Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

RCT (n=138) found daily urinary HGA excretion significantly decreased by 99.7% in nitisinone group vs no treatment (mean ratio of nitisinone/control 0.003, p<0.0001) as was Clinical evaluation Alkaptonuria Severity Score Index (adjusted mean difference –8.6 points, p=0.023)

SPS commentary:

The study also found that nitisinone decreased ochronosis (bluish-black discoloration of the skin and cartilage) and improved clinical signs, suggesting slower disease progression.

A commentary discusses this research. It covers the rarity of alkaptonuria, a genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA), that  (affects only one in 25000 to 1,000,000 people. It states that this study is important for the management of alkaptonuria as, to date, treatment was symptomatic, meaning that ochronotic complications were inevitable. It adds that his it shows not only a biochemical cure, but also, for the first time, a clinical impact in a large cohort,giving hope that the course of disease in alkaptonuria can be fundamentally changed in the future.

It acknowledges that open questions remain. When does treatment need to be started? After what age do the ochronotic changes become irreversible and clinically relevant? Additional studies are needed to determine the ochronotic process during presymptomatic years and to define the optimal time point for start of treatment. An optimal dose also needs to be identified. One consequence of treatment with nitisinone will be an increase of tyrosine in the blood that could cause keratopathy. Patients on treatment will therefore require a diet with low phenylalanine and tyrosine, which impacts on quality of life. The minimum effective dose of nitisinone should be used, which needs to be determined in future trials. In addition, it remains unclear whether all patients need to be treated. If a patient only has moderately elevated homogentisic acid, is there a benefit of homogentisic acid-lowering treatment?


The Lancet Diabetes & Endocrinology

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