As emphasised by the ongoing COVID-19 pandemic, seeing our loved ones impacted by something can really motivate us to make a difference. At the Festival of Genomics and Biodata 2021, we were joined by Nick Sireau (Chair and CEO, AKU Society) who gave an inspirational talk about his experience advocating for people with alkaptonuria and the journey to finally finding a treatment.
Alkaptonuria (also known as AKU or Black Bones Disease) is a rare genetic metabolic disorder. It is characterised by the accumulation of homogentisic acid (HGA) in the body. It is caused by mutations in the HGD gene – which encodes the enzyme homogentisate 1,2-dioxygenase. This enzyme is important to breakdown HGA. The build-up of HGA causes patients’ bones and cartilage to become discoloured and brittle. People with AKU also typically have urine that turns dark brown or black when exposed to air. The condition affects about 1 in 250,000 to 1 million people worldwide. To date, treatment of AKU has mainly been focused on managing symptoms.
During his talk, Nick discussed his journey supporting his two sons with AKU and fighting for awareness. Nick’s first son Julien presented with black urine two-weeks after birth. Despite being told by a physician that the pigment was from red cabbage that his wife Sonya had eaten for lunch, Nick and Sonya sought a second opinion. After several tests, it was revealed that Julien in fact had AKU. When Nick’s second son, Daniel, was also diagnosed with AKU, both Nick and Sonya decided to actively try and find some relief for their children. In 2003, Nick joined forces with another patient and a doctor in Liverpool to set up the AKU Society – the first-ever patient group for the disease.
Nick spoke about the history of AKU and how it was the first disease ascribed to an inherited cause. In 1902, Archibald Garrod first described AKU and noticed that it followed Mendelian inheritance patterns. AKU since then has become a staple of genetic textbooks. Unfortunately, like many other rare conditions, AKU is not considered enticing enough to warrant attention from drug developers.
Nitisinone was originally developed as a weedkiller in the 1980s but was found to have toxic effects in fish and rats. While the development as a weedkiller was halted, specialists continued to investigate how nitisinone worked. Researchers found that it disabled an enzyme called HPPD. In 1991, Sven Lindstedt, a clinician at a hospital in Gothenburg, Sweden, was the world’s leading expert on HPPD. Lindestedt was searching for a way to inhibit the enzyme to save children with type-1 hereditary tyrosinemia. This condition arises from a disruption within the same metabolic pathway affected in AKU. Using nitisinone in children with HT1 was found to have profound effects and has since gone on to generate millions of dollars in sales.
The success of nitisione in HT1 – led some to question whether it would work in AKU? HPPD halts the breakdown of the amino acid tyrosine. Therefore, it was reasoned that slowing down the metabolism of tyrosine in AKU patients would stop them producing excess HGA.
Between 2002-2008 clinical trials were conducted that explored the use of nitisonone in AKU yet failed as it did not meet primary endpoints. Retrospectively, Nick noted that this trial was not successful as there were not enough participants, it did not last long enough and the endpoint they used (hip movement) was not sensitive enough.
Not giving up
In 2010, Nick gave up his job and started working on AKU fundraising, securing £500,000 from Britain’s Big Lottery Fund. This money went to James Gallagher, a musculoskeletal researcher at the University of Liverpool, to develop a mouse model of the condition. With the right gene knocked out, these mice showed the expected build-up of HGA. Most importantly, when given nitisionone the mice showed an expected decline in the chemical.
The group at Liverpool managed to identify and analyse the symptoms of 81 patients with AKU in the UK – generating a severity index and combined impact of symptoms. They found that the use of unlicensed nitisinone in these patients was well tolerated and safe.
By 2012, having gained more information about the disease, the European Commission agreed to fund a full-scale clinical trial. The European nitisinone trial began in 2015 with 138 patients, where a statistical significance was reached. The results showed a drop in circulating HGA and a reduction in speed of disease progression. The paper simply summarises: “Nitisinone is a beneficial therapy for alkaptonuria.”
In October 2020, the European Commission granted marketing authorisation for nitisinone. Fortunately, Julien Sireau and his brother Daniel are currently taking nitisinone, which is already beginning to reduce HGA levels. Nonetheless, nitisinone will still need to be approved by the US Food and Drug Administration to reach patients overseas.
Nick emphasised the value of support that he received from the team at Liverpool. He recalled that the most difficult time was when he first received the diagnosis for Julien and the clinician said “there is nothing you can do”. Nick and Sonya however used this as a driving force to find a cure for their children. Nick considers himself lucky as with many other rare diseases, the symptoms are immediate and overwhelming from birth, leaving parents little spare time to work on developing a treatment.
One of the biggest challenges Nick noted was funding. This is a major issue across the rare disease community. Rare diseases often affect very few individuals and are therefore not considered worth the investment for many companies. Nick expressed: “I think if there was more funding available to rare disease patient groups it could make a significant difference.” He emphasised that industry in particular should be funding more patient groups as fundamentally the work these groups do benefits those organisations.