamine treatment period.”

Trial 4 includes patients continuing treatment from Trial 3 and consisted of 40 patients treated longer than one year. Similar adverse reactions occurred during the extension period.

The conclusion from Trial 3 is that at “steady-state, Procysbi administered Q12 H was non-inferior to immediate-release cysteamine bitartrate administered Q6H with respect to the depletion of WBC cystine levels.”

Thus, tomorrow’s medicine marches on with an improvement for patients born with this genetic disease allowing them to sleep through the night. It also allows these children and adults to have a drug that can be given half as many times per day with clinical trial proof that the delayed release is not inferior to the existing legacy form of this chemical.

But that improvement comes at a very high additional cost. The New York Times reported that the cost of the enteric-coated formulation will be about $250,000 annually on average. This compares to an annual cost of $8,000 for the existing immediate-release formulation.

Managed care implications

Procysbi comes at an astronomical increase in price over the existing drug with no proven improvement. There were no data in the FDA label that demonstrated any other advantages over the immediate-release form. The question can be reasonably raised: why should the cost increase over 3,000%? Will the decreased frequency of administration lead to improved adherence and eventually improved clinical response? Should society, through insurance and government programs, pay nearly a quarter of a million dollars in additional costs each year, per patient, to avoid having to awaken once during sleep and to avoid a mid-day dose? And perhaps what also needs to be asked is why it costs so much to obtain FDA approval for what basically is just a coating on an existing drug.

Certainly, the company that developed the delayed form of cysteamine bitartrate, Raptor Pharmaceuticals, feels the need to recoup its reported $37.4 million in development costs directly attributed to this drug and an additional $70 million in total corporate expenses during the development period. But without demonstrated improvement, payers will be hard pressed to cover this drug.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at

The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.

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