Alkaptonuria Patients See Several Benefits from Daily Nitisinone

Investigators in Liverpool, United Kingdom, have published the first human study showing that the drug nitisinone stops the progress of alkaptonuria (AKU), a highly rare disease with no known cure.

AKU, also known as black bone disease, is a rare genetic metabolic condition caused by mutations in the HGD gene, which is involved in the production of the enzyme homogentisate oxidase. As a result of these mutations, those with AKU experience a buildup of homogentisic acid (HGA) in the body, which causes black pigment to deposit into connective tissue and darken skin and cartilage, a side effect called ochronosis that typically appears after 30 years of age. Other symptoms of AKU can include darkened urine from excreted HGA, dark spots on the eyes, arthritis, heart problems, osteoporosis, kidney stones, and prostate stones.

While there is no cure for AKU, individuals with joint pain and arthritis from the condition can manage their symptoms with physical and occupational therapy, surgery, and moderate exercise. There is currently no treatment to prevent or reverse the pigmentary changes associated with AKU. However, in a new study published in the journal Molecular Genetics and Metabolism, investigators from the Royal Liverpool University Hospital and the University of Liverpool have found that a drug called nitisinone—which works by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase—can halt the progress of AKU. Previous short-term studies have found that nitisinone can reduce urinary HGA levels in patients and can help to reduce pain in affected joints.

The observational study took place at the Robert Gregory National Alkaptonuria Centre (NAC), and was funded by the National Health Service (NHS) with support from the charity AKU Society. Thirty-nine individuals with the disease were included in the study, with each participant receiving a daily 2 mg dose of nitisinone; participants were monitored for up to 3 years. The investigators found that the drug worked to slow the progression of AKU, halting and partially reversing ochronosis, and significantly reducing joint damage. In addition, patients enrolled in the study saw other health benefits, including a reduction in the risk of heart disease, as well as less severe osteoarthritis in the spine, knees, and elbows.

“These results bring hope to the more than 30,000 people who suffer from this disease worldwide,” said study author Lakshminarayan Ranganath, MD, in a recent statement. “We knew already from earlier research that nitisinone substantially reduces HGA. We also knew that nitisinone prevented joint disease in AKU mice through research at the University of Liverpool. However, to show the benefit of nitisinone in people with AKU, for the very first time, the NAC team had to come up with innovative and pioneering approaches to study outcomes. I am very proud of everyone who helped us to get here.”

Individuals diagnosed with AKU who are 16 years or older and live in England or Scotland can receive free care at the NAC, including access to nitisinone.