A 3-year randomized therapeutic trial of nitisinone in alkaptonuria

Abstract

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis.

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria

“…It converts homogentisic acid (HGA, 2,5-dihydroxyphenylacetic acid) to 4-maleylacetoacetic acid. Inability to metabolize HGA leads to urinary excretion of at least 90% of the compound, or 3-6 g per day, in patients with AKU (Garrod 1902;Lustberg et al 1969;Introne et al 2011). Despite this pronounced renal elimination, some HGA is oxidized to a melanin-like polymeric pigment via benzoquinone acetic acid.…”

“…In HT-1, nitisinone prevents the formation of the highly toxic metabolites maleylacetoacetate, fumarylacetoacetate, and succinylacetone (Lindstedt et al 1992), and in combination with a tyrosine-restricted diet, it serves as a successful therapeutic intervention. In AKU, nitisinone can effectively reduce HGA and prevent ochronosis in mice (Suzuki et al Preston et al 2013) and reduce HGA in patients (Introne et al 2011).…”

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

“…This is based on the experience of using nitisinone in the National Institutes of Health, USA (Phornphutkul et al 2002;Suwannarat et al 2005;Introne et al 2011). However, one patient in the clinical trial of nitisinone in AKU developed corneal keratopathy that resolved fully with discontinuation of nitisinone (Introne et al 2011).…”

Alkaptonuria: Leading to the Treasure in Exceptions

“…As expected, plasma tyrosine concentrations rose approximately from 70 to 760 AE 181 mM with no ill-effects attributable. At dose administered and as predicted, nitisinone was well tolerated; and although the trial failed its primary therapeutic endpoint, improvement of joint symptoms in some patients with established joint disease was identified (Introne et al 2011). …”

“…Alkaptonuria, a neglected ultraorphan disease and the firstidentified inborn error of metabolism, represents an extreme case for therapeutic advance. While in retrospect, it is not surprising that nitisinone failed to increase hip mobility in alkaptonuric patients with established ochronotic arthropathy, given the definitive effects of nitisinone on the primary biochemical defect in alkaptonuria, it is difficult to ignore the potential for clinical utility (Phornphutkul et al 2002;Suwannarat et al 2005;Introne et al 2011). However, the problem of how best to investigate its putative therapeutic and more likely preventative action on disease-related events that are meaningful for patientsand obtain appropriate funding for long-term studies and regulatory approval -remains (Buckley 2008;Griggs et al 2009).…”