Lets Talk Research 2015 - Anna Milan - Suitability of Nitisinone in Alkaptonuria
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Suitability of Nitisinone in Alkaptonuria (SONIA 1) AM Milan, AT Hughes, AS Davison, J Gallagher & L Ranganath
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Lets Talk Research 2015 - Anna Milan - Suitability of Nitisinone in Alkaptonuria
- 1. Suitability of Nitisinone in Alkaptonuria (SONIA 1) AM Milan, AT Hughes, AS Davison, J Gallagher & L Ranganath
- 3. Alkaptonuria • Described in 1902 by Garrod – First inborn error of metabolism • Rare autosomal recessive disorder – Prevalence 1 in 500,000 – Increase prev in Slovakia (1 in 20,000) – Report suggests 1 in 125 in Jordan • Homogentisic acid (HGA) accumulates – Urine, plasma, cartilage and connective tissues • Urine darkens upon standing or in alkaline pH
- 4. Alkaptonuria • HGA oxidises to benzoquinones – Polymerize and bind to cartilage / connective tissues – Early onset destructive arthritis of spine and large joints – Valvular heart disease • Orthopaedic complications – Begin with vertebral disk narrowing in 30s – Large joint destruction 40-50s – Kidney stones, prostate stones
- 5. Ranganath LR, et al. J Clin Pathol 2013 66: 367-373 Nitisinone
- 6. NTBC HT-3 HT-1 Mild mental deficiency Ataxia Convulsions Mental deficiency Cardiomyopathy Dermal tyrosine effects Hepatotoxicity Renal toxicity Death Genetic Disorders of Tyrosine Pathway AKU Arthritis Aortic valve disease Ruptures Stones CH2 CH COOH NH 2 CH2 CH COOH NH2 HO CH2 C COOH O HO OH CH2 COOH HO Phenylalanine Tyrosine 4-OH- Phenylpyruvic Acid Homogentisic Acid Maleylacetoacetic Acid Fumarylacetoacetic Acid Succinylacetoacetic Acid Succinylacetone Phenylalanine hydroxylase Tyrosine aminotransferase 4-hydroxyphenylpyruvic acid dioxygenase Homogentisic acid oxygenase AKU HT 3 HT 1 HT 2 Catecholamines Thyroid Hormones (T3 and T3) Melanin HT-2 Calluses on palms /feet Eyes – tearing, photophobia, pain Mental development Fumarylacetoacetate hydrolase Fumaric Acid + Acetoacetic Acid
- 7. Nitisinone dosing in HT 1 • Lindstedt predicted that nitisinone should be effective in HT 1 • In Feb 1991, the first HT 1 patient was given nitisinone with a dramatic positive outcome • Licenced and standard dose is 0.5 to 2.5mg/kg body weight in HT 1 • Replaced liver transplant as first line treatment for HT1
- 8. • Robert Gregory National AKU Centre – Established April 2012 – Officially opened in Jan 2013 – NHS National Specialised Services Commissioning Group – Patients over 16 years of age access to full surgical and medical assessment – Treatment with nitisinone (off licence)
- 9. Patient Ophthalmology Nutrition Bone Health inc MRI and DEXA Gait analysis Cardiology Genetics Metabolomics, oxidative stress markers, connective tissue damage markers Psychometrics
- 10. Aims • Establish and validate quantitative methods • Serum tyrosine, HGA and Nitisinone (NTBC) • Urine tyrosine and HGA • Biochemical identification of AKU by measurement of urine and serum HGA • Monitor NTBC therapy by change in: • Urine HGA and tyrosine • Serum HGA, tyrosine and NTBC • Apply method to clinical trials to aid in licencing of NTBC for AKU
- 11. Challenges • Analysis of tyrosine, HGA and nitisinone simultaneously in serum and urine – Serum amino acid – Urine organic acid – Spectrophotometric analysis UV detection – LC-MS/MS for nitisinone • Large dynamic range covering pre- and post treatment – Urine HGA linearity 6-60 µmol/L (Lustberg et al.,1971) – Serum HGA 0.25-50µg/mL (Suwannarat et al., 2005)
- 12. Hughes AT et al. J Chrom B 2014;963:106-112
- 13. Hughes AT et al. Ann Clin Biochem 2015, In Press
- 14. 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 BASELINE DAY 4 3 MONTHS 6 MONTHS 12 MONTHS 24 MONTHS UrineHGAµmol/24hr 0 1000 2000 3000 4000 5000 6000 7000 3 MONTHS 6 MONTHS 12 MONTHS 24 MONTHS UrineHGAµmol/24hr Dose increased to 2mg daily Urine HGA
- 15. 0 200 400 600 800 1000 1200 BASELINE DAY 4 3 MONTHS 6 MONTHS 12 MONTHS 24 MONTHS SerumTyrosineµmol/L Serum Tyrosine
- 16. Adverse Event on Nitisinone Male, 23 year old • 7 weeks after starting on 2mg alternative days – Tearing and blurring of eyes (watching TV in evening) – Cleared by next day – No pain / red eyes – Skin rash U-HGA µmol/day S-HGA µmol/L U-TYR µmol/day S-TYR µmol/L Baseline 14,246 33 64 42 2 days post NTBC 12,773 10.8 566 384 9 weeks 2mg alt days - - - 941 12 months 2mg weekly 2880 (80%↓) 16.7 (49%↓) 538 582
- 17. Week 9 Week 10
- 18. • European FP-7 Funding – 13 Partners, 3 sites (Liverpool, Piestany and Paris) • Large International Clinical Trial – Suitability Of Nitisinone In AKU (SONIA) – SONIA-1 • Dose dependent study • 40 patients from Europe – SONIA-2 • 140 randomly on decided dose or no treatment • Licensing of Nitisinone for AKU
- 19. AKU Patients Patient groups AKU Society UK ALCAP - France Universities Liverpool Sienna Slovakia Hospital Trusts RLBUHT Paris Slovakia Other PSR Cudos Nordic Bioscience SOBI Institut Necker
- 20. SONIA-1 Ranganath LR, et al. Ann Rheum Dis 2014;0:1–6. doi:10.1136/annrheumdis-2014-206033 Randomised, open label, parallel-group design
- 21. Ranganath LR, et al. Ann Rheum Dis 2014;0:1–6. doi:10.1136/annrheumdis-2014-206033 SONIA-1 – Primary outcome urine HGA
- 22. Ranganath LR, et al. Ann Rheum Dis 2014;0:1–6. doi:10.1136/annrheumdis-2014-206033
- 23. Discussion • Urine HGA suppressed to 98.8% compared with baseline (8mg dose) – Minimal dose compared with HT1 – Not suppressed to ‘normal’ reference range • Serum tyrosine increased – Long term affects being examined • No adverse events in SONIA 1 – Eye keratopathy in patient attending NAC
- 24. Study Design n Dose Duration Results Phornphutkul et al Open, uncontrolled, proof of concept 2 0.35mg bd to 1.4mg bd 9 & 10 days Marked reduction in [HGA] Suwannarat et al Open, uncontrolled, proof of concept 9 0.35mg bd to 1.05mg bd 3 months Marked reduction in [HGA] Introne et al Randomised, parallel group, single blind, untreated controls. 20 2mg od 36 months Marked reduction in [HGA] No significant effect on clinical parameters Phomphutkul C et al. New England Journal of Medicine 2002;347:2111-21 Suwannarat P et al. Metab Clin Exp 2005;54:719-28 Introne WJ et al. Molecular Genetics and Metabolism. 2011;103:307-14 Ranganath LR, et al. Ann Rheum Dis 2014;0:1–6. doi:10.1136/annrheumdis-2014-206033 Ranganath et al Randomised, open label, parallel-group design 40 No treatment, 1, 2, 4, 8mg od 4 weeks Marked reduction in [HGA]
- 25. Discussion • Previous study inconclusive for rheumatology end point at 3 years – ?Due to low dose (2mg) not inhibiting enzyme activity to near-normal • SONIA 2 – 140 patients across Europe; 10mg v no treatment – Visits at baseline (3 days), 3 months and 1 year – Annual checks – Patient retention for 5 years – Initial one year analysis due March 2016
- 27. Acknowledgments • Jim Gallagher • Jonathan Jarvis • AKU Patients • Staff on NAC Centre • NHS England Highly Specialised Services • Andrew Hughes • Prof Ranganath • Andrew Davison • Jean Devine • Jeannette Usher • Bill Taylor • AKU Research Group
Editor's Notes
- Alkaptonuria (AKU) is a rare inherited metabolic disorder of phenylalanine and tyrosine metabolism. It occurs in approximately 1 in 250 000 in the general population. It results from a defect in the enzyme homogentisate dioxygenase. To date treatments have been supportive including; analgesia, vitamin C (anti-oxidant), physiotherapy and joint replacement. Three studies have evaluated the use of a drug called nitisinone. This is a competitive inhibitor of HPPAD. The net result of using a 2mg dose was a ~95% reduction in HGA. Work carried out at the NAC has demonstrated a similar efficacy using this dose (2mg every other day until wk 3 when patients were given NTBC daily). NTBC is already licensed for use in hereditary tyrosinaemia-1.
- HT3 is characterized by elevated blood concentrations of Tyr and massive urinary excretion of 4-hydroxyphenylpyruvic acid (4-HPP), 4-hydroxyphenyllactic acid, and hydrophenylacetic acid (3). Clinical symptoms in some patients include mild mental retardation, ataxia, and convulsions, and these symptoms are likely due to the elevation of 4-HPP and Tyr in body fluids Tyrosinemia type II (Oculocutaneous tyrosinemia,[1] Richner-Hanhart syndrome[1]:543) is an autosomal recessive condition with onset between ages 2 and 4 years, when painful circumscribed calluses develop on the pressure points of the palm of the hand and sole of the foot. Type II tyrosinemia is caused by a deficiency of the enzyme tyrosine aminotransferase (EC 2.6.1.5), encoded by the gene TAT. Tyrosine aminotransferase is the first in a series of five enzymes that converts tyrosine to smaller molecules, which are excreted by the kidneys or used in reactions that produce energy. This form of the disorder can affect the eyes, skin, and mental development. Symptoms often begin in early childhood and include excessive tearing, abnormal sensitivity to light (photophobia), eye pain and redness, and painful skin lesions on the palms and soles. About half of individuals with type II tyrosinemia are also mentally challenged. Type II tyrosinemia occurs in fewer than 1 in 250,000 individuals. Type 1 Tyrosinemia, also known as hepatorenal tyrosinemia, is the most severe form of tyrosinemia. It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase and p-hydroxyphenylpyruvic acid oxidase. Type 1 tyrosinemia is inherited in an autosomal recessive pattern. Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in Quebec is about 1 in 16,000 individuals. In the Saguenay-Lac-Saint-Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846.[1] The carrier rate has been estimated to be between 1 in 20 and 1 in 31. Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of tyrosine - fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems. Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to jaundice, ascites and hemorrhage. There is also an increased risk of hepatocellular carcinoma. The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The primary treatment for type 1 tyrosinemia is nitisinone (Orfadin). Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-OH phenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.
- The development of nitisinone as a drug for HT 1 Following the recognition that nitisinone was a potent inhibitor of pHPPD, it was soon realised that pHPPD deficiency (tyrosinaemia type III, McKusick 276710) occurred in humans. Lindstedt et al at the University of Gothenburg, had isolated, purified, sequenced and characterized pHPPD from human liver 26, 27. In vitro studies on the purified pHPPD enzyme established that nitisinone is a potent inhibitor of human liver pHPPD, a concentration of 5 nmol/L preincubated with the enzyme for 3 min producing about 50% inhibition. Lindstedt et al then came up with the idea to try nitisinone in HT-1, which is caused by a deficiency of the enzyme fumarylacetoacetase (EC 3.7.1.2) where the build-up of the electrophilic metabolites fumarylacetoacetate, maleylacetoacetate and succinylacetone leads to hepatotoxicity, nephrotoxicity and porphyria 28. A formal request to use nitisinone to treat HT-1 patients was made by Dr Lindstedt in October 1989. However it was only in February 1991, after obtaining full approval a quantity of nitisinone for treatment of a seriously ill 2-month-old child with HT-1 was released. The outcome of the treatment was dramatic. Many of the clinical chemical markers of liver function rapidly returned to approaching their normal range, and subsequently the patient has been able to lead a fairly normal life. The outcome of this landmark case and of four other cases subsequently treated with nitisinone in Sweden was reported in 1992 29. No adverse ocular effects were seen in any of these patients. This has led to nitisinone being the standard of care for HT-1 and the subject of several excellent monographs since 4. Nitisinone was patented and is now owned by Swedish Orphan Biovitrum International. Nitisinone is licensed for treatment of HT-1 at a dose of 0.5 to 2.5mg/kg body weight.
- Suitability of Nitisinone in Alkaptonuria-1 (SONIA-1) is part of DevelopAKUre programme Patients from Liverpool (n=15) and Piestany (n=25) (Slovakia) – May to Oct 2013. 2/3 male, mean age 47y. 37 caucasian. eGFR normal in all patients. AKU diagnosed biochemically by measuring U-HGA and by gene analysis of HGD. Study was open labelled as it is not possible to blind due to the nature of urine changing colour on standing due to the oxidation of HGA. Participants ask to maintain stable diet; specifically not to alter protein intake. Patients were not included if they had taken NTBC 60 previously. Dose selection based on previous reports – Introne et al (2011) using 2mg/d showed 95% decrease in U-HGA (5.1g/d to 113mg/d). Aim was to see if HGA could be suppressed further and to assess impact on tyrosine concentration. NTBC – oral suspension given in the morning 4mg/mL, T ½ ~52-55h
- Primary end-point of the dosing study was [HGA] at the end of 4 weeks of NTBC treatment – 8mg dose reduced U-HGA 24h by 98.8% compared to baseline. Secondary end points were U-HGA at weeks 2 and 4; S-HGA and S-TYR at weeks 2 and 4 U-HGA data were skewed so data were log transformed, data were analysed using a mixed model for repeat measurements (MMRM) Clear dose response relationship with greatest reduction in HGA with 8mg NTBC
- S-HGA and S-TYR were performed at weeks 0, 2, 4 from patients in the fasted state. Samples collected into serum tubes – samples acidified using perchloric acid (10% v/v 5.8M) All treated patients had [TYR] >500umol/L, greatest 1117umol/L (4mg)
- Introne et al (2011) using 2mg/d showed 95% decrease in U-HGA (5.1g/d to 113mg/d).