Horizon Scanning Research July 2015 & Intelligence Centre

Glycerol phenylbutyrate (Ravicti) for urea cycle disorders (hyperammonaemia)

SUMMARY NIHR HSRIC ID: 5089

Glycerol phenylbutyrate (Ravicti) is intended to be used for the treatment of This briefing is urea cycle disorders (hyperammonaemia) in adults and paediatric patients based on over two years of age. Glycerol phenylbutyrate is a prodrug of sodium information phenylbutyrate, an ammonia scavenger and it provides an alternative available at the time pathway to the urea cycle for the disposal of nitrogen waste via renal of research and a excretion of phenylacetylglutamine formed from phenylacetic acid and limited literature glutamine.

search. It is not Urea cycle disorders (UCDs) include several inherited enzyme transporter intended to be a deficiencies that result in the accumulation of toxic levels of ammonia in the definitive statement blood and brain (hyperammonaemia). Urea cycle disorders are inborn errors on the safety, of ammonia detoxification/arginine synthesis due to defects affecting the efficacy or catalysts of the Krebs-Henseleit cycle. Inter-current infection is the most effectiveness of the common precipitant of acute hyperammonaemia, accounting for 34% of health technology episodes, with respiratory virus a leading cause. The estimated incidence of covered and should urea cycle disorder is 1 in 8,000, and it may present either shortly or after not be used for birth (50%), or at any age. commercial purposes or The main aim of therapy for hyperammonaemia is to correct the biochemical commissioning abnormalities and to ensure adequate nutritional intake. Pharmaceutical without additional treatment involves compounds that increase the removal of nitrogen waste information. and antiemetic agents such as ondansetron, granisetron, palonosetron and dolasetron may also be used. Other management approaches include dietary restriction of protein and/or nitrogen intake and parenteral intake of calories. Surgical interventions include liver transplant or liver cell transplantation.

Glycerol phenylbutyrate is currently in phase III clinical trials, comparing its effect on biochemical markers against treatment with sodium phenylbutyrate.

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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Urea cycle disorders: hyperammonaemia in adults and paediatric patients over two years of age – second line.

TECHNOLOGY

DESCRIPTION

Glycerol phenylbutyrate (Ravicti; HPN 100 HPN-100; HPN100) is a nitrogen-binding agent intended for the management of adult and paediatric patients over two years of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Glycerol phenylbutyrate is a prodrug of sodium phenylbutyrate, an ammonia scavenger. It provides an alternative pathway to the urea cycle for the disposal of waste nitrogen via renal excretion of phenylacetylglutamine formed from phenylacetic acid and glutamine. In phase III clinical trials, glycerol phenylbutyrate was administered orally at 17.4mL daily.

Glycerol phenylbutyrate is also in phase III clinical trials for hepatic encephalopathy. Glycerol phenylbutyrate is not currently licensed for any other indication.

INNOVATION and/or ADVANTAGES

If licensed glycerol phenylbutyrate will provide an additional treatment option for patients with urea cycle disorders that may offer more convenient dosing and a more palatable option than the current licensed sodium phenylbutyrate preparations.

DEVELOPER

Horizon Pharma plc (previously Hyperion Therapeutics).

AVAILABILITY, LAUNCH OR MARKETING

Glycerol phenylbutyrate is a designated orphan drug in the EU.

Glycerol phenylbutyrate is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Urea Cycle Disorders (UCDs) include several inherited enzyme transporter deficiencies that result in the accumulation of toxic levels of ammonia in the blood and brain (hyperammonaemia). UCDs are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle. They can present in the neonatal period or later in life depending on the severity of the defect1,6. Symptoms include lethargy, anorexia, hyperventilation or hypoventilation, hypothermia, seizures, neurological posturing and coma2. Latent forms of the disease, often with more subtle symptoms, can be triggered by infections or periods of stress at almost any time of life3. UCDs are long-term debilitating and life-threatening diseases that can lead to learning disabilities and are

2 Horizon Scanning Research & Intelligence Centre

associated with high mortality rate4. A study of twenty four children surviving neonatal episodes of hyperammonaemic coma due to UCDs found that 79% subsequently had one or more developmental disabilities at 12 to 74 months of age5.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Metabolic Disorders (Adult). E06/S/a. • NHS England. 2013/14 NHS Standard Contract for Metabolic Disorders (Children). E06/S/b. • NHS England. 2013/14 NHS Standard Contract for Metabolic Disorders (Laboratory Services). E06/S/c.

CLINICAL NEED and BURDEN OF DISEASE

The estimated incidence of UCDs is 1 in 8,000, and the condition may present either shortly after birth (around 50%) or later, at any age6. Coma and cerebral oedema are the major cause of death; the survivors of coma have a high incidence of intellectual impairment7. Up to 20% of Sudden Infant Death Syndrome (SIDS) cases may be attributed to an undiagnosed inborn error of metabolism, such as UCD8. Research studies are ongoing to more accurately determine the incidence and prevalence of UCDs8.

In UCDs, acute deterioration in metabolic status is characterised by potentially life threatening episodes of hyperammonaemia9. Acute hyperammonaemia in UCDs may be precipitated by any factor that affects metabolic balance, including dietary indiscretion, and enhanced protein catabolism owing to dietary over-restriction and infection. Inter-current infection is the most common precipitant of acute hyperammonaemia, accounting for 34% of episodes, with respiratory virus a leading cause9.

Three deaths from UCDs were registered in England and Wales during 2013 (ICD10- E72.2)10. In 2013-14, there were 163 admissions due to hyperammonaemia (ICD-10 E72.2) in England, resulting in 912 bed days and 207 finished consultant episodes11.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• None identified.

Other Guidance

• British Inherited Metabolic Disease Group. Hyperammonaemia: Urea Cycle Disorders 201412

CURRENT TREATMENT OPTIONS

The aims of therapy for hyperammonaemia are to correct the biochemical abnormalities and to ensure adequate nutritional intake7. Treatment involves compounds that increase the removal of nitrogen waste7. Pharmacological therapies include: sodium phenylbutyrate,

3 Horizon Scanning Research & Intelligence Centre

carglumic acid, sodium phenylacetate and sodium benzoate. In addition, antiemetic agents e.g. ondansetron, granisetron, palonosetron and dolasetron may also be used7. Other management approaches include: cessation or reduction of protein and/or nitrogen intake, haemodialysis, and supportive care with parenteral intake of calories. Surgical intervention for patients with hyperammonaemia include liver transplantation for correction of the metabolic error and/or liver cell transplantation as an alternative or bridge to liver transplantation13,14.

EFFICACY and SAFETY

Trial Treat UCD, NCT00947297, HPN-100- Help UCD, NCT00992459; HPN-100 vs 007; glycerol phenylbutyrate; phase III sodium phenylbutyrate (Buphenyl); phase III Sponsor Horizon Pharma Ireland Ltd. Horizon Pharma Ireland Ltd. Status Completed. Completed Source of Trial registry15. Trial registry16. information Location USA and Canada. USA and Canada. Design Non-randomised; single arm. Randomised, active-controlled. Participants n=60; aged ≥6 years old; diagnosis of n=46; ≥18 years; diagnosis of UCD; no urea cycle disorder, completed study clinical evidence of hyperammonaemia NCT0092459 or were not eligible (e.g. (ammonia level ≥ 100µmol/L) during the 2 were aged 6-17 years of age). weeks preceding screening. Schedule Participants received 17.4ml of glycerol Randomised to 17.4ml of glycerol phenylbutyrate orally. phenylbutyrate orally or sodium phenyl butyrate orally (dose not stated), both for 28 days, followed by alternate treatment for 28 days.

Follow-up Active treatment for 1 year. Active treatment 28 days. Primary Adverse events. Blood ammonia levels on days 14 and outcome 28. Secondary Number and causes of 24-hour urinary phenylacetylglutamine outcome hyperammonaemic events; blood excretion; maximum ammonia values; ammonia levels. number of severity of symptomatic hyperammonaemic crises; adverse events. Key results Not reported. Not reported. Adverse Gastrointestinal disorders 1.6%, For the sodium phenylbutyrate group vs effects (AEs) metabolism and nutrition disorders 15%, HPN-100 group respectively: nervous system disorders 1.6%, gastroenteritis 0% vs 2.27%, psychiatric disorders 1.6%, reproductive hyperammonaemia 2.22% vs 0%. system disorders 1.6% and respiratory disorders 1.6%. Expected Not reported. Not reported. reporting date

Trial NCT01257737, HPN-100-011; HPN-100; NCT00551200, UP1204-003, HPN-100- phase IV. 003, HPN-100 vs sodium phenylbutyrate (Buphenyl); phase II. Sponsor Horizon Pharma Ireland Ltd. Horizon Pharma Ireland Ltd. Status Ongoing. Completed. Source of Trial registry17. Trial registry18. information

4 Horizon Scanning Research & Intelligence Centre

Location USA and Canada. USA. Design Non-randomised, single arm. Randomised, active-controlled. Participants n=88; aged ≥1 year; completed study n=14; ≥18 years; diagnosis of UCD; HPN-100-005, HPN-100-007, or HPN- currently treated with sodium 100-012. phenylbutyrate for a minimum of 2 weeks prior to visit 1. Schedule Participants received HPN-100 orally Randomised to HPN-100 orally or sodium three times daily (subjects weighing less phenylbutyrate orally (dose not stated). than 20kg receive 53ml/kg/day, otherwise participants receive 11.48ml/m2/day).

Follow-up Not reported. Not reported. Primary Adverse events. Blood ammonia levels over 24 hours, outcome adverse events and serious adverse events. Secondary Blood ammonia levels; number and Pharmacokinetics, preference for glycerol outcome causes of hyperammonaemic crises; phenylbutyrate or sodium phenylbutyrate neuropsychological testing (Wechsler assessed by global preference question. Abbreviated Scale and Intelligence (WASI), California Verbal Learning Test (CVLT), Digit Span, Child Behaviour Checklist (CBCL), Behaviour Rating Inventory of Executive Function (BRIEF). Expected Study completion date reported as Not known. reporting December 2015. date

Trial NCT01347073; HPN-100-012; phase III. NCT0097544; HPN-100-005; HPN-100 vs sodium phenylbutyrate phase II. Sponsor Horizon Pharma Ireland Ltd. Horizon Pharma Ireland Ltd. Status Completed. Completed Source of Trial registry19. Trial registry20. information Location USA. USA and Canada. Design Non-randomised, open-label. Non-randomised, open-label. Participants n=23; aged 29 days to 6 years, n=17; aged 6-17 years, diagnosis of suspected or confirmed UCD diagnosis, UCD, on a stable dose of sodium on stable dose of sodium phenylbutyrate phenylbutyrate for at least 1 week prior to for at least 5 days before day 1, not starting glycerol phenylbutyrate. receiving sodium benzoate for at least 5 days before day 1, able to receive medication orally and not undergone liver transplantation, including hepatocellular transplantation. Schedule Participants receive approximately Participants receive HPN-100 orally for 1 17.4mL of HPN-100 orally three times week followed by option to continue for daily for 12 months after a switch over up to 12 months. period of 10 days. Follow-up Active treatment, up to 12 months. Active treatment, up to 12 months Primary Adverse events. Adverse events. outcome Secondary Blood ammonia levels; Number and causes of outcome hyperammonaemic crises. hyperammonaemic events; quality of life assessed by SF-15 questionnaire. Expected Not known. Not known. reporting date

5 Horizon Scanning Research & Intelligence Centre

ESTIMATED COST and IMPACT

COST

The cost of glycerol phenylbutyrate is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: may be reduced volume/number of  No impact identified tablets required and improved palatability compared to existing preparation.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs

 Other: uncertain unit cost compared to  None identified existing preparation.

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Mokhtarani M, Diaz G.A, Rhead W et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Molecular Genetics and Metabolism 2012;107(3):308-314. 2 The Rare Disease Clinical Research Network. Urea Cycle Disorders Overview. https://www.rarediseasesnetwork.org/ucdc/learnmore/index.htm Accessed 23 June 2015. 3 Testai F.D and Gorelick P.B. Inherited Metabolic Disorders and Stroke Part 2. Archive of Neurology 2010; 67(2):148-153 4 Enns GM, Berry SA, Berry GT et al. Survival after treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders. New England Journal of Medicine. 2007; 356(22):2282-92. 5 Msall M, Batshaw M, Suss R et al. Neurological outcomes in children with inborn errors of urea synthesis: outcome of urea-cycle enzymopathies. New England Journal of Medicine. 1984. 310(23):1500-1505 6 Haberle J, Boddaert N, Burlina A et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases 2012;7(1):32. 7 Medscape. Hyperammonemia. http://emedicine.medscape.com/article/1174503-overview#a6 Accessed 24 June 2015. 8 National Urea Cycle Disorders Foundation. What is urea cycle disorder? http://www.nucdf.org/ucd.htm Accessed 26 June 2015.

6 Horizon Scanning Research & Intelligence Centre

9 McGuire P.J and Lee H. Infectious Precipitants of Acute Hyperammonemia Are Associated with Indicators of Increased Morbidity in Patients with Urea Cycle Disorders. The Journal of Pediatrics 2013; 163(6):1075-1710. 10 Office for National Statistics. Deaths registered in England and Wales (series DR) – 2013. www.ons.gov.uk 11 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 12 British Inherited Metabolic Disease Group. Hyperammonaemia: Urea Cycle Disorders 2014. http://www.bimdg.org.uk/store/guidelines/ER-NAGSv3_249891_18032015.pdf Accessed 24 June 2015. 13 Meyburg J, Das AM, Hoerster F, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. 2009 87(5):636-41 14 Meyburg J, Schmidt J and Hoffmann GF. Liver cell transplantation in children. Clinical Transplantation. 2009 21:75-82 15 ClinicalTrials.gov. A phase III open-label study of the safety of HPN-100 for the long-term treatment of urea cycle disorders (treat UCD). https://clinicaltrials.gov/ct2/show/NCT00947297?term=nct00947297&rank=1 Accessed 25 June 2015. 16 ClinicalTrials.gov. A Phase 3, Randomized, Double-Blind, Cross-Over, Active-Controlled Study of the Efficacy and Safety of HPN-100, Glyceryl Tri-(4-phenylbutyrate), for the Treatment of Adults With Urea Cycle Disorders (Help UCD). https://clinicaltrials.gov/ct2/show/NCT00992459?term=nct00992459&rank=1 Accessed 25 June 2015. 17 ClinicalTrials.gov. To Evaluate the Safety of Long-term Use of HPN-100 in the Management of Urea Cycle Disorder. https://clinicaltrials.gov/ct2/show/NCT01257737?term=NCT01257737&rank=1 Accessed 26 June 2015. 18 ClinicalTrials.gov. A phase II, open-label, switch-over, dose-escalation study of the safety and tolerability of HPN-100 compared to buphenyl (sodium phenylbutyrate) in patients with urea cycle disorders. https://clinicaltrials.gov/ct2/show/NCT00551200?term=NCT+00551200&rank=1 Accessed 26 June 2015. 19 ClincalTrials.gov. A switch-over, open-label study of the safety, pharmacokinetics, and efficacy of HPN-100, followed by long-term treatment with HPN-100 in paediatrics subjects under 6 years of age with urea cycle disorder. https://clinicaltrials.gov/ct2/show/NCT01347073?term=NCT01347073&rank=1 Accessed 26 June 2015. 20 ClinicalTrials.gov. A phase 2, fixed sequence, open-label, switch-over study of the safety and tolerability of HPN-100 compared to sodium phenylbutyrate in children 6-17 years of age with urea cycle disorders, with a long term safety extension. https://clinicaltrials.gov/ct2/show/NCT00947544?term=nct00947544&rank=1 Accessed 26 June 2015.

7