Nitisinone Becomes First and Only FDA-Approved Treatment for HGA in Adults With AKU

The FDA approved nitisinone tablets (Harliku; Cycle Pharmaceuticals) for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU). With this action, nitisinone is the first and only FDA-approved treatment for AKU.¹

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“We look forward to making [nitisinone tablets] available to US [patients with AKU] as soon as possible and remain committed to supporting the AKU community to the fullest extent of our capabilities,” Steve Fuller, chief strategy officer of Cycle Pharmaceuticals, said in a news release.¹

AKU, also known as black urine disease, is a rare inherited disorder that prevents the patient’s body from completely breaking down 2 amino acids, tyrosine and phenylalanine. It results in a buildup of a chemical, HGA, in the body, turning urine and parts of the body a dark color. Over time, it can lead to a wide range of health problems if not treated.² Patients with AKU often develop pain and reduced joint mobility and require large joint replacements, and such symptoms impede their physical functionality, emotional well-being, and quality of life.^1,2

Nitisinone is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase enzyme, the second enzyme in tyrosine catabolism, and dramatically reduces HGA production. Despite the previously confirmed biochemical efficacy and tolerability of nitisinone in patients with AKU, the investigators noted that the selected primary outcome did not demonstrate significant clinical benefit.^1,3

Its approval was based on data from a 3-year, interventional, randomized phase 2 clinical trial (NCT00107783),⁴ which assessed the safety and effectiveness of long-term nitisinone treatment for joint problems in patients aged 30 to 80 years with AKU. A total of 40 patients were randomly assigned to 1 of 2 treatment groups: group 1, which takes their regular medicines plus a 2-mg nitisinone capsule once per day (n = 20); and group 2, which takes only their regular medicines (n = 20). Of note, patients taking nitisinone had blood tests to measure liver function 2 weeks and 6 weeks after starting treatment.^1,3,4

The study’s primary end point was change in total range of motion in the worse hip. Findings were published in Molecular Genetics and Metabolism.^1,3,4

The study findings indicated that, following 3 years of treatment, nitisinone helped patients improve pain, energy levels, and physical functioning in adult patients. The improvements were observed using the 36-Item Short-Form Survey and 6-min walk test.^1,3

Prior trials reported that the most common adverse events (AEs) in patients with AKU receiving nitisinone were elevated tyrosine levels, thrombocytopenia, and keratitis. Other possible and more severe AEs are ocular symptoms (eg, corneal opacities, corneal ulcers, conjunctivitis, eye pain), hyperkeratotic plaques because of an elevated plasma tyrosine level, leukopenia, and severe thrombocytopenia.¹

“The approval of [nitisinone tablets is] an important advance for the AKU community. Our scientific team has translated decades of research into launching nitisinone as a new treatment option, and we stand hopeful that it can ease the significant burden of AKU,” Wendy J. Introne, MD, National Human Genome Research Institute, National Institute of Health, said in the news release.¹

REFERENCES

1. Businesswire. Cycle Pharmaceuticals’ HARLIKU™ (nitisinone) Tablets Receive First FDA-Approval as Treatment for Alkaptonuria (AKU). News release. June 19, 2025. Accessed June 19, 2025. https://www.businesswire.com/news/home/20250611798305/en/Cycle-Pharmaceuticals-HARLIKU-nitisinone-Tablets-Receive-First-FDA-Approval-as-Treatment-for-Alkaptonuria-AKU

2. NHS. Alkaptonuria. Accessed June 19, 2025. https://www.nhs.uk/conditions/alkaptonuria/

3. Spears KR, Rossignol F, Perry MB, et al. Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial. Mol Genet Metab. 2024;143(1):108562. doi:10.1016/j.ymgme.2024.108562

4. Long-Term Study of Nitisinone to Treat Alkaptonuria. ClinicalTrials.gov identifier: NCT00107783. Updated August 26, 2021. Accessed June 19, 2025. https://clinicaltrials.gov/study/NCT00107783