AKU Society

Currently AKU has no cure. A patient's only option is to manage the severe joint and back pain with increasingly strong painkillers and ultimately, most patients will need joint replacement surgery. We do not think this is good enough. 

A potential cure does exist. In the early 2000s, the US National Institutes of Health began to study AKU patients and realised that an existing drug, Nitisinone, could be used as a treatment for alkaptonuria. Their early stage trials, published as "Natural History of Alkaptonuria" and "Use of Nitisinone in patients with Alkaptonuria" included a dose ranging study showing effective reduction of homogentisic acid (HGA - the culprit molecule of AKU) at a dose 50 times smaller than that used in tyrosinaemia type I, another rare disease.

However, to get a drug licensed and used as the treatment of choice for a disease, there needs to be a more in depth study - the phase III clinical trial. The NIH recently published the results of their phase III trial "A 3-year randomized therapeutic trial of nitisinone in alkaptonuria" that concluded with a statistically insufficient result. Even though the study showed a reduction of HGA by 95% and patients reported much less pain (to the extent that they could reduce the number of painkillers they took), the study did not show sufficient improvement in its pre-determined end point, of measuring hip rotation.

Nitisinone has been proven to reduce HGA in the urine by 95%. The picture 

shows the reduction of black pigment in urine samples taken over 7 days.

Even though the trial was unsuccessful, many patients felt Nitisinone improved their lives. One AKU patient, Simon Laxon, participated in the trial, and recently wrote about the effect the drug had on his quality of life in the British Medical Journal, "A Patient's Journey: Living with alkaptonuria". Simon credits Nitisinone with a return to his normal life: he could live without pain and was able to do everyday tasks, such as playing with his two daughters. When the trial ended, he could no longer access the drug and went back to a life blighted by AKU, with severe joint and back pain stopping him from doing many of the activities he used to enjoy. 

Encouraged by the patients who felt the benefits of Nitisinone, the AKU Society wants to do a new phase III clinical trial. We have worked with the NIH, in particular with Dr Bill Gahl and Dr Wendy Introne to learn from the last trial and have determined:

1) There were too few patients - only 40 patients were trialed

2) The trial was too short - it lasted for 36 months

3) That the patient group was too old - AKU is progressive, so older patients have a greater burden of disease. Nitisinone is likely to have greater impact for younger patients.

4) An incorrect endpoint was used - success was based on measuring hip rotation, which ignored many other symptoms of AKU.

Our work has now been directed at addressing each of the points above to ensure the next trial has a good chance of success.

Nitisinone is a licensed drug with another disease, tyrosinaemia type I. This means that UK patients should be able to access the drug off-label from the NHS. One such person is Dr Duncan Batty, an AKU patient, who guided by his training as a biochemist and career in the pharmaceutical industry, is convinced of the benefits of Nitisinone. Duncan is one of only two patients in the UK who is taking nitisinone off-label and wrote about his experiences in Taking Nitisinone - a Patient's perspective; a downloadable guide for patients, available on the AKU Society website.

However, the majority of patients are not so fortunate. We know of many AKU patients who have applied to use Nitisinone but have been turned down by the local NHS Primary Care Trust. One such patient, Ann Kerrigan, has applied three times with support from the AKU Society, leading AKU doctors, and her local MP; only to be turned down every time.

The only way to guarantee patient access to Nitisinone is through a successful phase III clinical trial.

There are clear reasons why the NIH study was inconclusive. Therefore, we know what to do to better prepare for the next study.

1) Increased patient identification - the AKU Society has made a dedicated effort to better identify AKU patients, including mailing to every GP in the UK, an international database of AKU patient records and targeted family screening. This work was published as "Identification of alkaptonuria in the general population"

2) Increased scientific support - through our international coalition, findAKUre, we have vastly increased the number of researchers working on alkaptonuria. This has led to increased knowledge about the origins of the disease, its development in patients and how best to assess the severity of disease.

3) An improved evaluation end point. Our Medical Director, Dr Ranganath, has developed the world's first AKU severity score index, a whole-body evaluation of the severity of AKU in an individual. This will be a more powerful end point for a clinical trial. It was published as "A quantitative assessment of alkaptonuria".

As it stands, we have the plans for a phase III clinical trial of nitisinone. The next step is to raise the funding.