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

Ranganath, L.; Psarelli, Eftychia Eirini; Arnoux, Jean Baptiste; Braconi, Daniela; Briggs, Michael; Bröijersén, Anders; Loftus, Nadia; Bygott, Helen; Cox, Trevor F.; Davison, Andrew S.; Dillon, J.P.; Fisher, Michael; Fitzgerald, Richard J.; Genovese, Federica; Glasová, H.; Hall, Anthony K; Hughes, Andrew T.; Hughes, Juliette H.; Imrich, Richard; Jarvis, Jonathan C.; Khedr, Milad; Laan, Dinny; Sang, Kim Hanh Le Quan; Luangrath, Emily; Lukáčová, Oľga; Milan, Anna M.; Mistry, Alpesh; Mlynáriková, Vanda; Norman, Brendan P.; Olsson, Birgitta; Rhodes, Nicholas P.; Rovenský, Jozef; Rudebeck, Mattias; Santucci, Annalisa; Shweihdi, Ella; Scott, Ciarán; Sedláková, Jana; Sireau, Nicolas; Stančík, Roman; Szamosi, Johan; Taylor, Sophie; Kan, Christa van; Vinjamuri, Sobhan; Vrtíková, Eva; Webb, C S; West, Elizabeth A.; Zanova, E.; Zaťková, Andrea; Gallagher, James A.

doi:10.1016/s2213-8587(20)30228-x

Cited by 88 publications

(138 citation statements)

References 27 publications

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“…Indeed, several recent studies have shown that chronic treatment with 10 mg nitisinone daily for a period up to 4 years did reduce the rate of progression of AKU-related symptoms and arrest or even reverse ochronotic pigmentation [ 6 ]. This was confirmed in a larger study, SONIA-2, in which nitisinone 10 mg daily was compared to no treatment in 138 patients with AKU from the UK, France and Slovakia [ 7 ]. Nitisinone in this dose decreased urinary HGA by 99%, and after 4 years, the increase in AKU symptom score was statistically lower in the nitisinone-treated patients.…”

Section: Recent Advances In Aku Treatmentmentioning

confidence: 75%

“…Although it was mentioned that nitisinone was tolerated well, there was a higher incidence of infections and eye-related adverse events in the nitisinone-group. In total, 13% of patients stopped treatment with nitisinone due to adverse events, while dose reduction was advised in 12% of patients [ 7 ]. Ophthalmologic complications like keratopathy may however develop as a consequence of increasing tyrosine concentrations caused by the treatment [ 7 ] as especially seen in Tyrosinaemia type II, but also in patients with TT1 although the relation with blood tyrosine concentrations is not that clear.…”

Section: Recent Advances In Aku Treatmentmentioning

confidence: 99%

“…Although these landmark studies demonstrated the beneficial effects of nitisinone in AKU, we must realise that this therapy was started late in the course of the disease; most patients involved in the were between 40 and 60 years (mean age 52 years in the US National Institutes of Health (NIH) study [ 8 ], mean age 48 years in SONIA-2 [ 7 ]), and many already had suffered the consequences of the disease. The dose of nitisinone used in the former study was 2 mg daily [ 8 ], which was adapted in the latter study to 10 mg once daily, because of the fact that this dose lowers urinary HGA even slightly more, and the US NIH study did not report a significant beneficial effect on its primary and secondary parameters, i.e.…”

Section: The Clinical Dilemmamentioning

confidence: 99%

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Preventive use of nitisinone in alkaptonuria

Wolffenbuttel

Heiner‐Fokkema

Spronsen

2021

Orphanet J Rare Dis

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Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.

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Section: Recent Advances In Aku Treatmentmentioning

confidence: 75%

Section: Recent Advances In Aku Treatmentmentioning

confidence: 99%

Section: The Clinical Dilemmamentioning

confidence: 99%

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Preventive use of nitisinone in alkaptonuria

Wolffenbuttel

Heiner‐Fokkema

Spronsen

2021

Orphanet J Rare Dis

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“…35 The European Medicines Agency recently approved nitisitinone in adults, as the first disease-modifying therapy for AKU. 36,37 Due to concerns around cognitive impairment associated with nitisinone therapy in hereditary tyrosinaemia 1, more justification is needed before children with AKU are treated with nitisinone. Establishing whether disease has taken hold in children would need to be shown before nitisinone can be considered in children with AKU.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients

Ranganath

Khedr

Vinjamuri

et al. 2021

J of Inher Metab Disea

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A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty‐seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty‐seven attended more than once and received nitisinone 2 mg daily. Twenty‐three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18FPositron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; ochronosis associated closely with spondyloarthropathy scores (R = .65; P < .0001). Nitisinone reversed ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy.

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“…The use of nitisinone reduces the level of HGA in the blood and lowers the urinary excretion up to 70% 10 . The phase III of SONIA 2 clinical trial testing nitisinone in the treatment of AKU was com-pleted in 2019, and showed promising results in treatment of this rare disease 38,39 . Furthermore, an interesting finding is that liver transplantation may reduce the level of HGA in the blood 8 .…”

Section: Treatmentmentioning

confidence: 99%

Arthropathia ochronotica

Matoković¹,

Plečko²,

Crnogaća³

et al. 2020

Rad Hrvatske akademije znanosti i umjetnosti

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Alkaptonuria (AKU) is a rare autosomal recessive metabolic disease caused by a disorder of phenylalanine and tyrosine metabolism, resulting in accumulation and deposition of homogentisic acid (HGA) in the body. This deposition further causes progressive functional disorders in different organ systems, with the locomotor system being the most affected one. A specific triad of symptoms occurs in patients suffering from AKU: 1. at birth, a change of urine color is present when urine is exposed to air, 2. occurrence of dark pigmentations in connective tissues becomes visible over time, 3. complications of the locomotor, urogenital and cardiovascular systems present gradually. Arthropathia ochronotica occurs in patients suffering from AKU due to precipitation and deposition of HGA in the joint tissue (cartilage, tendons, ligaments, menisci, etc.). The accumulation can be seen as small foci of blue-black pigmentations. HGA deposits in collagen fibers, causing tendons and ligaments thickening. This causes them to be less resistant to mechanical forces, resulting in frequent ruptures caused by minimal trauma. Also, the deposition facilitates cartilage degeneration, often requiring an operative treatment. The knees are the most commonly affected joints, while changes can be seen in the spine and other large joints. As there is no specific treatment, alleviation of symptoms is the only treatment option. It has the goal of increasing individual functionality and quality of life. As an option for end-stage treatment, joint replacement surgery proved to be effective. In the future, an enzyme replacement therapy or gene therapy may be developed to treat AKU successfully.

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

Cited by 88 publications

References 27 publications

Preventive use of nitisinone in alkaptonuria

Preventive use of nitisinone in alkaptonuria

Characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients

Arthropathia ochronotica

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