Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Leadiant GmbH, Liebherrstr. 22, 80538 Munich, Germany, Telephone: +49 (0)89 5506675 – 0, Fax: +49 (0) 89 55 066 75 25, e-mail: info@leadiantbiosciences.com
Pharmacotherapeutic group: Alimentary tract and metabolism – Bile therapy – Bile acid preparations
ATC code: A05AA01
Exogenous chenodeoxycholic acid is used as replacement therapy to restore the feedback inhibition lost due to the deficiency/absence of endogenous chenodeoxycholic acid. In CTX, a defect in the CYP27A1 gene results in a deficient mitochondrial sterol 27-hydroxylase enzyme. This deficiency blocks the synthesis of primary bile acids via the classical (neutral pathway) and the alternative (acidic) pathway. However, cholic acid is still formed via an alternate microsomal pathway. The net result is a total bile acid pool that is severely deficient in chenodeoxycholic acid but relatively enriched with cholic acid.
In CTX, deficiency of chenodeoxycholic acid causes a lack of feedback of cholesterol 7 alpha hydroxylase (CYP7A1) and HMG CoA reductase, causing increased production of atypical bile acids, bile alcohols and cholestanol that lead to the pathological consequences of the condition. Exogenous replacement with Chenodeoxycholic acid inhibits CYP7A1 (via nuclear receptor, FXR) and HMG CoA reductase, thus restoring the feedback inhibition.
The primary pharmacodynamic effects of chenodeoxycholic acid are:
Efficacy and safety was studied in two retrospective trials in two centres in Europe. The mean age of the patient population in the pivotal study was younger at 25.8 years than the supporting study population at 35 years which also reflected the level of disability present in the two cohorts prior to treatment start, with the supporting study having a higher disability score at baseline.
In the pivotal study CDCA-STUK-15-001 treatment of CTX patients with chenodeoxycholic acid 750-1000 mg/day in adults or 5-15 mg/kg/day in infants and children was associated with statistically significant decreases in mean serum levels of cholestanol from baseline to post-baseline in the overall population and in the two subgroups of patients aged <21 years or ≥21 years at first treatment. Urinary bile level alcohol levels decreased. Neurological disability scale scores (Rankin and EDSS) stabilised or improved by the clinical current visit in 84.6% and 76.9% of patients respectively. Mean Rankin and EDSS scores showed a very small increase (worsening) from baseline to clinical current visit at 0.08 ± 0.74 and 0.27 ± 1.24 in the overall population and this increase was not statistically significant. There was a statistically significant (p=0.04) improvement (decrease) of -0.31 ± 0.48 in the mean Rankin score for the <21 years of age subgroup.
Disease signs and symptoms resolved, improved or stabilised in a majority of patients over the course of the study. Diarrhoea disappeared in 100% (23/23 patients) of the patients who had this symptom at baseline. There was a resolution, improvement or stabilisation in 88.9% (16/18) of patients with cognitive impairment. Epilepsy resolved in 100% (3/3 patients) and polyneuropathy stabilised or improved in 100% (11/11). Pyramidal dysfunction improved or stabilised in 60% (10/15) and cerebellar dysfunction in 88.7% (12/14). Psychiatric impairment resolved, improved or stabilised in 85.7% (6/7) of patients. However, parkinsonian symptoms, a rare disease manifestation/association that occurred in only 2 patients during the course of the study, did not respond.
In the supportive study CDCA-STRCH-CR-14-001 treatment of CTX patients with chenodeoxycholic acid 750 mg/day given for a median duration of 5.75 years was associated with statistically significant decreases in mean serum levels of cholestanol from baseline to any post-baseline visit. The mean levels of 7α-hydroxy-4-cholesten-3one significantly decreased from baseline to post-baseline Visits 1 and 2. Vitamin D and PTH levels decreased from baseline to both post-treatment visits and mean pyruvate levels decrease from baseline to the first post-treatment visit. Rankin and EDSS scores remained stable in 61.5% and 50% of patients respectively, however there was an overall worsening of the mean score from baseline. Increases in bone mineral density (Z-score) were observed at lumbar spine at both post-treatment visits and at total hip at post-treatment at post-treatment Visit 2. Signs and symptoms of the disease remained stable in most of the patients. Diarrhoea improved or disappeared in 64.3% of the patients who had this symptom present at baseline.
None of the patients had treatment-related adverse events and chenodeoxycholic acid exhibited a satisfactory safety profile in relation to routine safety laboratory parameters (haematology and clinical chemistry).
Data exists only in the adult population.
Chenodeoxycholic acid is an endogenous bile acid in humans, which is tightly regulated by its secretion into bile via exporter pumps and detoxification by sulfation. In addition to sulfation, bile acid can also be detoxified through glucronidation.
Chenodeoxycholic acid given orally is absorbed in the small intestine. Reabsorption is not complete. A small portion of chenodeoxycholic acid is excreted with faeces.
After reabsorption in the intestine, the bile acid is nearly completely conjugated to the amino acids glycine and taurine and then excreted again in the bile.
In the intestine Chenodeoxycholic acid and its glycine or taurine conjugate are decomposed by bacteria. Deconjugation results in the free bile acid, oxidation in the 7-keto-lithocholic acid and lithocholic acid (3α-hydroxycholanic acid) is formed by elimination of the 7-hydroxy group. Whereas 7-keto-lithocholic acid can be formed partially in the colon and also in the liver to chenodeoxycholic acid and ursodeoxycholic acid (3α-, 7β-di-hydroxycholanic acid), lithocholic acid is absorbed to a small extent only and is thus largely lost with faeces.
Biological half-life of chenodeoxycholic acid is about 4 days.
Reabsorption of chenodeoxycholic acid is variable (29-84%). After treatment with chenodeoxycholic acid, the endogenous synthesis of the primary bile acids, cholic acid and chenodeoxycholic acid, is inhibited.
No formal preclinical safety studies have been conducted however data in the literature reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Rodent and primate toxicity species lack efficient-sulfating capacity for conjugation of lithocholic acid, and therefore have shown hepatotoxicity. In contrast, Lithocholic acid sulfate conjugation in humans prevents the overt hepatotoxicity, as seen in animal toxicity species after repeat dosing.
Developmental toxicity studies in rats, hamsters and primates showed an absence of teratogenic effects. In rhesus monkey and baboon studies it was demonstrated that chenodeoxycholic acid dose to pregnant animals (at 5-120 mg/kg/day for rhesus monkey; at 18-38 mg/kg/day for baboons) produced liver pathology in the developing foetus. Pathological effects on adrenals and kidneys were also seen in rhesus monkey foetuses. Maternal effects in the rhesus monkeys, but not baboons, included diarrhoea, emesis, weight loss and reduction in food consumption.
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