Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria—An approach using statistical modelling

BACKGROUND: Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared. PATIENTS AND METHODS: Sixty‐nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24‐h urine homogentisic acid (uHGA(24)), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc. RESULTS: The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the x‐axis was −132, −411, −295, and − 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC (p < 0.001) and the SONIA 2 (p < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively. DISCUSSION: The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively. CONCLUSION: Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low‐protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone. HIGHLIGHTS: 1. Nitisinone 10 mg apparently slows alkaptonuria disease progression more than 2 mg in adults. 2. Corneal keratopathy during nitisinone therapy was more common in men. 3. Serum nitisinone concentrations increased significantly over time. 4. Nitisinone may inhibit cytochrome P450 self catabolism.