Harliku (nitisinone): first FDA-approved disease-modifying therapy for alkaptonuria

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder due to a deficiency of homogentisate 1,2-dioxygenase, subsequently leading to the progressive acquisition of ochronosis, osteoarthropathy, systemic complications, and the pathological retention of homogentisic acid (HGA). Until recently, apart from supportive management which involved orthopedic surgery and symptomatic treatment, there was no attempt to slow the progress of the disease. On 19 June 2025, the U.S. Food and Drug Administration approved Harliku (nitisinone) as the first therapy to modify the progression of the disease. As a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, nitisinone exerts biochemical efficacy with a greater than 95% reduction of urinary excretion of HGA. The SONIA 2 and other studies funded by the NIH have demonstrated long-standing metabolic control with nitisinone, as well as improved functional outcomes and possibly cardioprotective effects. Although the evidence of long-term benefits is promising, risks of treatment, such as tyrosinemia, require attention to diet and continued monitoring. As the first single agent to be taken orally once daily, Harliku changes the paradigm of management for the rare metabolic disorder AKU from symptomatic treatment to disease-modifying therapy. It is a huge leap for other disorders of metabolism and paves the way for future innovations in therapy.