Management

Available treatment
Currently, chenodeoxycholic acid (CDCA) is the preferred therapy.

Although in the US it lacks FDA approval in CTX, it has been approved since 1983 to treat a particular type of gallstones. The situation is similar in Japan. In Europe, off-label use of CDCA started in the 70s (with a price of €370 per year of treatment). In 2017, EMA designated CDCA as an orphan drug in CTX therapy. Unfortunately, this led to 5 fold increase in yearly therapy costs resulting in some countries in €150,000 per year of treatment. In response to the withdrawal of health insurers from financing such expensive treatment, the Amsterdam University Hospital launched manufacturing its drug version costing less than €30,000 per year. Unfortunately, it can only be used by the patients of this hospital. The financing of treatment is variable and often depends on national conditions. Therefore physicians should always consult health insurers for up-to-date information.

It should be noted that there are some alternatives despite the leading role of CDCA in current CTX treatment programs. Dutch researchers signaled the effectiveness and safety of cholic acid as early as 1985. In 2019 French researchers had documented a cohort of 12 patients treated with cholic acid. They observed decreased cholestanol levels in 12/12 cases and improvement or stabilization of CTX manifestations in 10/12 cases. Moreover, they did not find adverse effects in patients treated with cholic acid, whereas they observed elevated transaminases in some patients treated with CDCA. Cholic acid was granted orphan drug designation in the EU since 2009 for treatment of inborn errors of primary bile acid synthesis (CTX included), but EMA withdrew it in 2020 at the manufacturer's request (commercial reasons). In 2015, cholic acid was approved in US by the FDA for bile acid synthesis disorders caused by a single enzyme defect (CTX included). Still, it should be emphad that the experiences with the use of cholic acid are much smaller than with CDCA.

Future treatment
As CTX belongs to bile acid synthesis disorders caused by a single enzyme defect, it is the perfect candidate for gene therapy. In late 2021 Spanish researchers published results of adeno-associated virus vectors expressing CYP27A1 in a CTX mouse model. The intervention was well tolerated and provided complete metabolic restoration in mice. Thus, the authors concluded that this makes gene therapy a feasible option for the etiological treatment of CTX patients.

Treatment regimen
Commonly CDCA is prescribed in adults at a dosage of 250 mg three times daily with meals. CDCA is dosed in a weight-based manner at 5–15 mg/kg total daily dose in children and is given in two or three divided daily doses with meals. To finally confirm the data on the effectiveness and safety of CDCA from scientific reports, a phase 3 double-blind study (RESTORE) is being conducted, and its completion is planned for 2023

However, the key to success is an early diagnosis of the disease and the implementation of treatment. In most cases, the initiation of therapy in a child will stop the progress of the disease, and in some cases, it may even lead to a marked improvement in the clinical condition. Of course, each case is different. An example of this may be deaths in infancy due to cholestasis. On the other hand, if the disease was already diagnosed in siblings and treatment was initiated from the first years of life, often no symptoms developed. In general, the increase in the effectiveness of CDCA treatment started as early as possible should be adopted as a rule. Scientific reports indicate that a significant decrease in the effectiveness of the treatment was observed when it was started after the age of 25 or after 15 years after the first symptoms. The risk of further disease progression then increased. Of course, in patients diagnosed in adulthood, treatment should not be abandoned in any way. It is worth noting here that treatment with CDCA positively affects both neurological symptoms and psychiatric or behavioral manifestations. Often the latter is the factor that worsens the patient's quality of life the most. Several reports confirmed the safety and effectiveness of the CDCA used in the long term.

Unfortunately, the management of pregnant women diagnosed with CTX remains unclear. Some scientific reports indicate that it is rational to include (or maintain) CDCA in this period to avoid early damage to the fetus. According to some authors, it would also be justified by the high percentage of miscarriages in CTX female patients, reaching 17.2%. However, no studies would assess the effectiveness and safety of such a procedure.

Metabolites and their ratios relevant to CTX pathology have been successfully used to screen newborns' dried blood spots. Unfortunately, screening tests were only carried out as part of research projects. Nevertheless, their technical capabilities and high sensitivity of the results have been proven based on studies on tens of thousands of infants. However, to the best of our knowledge, there are currently no national screening tests for CTX. This fact remains strange, especially since many studies have shown that children diagnosed with CTX can be safely treated, preventing the disease from the subclinical phase.

Monitoring of plasma cholestanol level is indicated after initiation of CDCA therapy. This helps assess the effects of supplementation and patients' compliance. Monitoring of plasma cholestanol is typically performed every 3–6 months in the first year. After that, it is usually sufficient to repeat the biochemical test every 6-12 months in a stable clinical state.

However, it should be remembered that due to the slow mobilization of cholestanol from the tissues, its plasma concentration after the introduction of therapy may remain elevated for 3-6 months.

It is also beneficial to initially monitor the concentration of liver transaminases, although their elevation has been observed rarely (9% in some sources). In the event of transaminase elevation, temporary discontinuation and drug reintroduction at a slowly escalating dose were most often sufficient. In some cases, CDCA was replaced by cholic acid with good results.

https://www.acm.nl/sites/default/files/documents/summary-of-decision-on-abuse-of-dominant-position-by-leadiant.pdf

https://www.ema.europa.eu/en/documents/public-statement/public-statement-kolbam-withdrawal-marketing-authorisation-european-union_en.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205750Orig1s000TOC.cfm