Rare diseases Xagena

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Alkaptonuria, Nitisinone therapy decreased urinary homogentisic acid excretion to low levels and was well tolerated

Alkaptonuria ( AKU ) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for alkaptonuria.
Nitisinone ( Orfadin ) decreases homogentisic acid ( HGA ) in alkaptonuria but the dose-response relationship has not been previously studied.

SONIA 1( Suitability Of Nitisinone In Alkaptonuria 1 ) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study.

The primary objective was to investigate the effect of different doses of Nitisinone once daily on 24-h urinary HGA excretion ( u-HGA24 ) in patients with alkaptonuria after 4 weeks of treatment.
Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of Nitisinone.

A clear dose-response relationship was observed between Nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively.

For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA.

Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of Nitisinone therapy.

In this study in patients with alkaptonuria, Nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. ( Xagena )

Ranganath LR et al, Ann Rheum Dis 2014; Epub ahead of print