Nitisinone

iStock, Andrii Dodonov Harliku is the only FDA-approved drug for alkaptonuria, a rare condition characterized by skin discoloration, arthritis and heightened risks of heart failure and stroke. The FDA approved the use of Cycle Pharmaceuticals’ oral drug nitisinone on Thursday. The product will be marketed under the brand name Harliku, for use in adult patients with alkaptonuria. Affecting one in 100,000 to 250,000 people worldwide, alkaptonuria (AKU) is an ultrarare genetic disease caused by a deficiency in the HGD an enzyme. Patients with AKU experience a pathological build-up of a particular acid in the skin, leading to ochronosis, or the bluish or reddish discoloration of patches of skin. Aside from ochronosis, AKU can also affect the bones and joints, causing arthritis, poor mobility and a heightened risk of fractures. The disease can also impair lung function, lead to heart failure and increase the risk of coronary artery disease and stroke. A small-molecule drug, Harliku works by blocking a key enzyme in the HGD cascade, ultimately reducing urine HGA levels. Cycle aims to launch Harliku, which is the first FDA-approved AKU treatment in the U.S., by July. The drug does not come with a boxed warning but carries precautions for lowered white blood and platelet counts, ocular symptoms and hyperkeratotic plaques, an abnormal thickening of the skin. Supporting Harliku’s approval are data from a 40-patient randomized clinical trial, which showed that the drug improved pain, physical function and energy after three years of treatment, Cycle said in Thursday’s release. The trial was published in October 2024 in Molecular Genetics and Metabolism . “The findings of this study suggest that the clinical impact of nitisinone aligns with its biochemical reduction of HGA, pointing to nitisinone as a therapy for alkaptonuria,” the researchers wrote at the time. Harliku’s approval comes as the rare disease space appears poised for newfound tailwinds, with health authorities voicing support for regulatory flexibility. In April, FDA Commissioner Marty Makary said his office is considering a “new pathway” for rare disease therapies, opening up approvals based on a “plausible mechanism.” Health Secretary Robert F. Kennedy Jr. has also agreed with this push , saying earlier this month that “we are going to continue to figure out new ways . . . of accelerating approvals for drugs and treatments that treat rare diseases.”

BOSTON & CAMBRIDGE, England--(BUSINESS WIRE)--Cycle Pharmaceuticals announced that the FDA has approved HARLIKU (nitisinone) Tablets for the reduction of urine homogentisic acid (HGA) in adult patients with AKU.1 Launching in July 2025, HARLIKU will be the first and only FDA-approved treatment for AKU,1 an ultra-rare genetic metabolic disorder in which patients have a buildup of HGA that leads to osteoarthritis, ochronosis, and complications in the kidneys, and heart.2 Patients with AKU often develop pain, reduced joint mobility, and require large joint replacements; the symptoms impede their physical functionality, emotional well-being, and quality of life.2, 3 The approval of HARLIKU is based on data from a randomized, no-treatment controlled study of 40 patients with AKU. As part of the intramural research program of the National Human Genome Research Institute at the National Institutes of Health (NIH), Dr. Wendy J. Introne, MD and her team showed that nitisinone helped patients improve pain, energy levels, and physical functioning after three years of treatment, assessed using the 36-Item Short-Form Survey.4 Steve Fuller, Chief Strategy Officer of Cycle Pharmaceuticals commented, "We are deeply grateful for Cycle’s collaboration with Dr. Wendy Introne, Dr. Bill Gahl, and the broader team at the NIH, whose pioneering work laid the foundation for this FDA approval. We look forward to making HARLIKU available to U.S. AKU patients as soon as possible and remain committed to supporting the AKU community to the fullest extent of our capabilities." “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 Dr. Wendy J. Introne, MD, of NIH’s National Human Genome Research Institute (NHGRI). Building on the company’s previous success in rare diseases, HARLIKU will be Cycle Pharmaceuticals’ eighth commercial product in the US. Indications HARLIKU™ is indicated for the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU). Important Safety Information Do not prescribe HARLIKU to patients allergic to nitisinone or any other contained ingredients. Warnings and Precautions: Ocular Symptoms and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Level: Ocular signs and symptoms including keratitis, corneal opacities, corneal irritation, corneal ulcers, conjunctivitis, eye pain, and photophobia, have been reported in patients. Perform slit-lamp examination prior to treatment and regularly thereafter. Reexamine patients if symptoms develop or tyrosine levels are > 500 micromole/L. Assess plasma tyrosine levels in patients with an abrupt change in neurological status. Perform a clinical laboratory assessment, including plasma tyrosine levels, in patients with an abrupt change in neurological status. Leukopenia and Severe Thrombocytopenia In clinical trials, patients with hereditary tyrosinemia type 1 (HT-1) treated with another oral formulation of nitisinone and dietary restriction, developed reversible leukopenia, thrombocytopenia, or both. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during HARLIKU therapy. Adverse Reactions: The most common adverse reactions (≥1%) reported in patients with AKU taking nitisinone in clinical trials are elevated tyrosine levels, thrombocytopenia and keratitis. Drug Interactions: Nitisinone is a moderate CYP2C9 inhibitor and a weak CYP2E1 inducer. Potential clinical impact of Harliku administration with CYP2C9 substrates. Reduce the dosage of the co-administered drugs metabolized by CYP2C9 by half. Additional dosage adjustments may be needed. Nitisinone is an inhibitor of OAT1/OAT3. Potential clinical impact of administration with OAT1/OAT3 substrates. Patients should be monitored for potential adverse reactions. Use in Specific Populations: Pregnancy: Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. Lactation: The developmental and health benefits of breastfeeding should be considered against the mother’s clinical need for HARLIKU, along with potential adverse effects on the breastfed infant from HARLIKU or from the underlying maternal condition. Pediatric Use: The safety and effectiveness of HARLIKU have not been established in pediatric patients with AKU. Geriatric Use: Insufficient data from clinical studies of HARLIKU to determine if patients ≥ 65 years of age respond differently. Elderly patients should be cautious reflecting any decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. For more detailed information, please refer to the full Prescribing Information at harliku.com/pi. To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals at 1-855-831-5413, or the FDA at: 1-800-FDA-1088 or www.fda.gov/medwatch. US-HKU-2500032 | May 2025 References HARLIKU (nitisinone) Tablets. Prescribing Information. Cycle Pharmaceuticals Ltd Introne WJ, Perry M, Chen M. 2003 (updated 2021). Alkaptonuria. Available at: https://www.ncbi.nlm.nih.gov/sites/books/NBK1454/ [Accessed May 29, 2025] Rudebeck M, Scott C, Sireau N, Ranganath L. 2020. A patient survey on the impact of alkaptonuria symptoms as perceived by the patients and their experiences of receiving diagnosis and care. JIMD Rep. 53(1):71-79. doi:10.1002/jmd2.12101 Spears KR, Rossignol F, Perry MB, et al. 2024 Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial. Mol Genet Metab . 143(1-2),108562. doi:10.1016/j.ymgme.2024.108562 ©2025 Cycle Pharmaceuticals Limited. All rights reserved. HARLIKU™ and Cycle Vita™ are trademarks of Cycle Pharmaceuticals Limited in the United States. About Cycle Pharmaceuticals Cycle Pharmaceuticals was founded in 2012 with the sole aim of delivering drug treatments and product support to the underserved rare disease community. Cycle Pharma focuses on rare genetic conditions in metabolic, immunology, urology, and oncology. In neurology, we focus on multiple sclerosis. Cycle Pharma is headquartered in Cambridge, UK and has offices in Boston, Massachusetts. For more information, please visit www.cyclepharma.com and follow us on X, LinkedIn and Facebook.