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

Abstract

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 À132, À411, À295, and À 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.

Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria

“…sTYR thresholds in NIT-treated adult AKU patients are more pragmatic as most of these patients are habituated to eating normally. In the United Kingdom National Alkaptonuria Centre, a specialist dietician manages the tyrosinaemia, to defined sTYR thresholds (Table S8), employing 7-day food diaries and fasting sTYR monitoring [27] . Daily dietary protein requirements designed to meet the need for limiting amino acids methionine, tryptophan, threonine and lysine [28] , [29] , result in obligate excess consumption of PHE and TYR.…”

Adequacy of nitisinone for the management of alkaptonuria

“…Similarly, a study conducted for four weeks proved the dose-response relationship as increasing nitisinone dosage concentration results in the decrease of 24-hr urinary HGA levels with the maximal effect obtained at 8 mg dose, which showed a 98.8% reduction in urinary HGA levels [ 5 ]. Another study found the same results at a 10 mg dose, which the European Medicines Agency has authorized to treat adult alkaptonuric patients [ 11 ].…”

Improving the clinical accuracy and flexibility of the Alkaptonuria severity score index

“…Results from the SONIA 2 trial, as well as the UK's National Alkaptonuria Centre (NAC), have demonstrated that once‐daily nitisinone is well tolerated and effective in reducing urinary excretion of HGA and slowing disease progression. 6 , 11 …”

“…Results from the SONIA 2 trial, as well as the UK's National Alkaptonuria Centre (NAC), have demonstrated that once-daily nitisinone is well tolerated and effective in reducing urinary excretion of HGA and slowing disease progression. 6,11 With nitisinone now approved as a treatment for AKU, 12 improving the cAKUSSI as a flexible and reliable tool to measure disease progression and treatment response globally is important for monitoring the realworld efficacy of nitisinone as well as any future treatments. A more flexible AKUSSI may be of particular relevance to registries and large cohort studies where the availability of equipment and clinical expertise is likely to vary across participating sites.…”

“…In this study, 138 patients were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Results from the SONIA 2 trial, as well as the UK's National Alkaptonuria Centre (NAC), have demonstrated that once‐daily nitisinone is well tolerated and effective in reducing urinary excretion of HGA and slowing disease progression 6,11 …”