Effect of Nitisinone on Aortic Stenosis Disease Progression in Patients With Alkaptonuria: An Analysis of the Suitability of Nitisinone in Alkaptonuria (SONIA) 2 Study

Background and aim Alkaptonuria (AKU) is a rare metabolic disorder characterised by the accumulation of homogentisic acid (HGA). Deposition of HGA in the aortic valve leading to progressive aortic stenosis is a serious complication. Nitisinone has been shown to improve morbidity and slow disease progression in AKU, but the effects of this treatment on aortic stenosis progression have not yet been described. The objective of this study was to evaluate whether treatment with nitisinone attenuated the progression of aortic stenosis, as assessed by peak trans-aortic valve pressure (P_max), in patients with AKU. This post-hoc analysis used longitudinal echocardiographic data from the Suitability of Nitisinone in Alkaptonuria (SONIA) 2, a four-year multicenter randomised controlled trial, to examine aortic stenosis disease progression. Methods Data were obtained from echocardiograms performed on 138 patients over 48 months of follow-up. A linear mixed-effects regression model was used to ascertain the difference in the maximal trans-aortic valve pressure gradient (P_max) at baseline and 48 months between the treatment and control groups, adjusting for baseline P_max and other covariates. Results At baseline, 18/138 patients (13.0%) had aortic stenosis of varying degrees of severity, and 25/138 (18.1%) had aortic sclerosis. The difference in P_max between the control (N=69) and treatment (N=69) groups at baseline was 0.063 mmHg [95% CI: -0.054 mmHg to 0.18 mmHg) and did not reach statistical significance (p=0.23). At the end of the four-year treatment period, the difference in P_max was 0.10 mmHg (95% CI: -0.0007 mmHg to 0.20 mmHg) (p = 0.05), representing a modest but statistically significant between-group treatment effect. Conclusion Nitisinone may attenuate the progression of aortic stenosis in patients with AKU. Given the small absolute effect size and post-hoc nature of the analysis, these findings should be interpreted as exploratory and hypothesis-generating rather than clinically definitive. Additional research is needed to determine whether nitisinone produces clinically meaningful outcomes for aortic stenosis in this population.