miércoles, 29 de mayo de 2013

Developing a cure for Black Bone Disease: are we nearly there? « Rare Disease Blogs.

Developing a cure for Black Bone Disease: are we nearly there? « Rare Disease Blogs.

April 3rd, 2013

Developing a cure for Black Bone Disease: are we nearly there?

So here we are, at last: the culmination of 10 years of work. We’re launching the first of three studies as part of our EC-funded clinical development programme for nitisinone as a treatment for Black Bone Disease, or Alkaptonuria (AKU for short) as it’s known in the scientific community.
It’s been a challenging journey, to say the least.
Our research effort started in 2005 when we raised funds from friends and family to carry out the autopsy of an AKU patient in order to understand better how the disease affects people. Our scientists in Liverpool were astonished by what they discovered: for some reason, the black pigment that causes all the damage in AKU (a process called ochronosis) was not evenly distributed in the body. Some parts were jet black and badly damaged. Others were clear and undamaged.
A global movement
Eight years later, we still don’t fully understand why the pigment spreads like this, but it generated a huge amount of interest among our scientists. It sparked the growth of a major global movement for the study and treatment of AKU that now includes teams in the UK, the USA, Italy, France, Slovakia, Sweden, the Netherlands, Spain, Germany, Jordan and India. We now have working cell and animal models of AKU, strong natural history data, and numerous publications – all crucial for our quest for a treatment.
The AKU patient movement has been at the heart of this. Ten years ago we were setting up the first AKU Society in the world, based in the UK. Now, we also have AKU societies across Europe, North America, the Middle East and Asia. All are led by patients and their relatives in strong collaboration with scientists and clinicians.
Building this hasn’t been easy. We’ve had to search everywhere for funding, approaching countless trusts, foundations and government bodies. We’ve organised international workshops bringing together scientists, clinicians, patients and industry in order to build a solid consortium and prepare a plan of action.
We’ve spoken at length to other patient groups and especially EURORDIS for their advice on how we should proceed. We’ve interacted with regulatory agencies, particularly the European Medicines Agency, for their feedback on our plans.
Two funding successes
The culmination of all these efforts came last year with two big funding successes. The first was a major grant by the UK’s Department of Health to set up a National AKU Centre at the Royal Liverpool University Hospital, with the first patients attending in June 2012.
The second was a major grant by the European Commission’s FP7 programme to help our international consortium set up a five year clinical development programme for nitisinone for AKU. The consortium includes 13 organisations—universities, hospitals, biotechs, pharma, patient groups and contract research organisations—from seven EU countries.
We launched the programme officially in November 2012, and since then progress has been fast, although the learning curve for me was steep. I’m amazed at the amount of work needed for carrying out a clinical trial: from drafting the protocol, to obtaining the approvals from ethics committees, regulatory agencies and all sorts of other bodies, to recruiting the patients.
The three studies
As I mentioned above, the programme has three studies. The first is a dose response study. Called SONIA 1 (Suitability Of Nitisinone in Alkaptonuria 1), it will last four weeks and take place in two clinical trial centres: Liverpool (UK) and Piestany (Slovakia). We are recruiting 40 patients, who will be randomised into five groups: four groups will receive different doses of nitisinone, and the fifth will be a non-treatment group as a control.
We have the required patients and we’re just putting the finishing touches on preparations before starting this study in the next couple of months.
Whichever dose reduces homogentisic acid (the culprit molecule in AKU) to normal levels will be used for the next study: a phase 3 study that starts in the autumn this year. This one’s the big study. It’s called SONIA 2 (Suitability Of Nitisinone in Alkaptonuria 2) and lasts four years. We will be analysing a range of criteria to understand better how nitisinone affects AKU and build a case for marketing authorisation.
For SONIA 2, we will recruit 140 patients to three trial sites: Liverpool, Paris and Piestany. We already have 100 of these patients motivated to join the trial. The challenge is recruiting the remaining 40. We believe we can achieve this with the help of metabolic clinicians across Europe. So if you’re a metabolic clinician (or you know someone who is) please get in touch with me at nick@akusociety.org.
The third study is on children and young people. They won’t be given nitisinone. Instead, we will attempt to find out at what age the black pigment starts to form in AKU. This is because it may take many years before patients feel the physical symptoms of joint deterioration, even though the disease may be affecting them at the sub-clinical level.
By finding out when the black pigment starts to form, we will get a better idea about when to begin treatment with nitisinone. That’s why this study is called the SOFIA study (Subclinical Ochronosis Features in Alkaptonuria).
If successful, these studies would allow us to apply for a license for nitisinone as the first ever treatment for AKU.

What we’ve learnt
It’s been a huge learning experience. We’ve had to build all the infrastructure from scratch: the cell and animal models, the consortium, the patient database, the research teams, the trial protocols. We want to share our experience as widely as possible. So please contact me at nick@akusociety.org to find out more or go to www.akusociety.org.

about the author

Dr Nicolas Sireau is Chairman of the AKU Society, a medical charity that works in partnership with the Royal Liverpool University Hospital to find a cure for AKU, an orphan disease affecting his two sons. He is a founding member of the international findAKUre coalition, which brings together leading research institutions, biotech companies and patient groups from across Europe and North America in order to find a cure to AKU. He is a former Director of GenSeq, a bioinformatics company. He is a fellow of the Ashoka Fellowship of Social Entrepreneurs and of the Royal Society of Arts. Dr Sireau’s previous career was in international development, where he set up SolarAid, an award-winning social enterprise bringing solar power to Africa, and wrote books on international aid. The AKU Society is also a partner in the RareConnect Global AKU Community: http://www.rareconnect.org/en/community/alkaptonuria-aku

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