Horizon Scanning Centre March Cholic acid (Orphacol) for inborn errors of primary bile acid synthesis first line SUMMARY NIHR HSC ID: 9468

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1 Horizon Scanning Centre March 2014 Cholic acid (Orphacol) for inborn errors of primary bile acid synthesis first line SUMMARY NIHR HSC ID: 9468 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Cholic acid (Orphacol) is intended to be used as first line therapy for the treatment of inborn errors of primary bile acid synthesis. It is a bile acid that replaces the primary bile acids absent in people affected by 3β-hydroxy-Δ 5 - C 27 -steroid oxidoreductase deficiency or Δ 4-3-oxosteroid 5β-reductase deficiency, thereby restoring a functional bile acid pool in the enterohepatic circuit. Orphacol offers a treatment option for this rare patient group, for whom there are no other licensed pharmaceutical therapies available. Inborn errors in primary bile acid synthesis affect approximately 0.6 per 100,000 population in the EU, equivalent to approximately 321 people in England. The company estimate that 15 patients in England are likely to be eligible for treatment with Orphacol. Inborn errors of bile acid synthesis are rare genetic disorders, usually presenting in neontates, and characterised by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. These acids can damage the liver, in some cases leading to liver failure. Orphacol was licensed in the EU for this indication in September Cholic acid has been used under named patient supply for a number of years and has been shown to be an effective and well-tolerated therapy for primary bile acid synthesis defects. No clinical trials have been conducted on Orphacol, as the use of cholic acid is well established. The published literature is comprised of case series only; the number of documented cases is low due to the rarity of the condition. However, the literature shows that treatment with cholic acid reduced the amount of abnormal bile acids in patients, restored normal liver function and helped delay or prevent the need for a liver transplant. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Inborn errors of primary bile acid synthesis: 3β-hydroxy-Δ 5 -C 27 -steroid oxidoreductase (3βHSD) deficiency or Δ 4-3-oxosteroid 5β-reductase (Δ 4-3-OxoR) deficiency; infants, children and adolescents aged from 1 month to 18 years, and adults first line. TECHNOLOGY DESCRIPTION Cholic acid (Orphacol) is a bile acid that replaces the primary bile acids absent in people affected by 3β-HSD deficiency or Δ 4-3-OxoR deficiency, thereby restoring a functional bile acid pool in the enterohepatic circuit. In addition, it also inhibits the formation of hepatotoxic bile acid metabolites through suppression of the rate-limiting enzyme in bile acid synthesis, cholesterol 7α-hydroxylase. Cholic acid is administered orally at doses ranging from 5-15mg/kg, with the minimum dose being 50mg, adjusted in 50mg steps. In adults, the daily dose should not exceed 500mg. Cholic acid (Orphacol) is licensed in the EU for inborn errors of primary bile acid synthesis due to 3βHSD deficiency or Δ 4-3-OxoR deficiency in infants, children and adolescents aged one month to 18 years and adults. Recognised adverse effects include diarrhoea, pruritus, increases in transaminases and possibly gallstones, although their frequency could not be reliably estimated from the available limited data 1. INNOVATION and/or ADVANTAGES Cholic acid (Orphacol) provides a treatment option for this rare patient group, for whom there are no other licensed pharmaceutical therapies available. DEVELOPER Laboratoires CTRS. AVAILABILITY, LAUNCH OR MARKETING Cholic acid (Orphacol) is a designated orphan drug in the EU and was granted a Marketing Authorisation throughout the EU in September 2013 for this indication. PATIENT GROUP BACKGROUND Inborn errors of bile acid synthesis are rare genetic disorders characterised by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries 2. These acids can damage the liver, in some cases leading to liver failure 3. The disease generally presents with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus 2. If recognised early, most patients with inborn errors of bile acid synthesis respond well to oral bile acid therapy 2. 2

3 NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: National Service Framework for Long-term Conditions (2005). NHS England. 2013/14 NHS Standard Contract for Metabolic Disorders (Children). E06/S/b. NHS England 2013/14 NHS Standard Contract for Metabolic Disorders (Adult). E06/S/a. NHS England 2013/14 NHS Standard Contract for Metabolic Disorders (Laboratory Services). E06/S/c. CLINICAL NEED and BURDEN OF DISEASE 3βHSD and 5β-reductase deficiencies are autosomal recessive conditions and the most common inborn errors of primary bile acid synthesis 4. 3βHSD deficiency usually presents in neonates, although onset can occur from 3 months to 14 years 2. Δ 4-3-OxoR deficiency causes defective bile acid steroid nucleus synthesis, causing rapid liver failure and has a 50% mortality rate in infants for whom diagnosis is delayed 2. Overall, inborn errors in primary bile acid synthesis affect approximately 0.6 per 100,000 population in the EU 5, equivalent to approximately 321 people in England a. However, based on an understanding of the relative frequency of different individual enzyme deficiencies, the company estimate that 15 patients in England are likely to be eligible for treatment with Orphacol. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance None identified. Other Guidance None identified. CURRENT TREATMENT OPTIONS Treatment of 3βHSD deficiency is targeted at stimulating bile flow and downregulating 7αhydroxylase activity to diminish or eliminate the production of hepatotoxic bile acids 4. With the exception of the recently licensed cholic acid preparation (Orphacol), there are no authorised treatments for inborn errors of primary bile acid synthesis 3. Cholic acid has been used under named patient supply for a number of years and has been shown to be an effective and well tolerated therapy for primary bile acid synthesis defects 4. Patients with severe liver disease may need a liver transplant 3. EFFICACY and SAFETY Laboratoires CTRS have not conducted any clinical trials on Orphacol for the treatment of inborn errors in primary bile acid synthesis. The use of cholic acid to treat this condition is well established, although the number of documented cases is low due to the rarity of the condition. a Based on Office for National Statistics population for England, mid

4 The EMA granted a Marketing Authorisation for Orphacol in September 2013 based on a systematic review of evidence from the scientific literature 6. This showed that treatment with cholic acid reduced the amount of abnormal bile acids in patients, restored normal liver function and helped delay or prevent the need for a liver transplant. The literature is limited to case series presenting data on 49 patients with inborn errors in primary bile acid synthesis; comparing the outcomes of 28 patients who received cholic acid with others who were given different bile acids or did not receive bile acid treatment. Based on this evidence, the Committee for Medicinal Products for Human Use (CHMP) determined that Orphacol s benefits outweighed potential risks. Safety and effectiveness will be monitored by the company and results submitted to the CHMP at regular, agreed, specified intervals. ESTIMATED COST and IMPACT COST The cost of cholic acid (Orphacol) is not yet known. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: Reduced symptoms or disability No impact identified Impact on Health and Social Care Services Increased use of existing services Re-organisation of existing services Other: Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: Other: uncertain unit cost compared to other formulations Decreased use of existing services Need for new services Reduced drug treatment costs: reduced use of immunosuppressants and other pre- and post-hepatic transplant medications Other reduction in costs: potentially reduces the need for paediatric hepatic transplantations Other Issues Clinical uncertainty or other research question identified: REFERENCES 1 European Medicines Agency. Orphacol cholic acid. n_med_ jsp&mid=wc0b01ac058001d124 Accessed 4 February Sundaram SS, Bove KE, Lovell MA et al. Mechanisms of disease: inborn errors of bile acid synthesis. Nature Clinical Practice Gastroenterology & Hepatology 2008;5(8):

5 3 European Medicines Agency. EU/3/09/ _orphan_ jsp&mid=wc0b01ac058001d12b Accessed 4 February Gonzales E, Gerhardt MF, Fabr M et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology 2009;137: European Medicines Agency. Public summary of opinion on orphan designation. Cholic acid for the treatment of inborn errors in primary bile acid synthesis pdf Accessed 4 February European Medicines Agency. Assessment report. Orphacol. Procedure No: EMEA/H/C/001250//0000. London: EMA; April