The results of the study have now been finalised and described below for your information.
Alkaptonuria (AKU) is a rare genetic disease patients are born with. It is caused by a lack of an enzyme called homogentisate dioxygenase (HGD). This leads to accumulation of homogentisic acid (HGA). Some of this HGA is deposited in connective tissue (such as joint and tendons) as a brown pigment. This process where pigment develops is called ochronosis. This causes most of the severe disabling symptoms of AKU. Although the defect is present from birth, usually there are few bone and joint symptoms until around the age of 25 years.
Nitisinone is a drug. It is a potential treatment in AKU. The drug is being used without a licence, in the UK National AKU Centre, also called NAC, with positive results. Nitisinone is also undergoing a clinical trial called SONIA 2.
Nitisinone has been shown to stop ochronosis in mice with AKU. These mice show ochronosis like humans and do so soon after birth. Since nitisinone is a potential treatment for AKU, SOFIA was carried out to find out when ochronosis begins in humans. This could allow nitisinone to be started before ochronosis begins. Hopefully this means that patients do not develop the symptoms of AKU.
SOFIA was carried out to identify the earliest age when ochronosis can be detected in AKU patients 16 years and older.
To detect ochronosis and what age it appears in the body, the following tests were carried out: ear cartilage biopsy, eye and ear photographs, MRI of joints, quality of life questionnaires, analysis of gait, questionnaire to assess severity of AKU, as well as blood and urine tests for HGA and tissue damage markers.
Blood and urine from AKU patients were also compared with matched subjects without AKU.
After the study was approved, 30 AKU patients in all, approximately four (2 male and 2 female) from each age ranges of 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50 and over-50, agreed to take part.
Briefly, the results from the eight separate tests were as follows:
Ear cartilage biopsy (main outcome)
Pigmentation within ear biopsies increases with age. Female pigmentation lags behind males. Pigmentation was found in a 16-year old male and so ochronosis can start in AKU patients before the age of 16 years.
Eye and ear photographs
Eye ochronosis was measured from photographs. Ochronosis in the eye increased with age and was first detected at the age of 22 years. Photographs of ear showed that ear ochronosis increased with age but was only detected after the age of 34 years.
Blood and urine HGA
AKU patients had HGA measured in 24-hour urine and blood test. HGA values much higher in those with AKU than those without AKU (called controls). Also, circulating HGA increased with age in males and females due to decreased excretion by the kidneys with age.
Biomarkers of damage to cartilage, bone and other tissue as well as inflammation biomarkers
The inflammation biomarker values for AKU patients were not significantly different from those without AKU. Blood and urine markers showed differences between people with AKU and those without AKU. But the change in markers with age was less clear and needs further studies.
MRI spine and knee analysis
The spine scores (called modified Pfirmann) show that AKU patients are likely to develop changes in the spine after the age of 30 years. Swelling of bone marrow due to AKU (called modified SPARCC scores) also seems to increase from the age of 30 years. Wear and tear of the knee (called WORMS score) only changes after the middle of the fourth decade. These suggest that MRI changes are late in AKU.
Quality of life by questionnaires
When AKU takes hold, people with AKU are able to do less in their life or in other words their quality of life decreases. The three quality of life (QoL) questionnaires showed that pain increases and quality of life in general decreases with age for AKU patients. For the Health Assessment Questionnaire (HAQ), deterioration starts around the age of 30 years. For the Short Form 36 (SF-36) questionnaire, only physical functions steadily decrease with age. Similarly for the Knee Osteoarthritis Outcomes Score (KOOS) questionnaire, the functions decrease with age. Overall, the quality of life appears to seriously deteriorate from the third decade.
Deviation of gait from normality as a function of age in alkaptonuria
AKU changes the way people walk. The change in gait from normal was significantly higher for AKU patients than for controls. But there was no clear association with age. All AKU patients, including the younger, had changed gait indicating that gait is affected at this early age.
Modified questionnaire-based Alkaptonuria Severity Score Index (modified q-AKUSSI)
AKU severity increases with age. The severity can be measured as scores called AKUSSI. AKUSSI scores of AKU increase with age, at a rate of 1.14 units per year. An overall global score of zero would mean no detectable AKU. There was no significant difference between genders. All AKU features individually increase with age. Even at the ages of 16 and 20, scores well above zero have been observed.
The overall conclusion is that the SOFIA study has shown that ochronosis starts at an early age, before adulthood, but was unable to assess the earliest age that it may start. Further data is needed from a paediatric study if this start point is to be established.
Thank you for reading this. Do contact myself or the AKU Society of you have further questions.
SONIA 2: Results of 1-year analysis
All SONIA 2 patients have received a letter, written by Chief Investigator Prof Ranganath, that takes patients through the effect on HGA and conclusions that have been made. This letter is now being made available to all those who may be interested in the findings. If you would like any more information about the information below, or would like more information about AKU, please contact Ciarán Scott, Clinical Trials Officer at the AKU Society on firstname.lastname@example.org.
SONIA 2 is a 4-year efficacy and safety study, designed to collect evidence on whether nitisinone can be used in the treatment of AKU. Patients who enter the study are split into two groups, one group receiving 10 mg of nitisinone daily, and another group not taking nitisinone. The diagram below shows the two different study groups. All study patients have now completed at least one year of the study and we have analysed some of the results in order to verify a continued effect of nitisinone on HGA (see below) and to look at the safety data collected so far. Due to the slow progression of the disease, the final analysis of nitisinone´s clinical effect on AKU symptoms will take place as planned after 4 years
1) Effect on HGA
Nitisinone acts to reduce the formation of HGA (homogentisic acid), which is the chemical that causes damage in AKU patients. Therefore, the main analysis for the trial looks at the reduction of HGA excreted in the urine. We are also measuring the concentration of HGA in the blood (known as serum HGA).
For patients who are treated with nitisinone, HGA excreted in the urine decreased by on average 99.5% and the decrease in the blood was 97.5% after one year. The effect did not change from the 3-month to the 12-month visit. Thus, the study so far shows that the HGA-lowering effect of nitisinone remains as long as treatment continues. The table at the end of this letter presents the actual HGA concentration numbers if you are interested in looking more closely at this.
Treatment with nitisinone leads to increased concentrations of tyrosine in the blood, as we expected. This may cause eye complications such as eye pain or blurred vision. After one year of treatment, nitisinone has been temporarily withdrawn in 5 patients, due to such eye problems most likely caused by the increase of tyrosine. All patients recovered after stopping taking nitisinone, and have thereafter continued on a lower dose (2 mg daily), and a reduced protein diet.
During the first year of the study, adverse events (i.e., any kind of health issues) were reported for 78 of the 138 (56.5%) patients participating in SONIA 2 (treated and untreated). Very few of these events, mostly those related to the eyes, were considered by the investigators to possibly be related to nitisinone. Most of the serious adverse events were due to medical issues commonly seen in AKU patients regardless of any treatment, and none of these were considered related to nitisinone. An adverse event is classified as serious if it results in hospitalisation, and examples of such events in SONIA 2 are joint replacements, fractures, etc.
Nitisinone was generally found to be safe and well tolerated in SONIA 2 following one year of treatment. As expected, the only safety concern related to nitisinone, was the elevated tyrosine levels affecting the eye. These eye effects all resolved upon stopping nitisinone. No patient on the reduced dose of nitisinone has had to withdraw from the study to date.
In summary, SONIA 2 one year study data shows that nitisinone treatment of AKU patients results in a significant reduction of HGA in the urine and blood with no safety concerns. To investigate the longer term effect of nitisinone in AKU disease progression, the study will now continue as planned and finish in March 2019. Your continued participation in the study is very important, whether you are in the group receiving treatment or in the untreated group. 4-year data from as many patients as possible are needed to understand the effect of nitisinone on all the clinical measures that are studied in SONIA 2.
Summary of HGA results:
This is a summary of the average HGA amounts excreted in urine, and the average concentrations measured in serum (blood), in patients before and after one year in SONIA 2.
SONIA 1 was completed in June 2014. The main scientific paper from the study was published in December 2014 in the Annals of Rheumatic Diseases. The paper is available online
here but requires a subscription to view.
Ultimately, the importance of SONIA 1 was to show evidence that nitisinone reduces HGA, and to choose the best dose to take forward into SONIA 2 (our current clinical trial).
SONIA 1 concluded that treatment with nitisinone in AKU patients does reduce HGA, and the reduction is dependent on dose. This means a larger dose of nitisinone results in a greater reduction of HGA.
The trial helped us to understand that 10 mg of nitisinone is the best dose to test the drug’s effectiveness in AKU patients. This is now the dose we are using for SONIA 2.
Prof Jim Gallagher from the University of Liverpool said “This is an outstanding example of impact in translational research, involving collaboration between clinical and basic scientists, patient organisations and pharma. Initially we demonstrated that nitisinone was completely effective and safe in AKU mice. We have now shown that it is an effective HGA-lowering therapy in AKU patients.”
While the study didn’t look especially at safety, there were no safety concerns at all during SONIA 1.