The FDA has approved nitisinone tablets (Harliku) for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU), marking the first and only FDA-approved treatment for this rare genetic metabolic disorder. The medication, developed by Cycle Pharmaceuticals, is expected to launch in July 2025.
Addressing an Unmet Medical Need
Alkaptonuria, also known as black urine disease, is a rare inherited disorder that prevents the body from completely breaking down two amino acids, tyrosine and phenylalanine. This results in a buildup of homogentisic acid in the body, which can turn urine and parts of the body a dark color. The condition affects approximately 1 in 250,000 to 1 million people in the United States.
The disorder leads to significant complications over time, including osteoarthritis, ochronosis (a characteristic feature occurring in connective tissues such as joints, tendons, and ligaments), and complications in the kidneys and heart. Patients often develop pain and reduced joint mobility, require large joint replacements, and experience impaired physical functionality, emotional well-being, and quality of life.
"The approval of Harliku 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," said Wendy J. Introne, MD, of NIH's National Human Genome Research Institute.
Clinical Trial Results
The approval is based on data from a 3-year, interventional, randomized phase 2 clinical trial (NCT00107783) that assessed the safety and effectiveness of long-term nitisinone treatment. The study enrolled 40 patients at the National Institutes of Health Clinical Center between April 2005 and March 2006.
Patients were randomly assigned to two groups: 20 received nitisinone 2 mg once daily plus their regular medicines, while 20 received only their regular medicines as controls. All patients were aged 18 to 65 years, except for one who was older than 65 years. Approximately 67.5% were male.
The study's primary endpoint was change in total range of motion in the worse hip. At baseline, the mean range of motion worse hip was 42.7, with additional functional assessments including the Schober test (average score 11.14), functional reach assessment (9.6), timed get up and go (8.63 seconds), and 6-minute walk test (1457 ft).
Significant Functional Improvements
After 36 months of treatment, patients receiving nitisinone demonstrated notable improvements compared to untreated controls. In the primary endpoint, untreated patients experienced a decline of 9.1 in total range of motion worse hip, while treated patients showed an increase of 1.6.
Secondary endpoints also favored the treatment group. For the Schober test, untreated patients had a decline of 0.06 in their score, while treated patients had an increase of 0.12. In the timed get-up-and-go test, patients treated with nitisinone showed improvement with a decrease of 1.33 seconds, compared to a decrease of 0.54 seconds in untreated patients. For the 6-minute walk test, patients in the treatment group increased their distance by 169 feet compared to 22 feet for untreated patients.
The study findings indicated that following 3 years of treatment, nitisinone helped patients improve pain, energy levels, and physical functioning, as measured by the 36-Item Short-Form Survey and 6-minute walk test.
Mechanism of Action and Safety Profile
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, investigators noted that the selected primary outcome did not demonstrate significant clinical benefit, though functional improvements were observed.
In the clinical trial, six patients in the treatment group experienced serious adverse events, including anemia, atrial fibrillation, keratitis, bile duct stone, liver enzyme elevation, sarcoidosis, accidental overdose, and muscle injury. Both treatment and control groups had 10 patients each experiencing other adverse events.
Prior trials reported that the most common adverse events in patients with AKU receiving nitisinone were elevated tyrosine levels, thrombocytopenia, and keratitis. Other possible and more severe adverse events include ocular symptoms such as corneal opacities, corneal ulcers, conjunctivitis, and eye pain, as well as hyperkeratotic plaques due to elevated plasma tyrosine levels, leukopenia, and severe thrombocytopenia.
Industry Impact
"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," said Steve Fuller, chief strategy officer of Cycle Pharmaceuticals.
The approval represents a significant milestone for the rare disease community, providing the first therapeutic option for patients with alkaptonuria who previously had no approved treatments available for their condition.
