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Clinical Development of Nitisinone for Alkaptonuria

Final Report Summary - DEVELOPAKURE (Clinical Development of Nitisinone for Alkaptonuria)

Executive Summary:
Executive Summary
AKU, also known as Black Bone Disease, is caused by the deficiency of the enzyme homogentisate 1,2-
dioxygenase (HGD), leading to the accumulation of a substance called homogentisic acid (HGA). A black
pigment formed from HGA is deposited in body tissues, particularly cartilage, leading to early onset, severe
arthritis, heart disease and disability. Nitisinone is an enzyme inhibitor that reduces the accumulation of HGA
and should prevent or slow the damage from AKU.
The DevelopAKUre project was established to improve the understanding of Alkaptonuria, especially in
patients of younger age (AKU) and to develop an orphan designated drug, nitisinone, for the treatment of
patients with AKU. To this end a group of clinical and basic scientists in addition to clinical trial experts came
together to carry out the clinical development of nitisinone for AKU.
The programme involved a dose-response study (SONIA 1) which for the first time clearly identified that a dose
of 8 mg daily was optimal for decreasing homogentisic acid in AKU. An efficacy study (SONIA 2) to
demonstrate improved clinical parameters was then undertaken using 10 mg nitisinone. The principal outcome
of sustained decrease in urinary HGA by nitisinone 10 mg was clearly shown. Of the 138 patients recruited to
the SONIA 2 4-year study, 110 completed the clinical phase by 31st January 2019. The results will now be
rigorously analysed so as to decide whether an application for marketing authorisation is justified by the data
by studying the clinical outcomes beyond HGA. A cross-sectional study (SOFIA) in children and young adults
was completed which showed that aspects of AKU disease other than HGA is already present by age 16 years,
the youngest age of a participant in SOFIA. This now provides support for the development of a paediatric
SOFIA study to further clarify the age when nitisinone therapy is likely to be beneficial.
The project was complex and required the co-operation of a large consortium that came together to deliver
DevelopAKUre. They include the Royal Liverpool University Hospital as the Coordinator, the AKU Society
(UK) and ALCAP (France) patient groups for communications/dissemination and enabling patient recruitment,
three SMEs (Nordic Biosciences (Denmark) for biomarker analysis, PSR (Netherlands) for clinical trial
coordination, and previously Cudos (Netherlands) for medical monitoring until the first 36 months, a mid-sized
pharma company Sobi (Swedish Orphan Biovitrum International) supplying the drug and providing regulatory
advice, three universities (Liverpool, Siena and the Biomedical Research Center of the Slovak Academy of
Sciences) for the analysis and interpretation of data, and three clinical trial centres (Liverpool, Hôpital Necker
(Paris), National Institute of Rheumatic Diseases (Slovakia)) to recruit sufficient participants.
Project Context and Objectives:
Summary Description of Project Context and Objectives
AKU is a serious, multisystem disorder of peak adulthood affecting approximately one in every 250,000 people,
although some countries such as Slovakia have a higher prevalence rate of around one in 19,000. Despite Sir
Archibald Garrod identifying AKU in London in 1902 as the first recognised inborn error of metabolism, little
has changed for patients. A recent study of 44 patients by our group showed they had received: 76 joint
replacements, 28 ruptures (tendons/ligaments/ muscle), 10 fractures, 4 with renal stones, 4 with prostatic stones
and 7 with aortic valve disease.
This morbidity is caused by the inability to fully metabolise tyrosine, resulting in increased HGA, despite
efficient urinary excretion. The high concentrations of HGA become converted to a melanin-like pigment - a
process termed ochronosis. The pigment is deposited in connective tissues, particularly cartilage, leading to
early onset, severe arthritis, starting at around the age of 30, with few symptoms or signs earlier in life.
Visible external ochronosis in ears and eyes begins at around the same time as serious and inevitable painful
spinal disease, which is characterised by disc disease/prolapse (resulting in spinal stenosis, cord compression
and myelopathy), vertebral fractures. Valvular heart disease is common, requiring valve replacement, as are
joint replacements. Aortic valve and aortic root disease appear to be especially common. Often patients and
their medical advisors do not fully appreciate the burden of disease, which is only detected through systematic
A recent survey by the AKU Society indicated that patients suffered constant pain, difficulty with activities of
daily living, poor sleep, depression, poor quality of life, unemployment and isolation. Current assumptions are
that ochronosis is irreversible. If true, early treatment is required to modify the disease. Later treatment leads to
greater residual disease.
Our understanding of AKU is incomplete since we do not know if ochronosis is present at a sub-threshold level
earlier. Early treatment in children and young pre-ochronotic patients would only be justified if evidence
suggested that it was. The SOFIA study was designed to address this issue. To detect the high prevalence of
occult disease, a systematic assessment system is necessary in clinical studies. An instrument that best reflects
the burden of disease, the AKUSSI (Alkaptonuria Severity Score Index) will be used as an outcome measure in
SONIA 2. The AKUSSI incorporates multiple, clinically meaningful outcomes that can be described in a single
score. It includes kidney and prostate stones, aortic stenosis, bone fractures, tendon/ligament/muscle ruptures,
kyphosis, scoliosis, joint replacements and all other clinical features of AKU. This score is sensitive to all
morbid features of AKU and not any one feature. AKUSSI, a quantitative, multidisciplinary assessment system,
changes over time, reflecting changes in disease severity. It will be used in SONIA 2, having been further
validated since its original description. Studies of other rare diseases, such as Fabry disease, have used a similar
Several therapeutic approaches have been previously evaluated in AKU patients with little success. Current
treatments for AKU are palliative and hence do not tackle the intrinsic cause of AKU. These include the use of
ascorbic acid, an antioxidant, since the formation of the melanin-like HGA pigment is an oxidative process.
Ascorbic acid has no effect on HGA excretion and no credible studies have shown that treatment with vitamin
C is clinically effective. We have recently shown that AKU mice, which create their own vitamin C
endogenously, are not protected from ochronosis. Similarly, low protein diets have been ineffective in AKU.
Since tyrosine (and therefore HGA) is derived from protein, restricting dietary protein and thereby tyrosine has
been a focus of previous treatments. Such an approach requires restricting dietary protein for life, for which is
not easy for patients to comply. Anecdotal reports of efficacy with low protein diet have not been confirmed in
any systematic long-term efficacy studies. AKU causes significant musculoskeletal disability with the limitation
of activity and consequent impairment of quality of life. Physiotherapy, while not addressing the causative factor
of AKU, namely HGA, has been shown to improve the range of joint motion and activity. Physiotherapy is
underused both by the medical profession and patients but can only be palliative at best. Systematic surveillance
for treatable complications of the heart, kidney and prostate after the fourth decade of life is important, but not
widely adopted by physicians due to lack of knowledge. This approach is also palliative at best. Effective pain
control is crucial, but efforts are often ineffective. Pain can be ameliorated by a wide range of drugs
(paracetamol, non-steroidal anti-inflammatory drugs, opioids, anticonvulsants, local anaesthetics and
gabapentin) in addition to physical modalities (TENS, acupuncture, physiotherapy and nerve blocks), but for
many patients pain is constant, severe and disabling. When liver or kidney transplantation has been conducted
in AKU patients, there have been reports of partial or total resolution of AKU. Timely palliative spinal and joint
replacement surgery is critical for the continued functioning of severely affected patients where analgesia fails.
Progressive disability often requires the use of physical aids, such as crutches and/or the use of a wheelchair.
Nitisinone inhibits 4-hydroxy-phenyl-pyruvate-dioxygenase and decreases the formation of HGA. Since high
levels of HGA in AKU leads to ochronosis, which in turn results in destructive functional consequences,
decreasing HGA, by inhibiting an enzyme proximal to HGA, could prevent the progression of disease in AKU.
Such an approach with nitisinone is now feasible. Because nitisinone targets and corrects the principal metabolic
abnormality causing AKU disease, it should prevent morbidity, if started before the symptomatic phase, and
alter progression in those already symptomatic.
An in vitro model of ochronosis employing osteosarcoma or chondrocyte cultures growing in medium
containing HGA resulted in ochronotic pigment formation in cells and associated matrix in a dose-dependent
manner. These results confirm that HGA concentration is the principal determinant of ochronosis and that
decreasing the concentration of HGA in vivo should prevent ochronosis.
An AKU mouse model (HGD-/-) has demonstrated that nitisinone administration can totally prevent ochronosis
in joint cartilage. This AKU mouse is a model of AKU biochemistry and joint pathology which is appropriate
for testing the drug nitisinone. Adding nitisinone at low doses in the drinking water over the lifetime of a of AKU mice resulted in the plasma levels of HGA falling close to zero. Mice on ntisisinone did not develop
pigmented chondrocytes, compared to the untreated AKU cohort. Electron microscopy of the joint tissues of
human AKU patients showed individual collagen fibres that had become decorated with pigment.
Nitisinone has been used in Hereditary Tyrosinaemia 1 (HT-1) for more than 20 years at a dose of 1-2 mg/kg
bodyweight. An early dose-ranging study in two older women with AKU indicated that the dose required to
decrease HGA significantly was up to 30-fold lower than that used in treating HT-1. Another open-label study
at the NIH, which employed nitisinone at 2.1 mg daily, decreased HGA by 95% and increased serum tyrosine
11-fold, in 9 AKU adult patients over a 4 month period. The tyrosinaemia did not cause corneal or any other
toxicity when patients received eye and other examinations. Six out of seven patients who received nitisinone
for more than 1 week noted decreased pain in their affected joints. In a third study, a three-year, single-blind,
controlled NIH clinical trial of 40 patients, the nitisinone group (2.1 mg/day) showed a sustained decrease in
mean urinary HGA from 5.1 g/day to 0.125 g/day. Mean plasma HGA levels fell from 5.74 mg/L to 0.306 mg/L
after treatment. Urine and plasma HGA decreased by 98% and 95% respectively.
These studies by colleagues at the NIH demonstrated that nitisinone is able to consistently decrease HGA. The
half-life of serum nitisinone is 52.1 hours. Steady state is achieved after 11 days. Because patients in the studies
described above were switched to a higher nitisinone dose within a week, and possibly higher doses than
necessary, is the reason why the SONIA 1 dose-response study was required. The NIH trial was inconclusive
because it used only the difference in range of hip motion between placebo and nitisinone groups as the primary
outcome and did not have sufficient patient numbers (40). Conversely, the SONIA 2 study was designed to
include a larger cohort and utilized AKUSSI to prove efficacy (WP 3).
The DevelopAKUre project was designed with the following aims:
1. A Phase 2 dose-response study (SONIA 1: Suitability Of Nitisinone In Alkaptonuria 1) to determine the doseresponse
curve of nitisinone in reducing HGA levels in circulating blood and the inter-patient variability, and
provide guidance on the useful dose range in the treatment of AKU.
2. A phase 3 clinical efficacy study (SONIA 2: Suitability Of Nitisinone In Alkaptonuria 2) to evaluate the longterm
efficacy and the safety of nitisinone for treating AKU.
3. A cross-sectional study (SOFIA: Subclinical Ochronosis Features In Alkaptonuria) to evaluate whether AKU
progresses subclinically prior to the development of overt ochronosis. This study aimed to determine at what
age treatment should begin.
4. To provide sufficient data to determine whether a marketing authorisation application could be filed to the
European Medicines Agency for use of nitisinone for the treatment of AKU.

Project Results:
Main S&T Results/Foreground
The most significant results arising from the project research are summarised below, in as much
detail that is possible without losing the rights of the consortium to the IPR embedded within the
1.3.1 SOFIA Study
The goal of the SOFIA study was to determine if the AKU progresses sub-clinically by conducting a
cross-sectional study in paediatric and young adult AKU patients without external ochronosis and
adults with external ochronosis. The results were used to determine at what age it might be appropriate
to begin nitisinone treatment. The SOFIA study concluded that ear ochronosis could be observed at
age 20 and could even be present earlier. A paediatric study to investigate this further is currently
underway in the UK.
• Normal ranges for the metabolic and non-metabolic measures used for AKU
Normal non-AKU data have been established for metabolic and non-metabolic measures by
recruiting non-AKU controls such as those for HGA and related metabolic measurements, in
addition to gait analysis.
• Ear biopsy outcome established
Ochronosis was identified on thin sections from the age 20, although it is possible it could be present
earlier than 20 years of age. A greater number of patients younger than 20 need to be studied to
have greater confidence of the earliest age when ochronosis begins. An additional study, developed
as a result of the outcomes of the SOFIA study, called SOFIA-Paediatric is near to commencement
studying children younger than 16 years of age.
• Development of eye ochronotic pigmentation (visual)
Visual inspection and grading of ochronotic pigment in the eye demonstrated that pigmentation was
visibile from the age of 20 years.
• Development of ear ochronotic pigmentation (visual)
Visual inspection and grading of ochronotic pigment of the surface of the ear in photographs
demonstrated the presence of such pigmentation from the age 30 years, unlike the cartilage biopsies
which generated visible colour 10 years earlier.
Alteration in metabolism with ageing
There was no change in 24-h-urine HGA levels with increasing age and homogentisicaciduria was
present even in the youngest patients. Serum HGA increased with age but increased levels were
observed in even the youngest subjects.
• Tissue damage evolved with age
The concentration of tissue damage markers varied with ageing but it was not possible to identify
the precise age at which biomarkers changed, which will require further study of younger patients.
Disppointingly, no clear tissue damage biomarker was reliably identified from the SOFIA study.
• Inflammation and oxidation increased with age but was not significantly higher in AKU
patients than controls
Levels of Amyloid A and protein thiols in serum increased with age, but no differences were
observed between AKU patients and controls. Disppointingly, no clear inflammatory and oxidation
biomarkers could be reliably identified from the SOFIA study.
• Changes in the structure in the spine and joints was found to occur in AKU patients as they
AKU led to worsening spine disease (using Pfirmann and SPARCC scores), first observed from the
age of 30 years, but no association could be identified between knee (WORMS score) and age up
to 45 years, after which there was an association between age and disease severity.
• Clinical gait analysis identified pathological changes in AKU changes even from an early age
that varied with age
The mean values of Movement Deviation Profile (MDP), a score for gait, were significantly higher
for AKU patients than they were for non-AKU controls. Gait deviations in AKU patients could be
observed even in the youngest age group.
• Quality of life deteriorated as paitents became older
An increase in pain was identified in older AKU patients and their general quality of life also
declined with age, from the 3
decade, with no difference between genders.
• Severity of symptoms of AKU increased with age
The severity of the symptoms of AKU increased with age, with no difference between genders, with
AKU found in even the youngest group.
The data and from this study have been accepted for publication, as follows:
• Cox TF et al. BMJ Innovations 2019 in press
SONIA 1 Study
The goal of this study was to investigate the dose-response of nitisinone in AKU patients. Although
extensive experiments had been performed in rodents, this information was not available in humans.
We successfully established reference ranges that allowed the consortium to later conduct a phase III
study with the most effective dose of nitisinone at its lowest and safest or least toxic concentration.
• Normal ranges for HGA and tyrosine established
The primary outcome in SONIA was to bring the excretion of HGA into urine over 24-hours into a
normal range. To undertake this, a study was conducted in non-AKU control subjects and reference
values obtained after 24 hours for HGA in urine and serum in addition to serum tyrosine. No
previous reliable data employing state-of-the-art analytical techniques had been available at the start
of the DevelopAKUre project.
• Effects on 24 hour excretion of HGA in urine of various doses of nitisinone clarified
There has never been a full dose-response study conducted for nitisinone in AKU. The dose
assessment in prior studies at the National Institutes of Health was determined in 2 patients only
(Phornphutkul C, Introne WJ, Perry MB, et al. Natural History of Alkaptonuria. N Engl J Med
2002;347:2111-21). The SONIA 1 study was the first detailed study of the effect of different doses
of nitisinone on metabolic parameters (pharmcaodynamic effect) in AKU.
• Acidification of serum stabilised serum HGA for the first time allowing reliable serum
There is little data on circulating HGA not only because the metabolite is present is low
concentrations, but also because it is labile and rapidly altered in vitro, epecially in alkaline
environments. In these circumstances, HGA rapidly oxidises to benozoquinone acetic acid. In order
to ensure accurate quantification of HGA in urine, collections are routinely acidified. However, no
such methodologies were available for serum. Thus, an acidification process for human AKU serum
samples was developed, validated and utilized for the first time, allowed reliable serum HGA
quantitation in all samples.
• Effects of various doses of nitisinone on serum HGA
The effects of various doses of nitisinone on the metabolic parameters (pharmcaodynamic effect)
of AKU patients was clarified. Administration of a liquid formulation of nitisinone at doses of 0, 1,
2, 4 and 8 mg daily to 5 groups of eight subjects allowed the effect of nitisinone on serum HGA to
be confirmed. The optimal dose was 8 mg, which was the least concentration that reliably (in all
eight patients) decreased serum HGA concentrations to the lowest value (>99% reduction).
Effect of various doses of nitisinone on serum tyrosine
For the first time it has been demonstrated that all doses of nitisinone increase levels of circulating
tyrosine. A near maximal increase is reached at a 2mg dose with small further increases at 4 and 8
mg in AKU patients in normal living environments.
• Data on the PK/PD effects of nitisinone generated
Data on nitisinone profiles over 24-hours provided information on the absorption, distribution,
metabolism and elimination of the drug, described as its pharmacokinetics (PK), in AKU for the
first time.
• Changes in the tyrosine pathway demonstrated in SONIA 1 study using a targeted metabolomics
A targeted metabolomics technique was developed and utilized for the first time in order to
characterise metabolites such as hydroxyphenyl-pyruvate (HPPA), hydroxyphenyllactate (HPLA),
in addition to phenylalanine, tyrosine and HGA, before and after treatment with nitisinone.
Analyses of the data clarified the magnitude of changes in levels of metabolites post-nitisinone.
• Renal handling of metabolites clarified in AKU and post-nitisinone
For the first time, the manner in which metabolites important in AKU (HPPA, HPLA, HGA,
tyrosine, phenylalanine) is managed and excreted by the kidney was clarified in AKU patients and
following treatment with nitisinone. HGA was excreted by the kidney through glomerular filtration
and net tubular secretion. For the first time local renal production of HGA was demonstrated.
Tyrosine and phenylalanine were shown to be mostly reabsorbed. HPPA, similar to HGA, was
excreted by the kidney through glomerular filtration and net tubular secretion. HPLA, to a lesser
extend was also excreted by the kidney through glomerular filtration and net tubular secretion.
• Even the largest dose of nitisinone was safe over a 4 week period
Although the SONIA 1 study was a short investigation employing nitisinone administration over a
4-week period only, it nevertheless revealed no safety issues during this time.
• HGA interference in urine creatinine measurement recognized and resolved
Interpretation of urine tissue biomarkers employing urine creatinine ratios was confounded by HGA
interference of the creatininase assay. Re-assay of urine samples for creatinine employing the Jaffe
reaction eliminated this interference allowing accurate interpretation of biomarkers. As a result,
systematic investigation of the interference of HGA on laboratory parameters was evaluated and
profiles of circulating metabolites profiles generated
For the first time, 24-h profiles of HGA, HPPA, HPLA in serum were generated in addition to
phenylalanine and tyrosine. These data will be helpful in understanding and managing tyrosinaemia
post-nitisinone as anecdotal evidence from clinical observations indicate that tyrosinaemia effects
may have a circadian rhythm.
• 24-hour profiles of tissue damage biomarkers generated in AKU
Data from this study revealed significant rhythms (>20%) for bone (CTX-1), cartilage (AGNx1)
and cardiovascular markers (MIM). These data are helpful in ascertaining the optimal time to obtain
samples in clinical practice.
• Status of inflammatory markers pre- and post-nitisinone clarified
Despite the speculation that there was likely little difference in levels of inflammatory markers in
AKU patients before or after treatment with nitisinone, these data were generated for the first time
and their status established.
• Genetic analysis data obtained
Novel mutations were discovered during genetic analyses (HGD mutations) conducted on samples
from SONIA 1, SOFIA and SONIA 2 studies. These data have been published and the HGD
database updated. This additional information will facilitate potential gene therapies that could be
considered for AKU in the future.
• Non-targeted metabolomic data developed
A comprehensive strategy for carrying out urine metabolomics in an iconic metabolic disease was
developed and published. This can be considered as state-of-the-art in high-resolution analysis in
• Changes to 5HIAA and metanephrines levels established after nitisinone treatment
3-methoxytyramine concentrations increased following nitisinone therapy. Conversely,
normetadrenaline and 5-hydroxyindole acetic acid concentrations decreased. The SONIA 1 study
for the first time demonstrated that catecholamine and serotonin metabolism is modified by
treatment with nitisinone.
• Dose of nitisinone to be used in a phase III trial (SONIA 2) identified
A 10mg capsule was chosen as the dose for the 4-year phase III SONIA 2 study as it matched the
liquid formulation used in the SONIA 1 study, which decreased HGA in urine by >99% in all 8
patients treated in this study.
data and discoveries from this study were published, or are in the process of being published, in
ten manuscripts, as follows:
• Curtis SL et al. Clin Biochem. 2014;47:640-7. PMID: 24373924
• Hughes AT et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;963:106-12. PMID:
• Hughes AT et al. Ann Clin Biochem. 2015;52(5):597-605. PMID: 25628464
• Olsson B et al. JIMD Rep. 2015;24:21-7. PMID: 25772318
• Genovese F et al. JIMD Rep. 2015;24:29-37. PMID: 25786641
• Davison AS et al. Clin Chem Lab Med. 2015;53:e81-3. PMID: 25252754
• Ranganath LR et al. Ann Rheum Dis. 2016;75:362-7. PMID: 25475116
• Davison AS et al. JIMD Rep. 2018;41:1-10. PMID: 29147990
• Norman BP et al. Clin Chem 2019;65:530-539. PMID: 30782595
• Milan AM et al. Scientific Reports (under review)
1.3.2 SONIA 2 study
The main goal of the SONIA 2 study was to carry out a phase III 4-year efficacy and safety study in
138 AKU patients, half on nitisinone and half in a no-treatment arm, to obtain data so that an
application could be made to the European Medicines Agency for approval for marketing authorisation
of nitisinone 10 mg in AKU, dependant on the final results of the trial.
The SONIA 2 study only completed its clinical phase in January 2019, several days before the official
end date of the project. The data are currently being cleaned with the database likely to be locked
imminently. Thus, the main conclusions from this study cannot be known until statistical analysis can
take place in the future. The only results available are those from the interim analysis at month 12.
• Significant reduction of urinary HGA was maintained after one year of treatment with
As agreed with the EMA, an interim analysis of data at 12 months concluded that AKU patients
given nitisinone for a year maintinaed a significant reduction in 24-h-urine HGA levels of 99.7%
that of control patient values.
Potential Impact
The observations from DevelopAKUre project, although definitive results of the 4-year study are not
yet known, already showed that over 12 months, nitisinone at a dose tolerable over that period can
reduce urine HGA levels by 99.7%. From our knowledge of the aetiology of the disease, this strongly
suggests that nitisinone could have a dramatice impact on the progression of AKU.
Thus, if the final 4 year results of the SONIA 2 study replicate those of the interim results, we can be
confident that it will have a significant impact on the ongoing care of established AKU patients.
Furthermore, if the study, from the AKUSSI results, finds that nitisinone improves the mobility and
reduces the impact of AKU on patients over the longer-term, the project will have positive implications
for healthier ageing and enhanced independent living for AKU patients in the future, even those that
currently have significant disability.
Successful results as described earlier in sections 1.2 and 1.3 would allow much younger patients, for
example those just starting adulthood, who have no apparent symptoms of the disease, to receive
treatment to modify serum HGA levels and so would be unlikely to suffer the classical ssymptoms of
AKU. Although not a cure, this would represent a considerable change to the quality of life of all
young individuals with AKU. Although patients with AKU probably have a normal life span, they
suffer a long decline with manifestations of multisystemic arthropathy, often combined with
depression and loss of employment. Patients often require multiple joint replacements and suffer
ruptures of tendons, ligaments and muscle, bone fractures, renal stones, prostatic stones and aortic
valve disease.
By treating the disease early and probably before morbid features evolve, the economic cost of the
AKU disease burden should be reduced considerably. A recent (unpublished) study estimated that a
typical AKU patient costs approximately €140,000/year in the UK (uprated for inflation). If
extrapolated to the estimated AKU population in Europe, using normal population statistics, a
conservative estimate of the total cost of AKU, including indirect costs (i.e. lost wages and production),
but excluding estimates of loss of quality of life, is €235 million per year. This estimate ignores
significant individually unquantifiable costs incurred related to drug therapy (specifically pain
management), health care devices and psychological distress which were found to occur across the
majority of patients who have been interviewed.

The longer a patient has lived with significant complications from AKU, the longer and more costly
the recovery from necessary surgery. Our research (unpublished) indicates that AKU patients who
have a first or second surgery generally require less than three days’ recovery in hospital. Those who
have lived with significant symptoms for longer and are having their third or more surgery can require
more than a week to recover in hospital, including several days in special or intensive care. It is
therefore clear that social, psychological, healthcare and family/individual costs for AKU are extremly
high. There are also significant costs for carers who are often crucial in providing support for disabled
and isolated patients. If successful, the DevelopAKUre would have a dramatic effect on AKU patients.
If translated around the world, the results would represent healthcare cost savings in the order of >€1B
with a concomitant improvement of the health and quality of life of thousands of AKU patients.
The AKU Society has been a key strategic partner in the dissemination of the project and its results. A
dissemination plan was created and successfully implemented. The key features of the plan were:
• Targeting scientific publications
• Speaking at conferences
In addition to scientific conferences, project participants have spoken at conferences aimed at
industry, patient representatives, healthcare professionals, governmental organisations, etc.
• Linking with IRDiRC and other networks
Nick Sireau (AKUS) was a member of the IRDiRC working group on drug repurposing, providing
advice from DevelopAKUre. We publicised how DevelopAKUre contributes to the IRDiRC’s goal
of 200 new therapies by 2020. AKUS were also represented on the council for RD-Connect, an
integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare
disease research.
• Communicating to family doctors and hospital specialists
Clinicians were kept informed about the process of the trial either by subscription to the AKU
Society e-newsletter, the website or directly via a patient letter written by the
chief investigator. This letter was designed to educate clinicians about the trial and nitisinone. Staff
members and partners attended numerous medical conferences on various related disciplines and
rare diseases more generally. AKU clinicians and researchers were invited to all AKU workshops
to discuss the project and the illness in length.

Communicating to Ministries of Health
Various governmental figures in the UK and its devolved nations have discussed DevelopAKUre
and its progress. The consortium has met with representatives from the EMA (European Medicines
Agency) and plans to use the MOCA network (Mechanism of Coordinated Access to Orphan
Medical Products) to understand the next steps for reimbursement if licensing is achieved.
• Communicating to AKU sufferers
The AKU Society has been in regular contact with AKU sufferers, using online communications
tools, social media etc., to keep patients updated and supported. We translated and edited patient
information as much as possible and have redesigned the website so that it was
far easier to use and automatically and accurately translated information into the viewer's native
language. It also hosted an innovative tool that increases the accessibility of the website through
read-aloud technology and other various ways to make the website as accessible as possible.
• Audio-visual work
Throughout the trial, SONIA 2 patients were interviewed and recorded to highlight the patient
centricity of the trial and to highlight participants’ experiences. AKUS produced webinars on the
SONIA 1 and SONIA 2 trials which are available in video format.
The Univerisity of Liverpool produced a video for the EC explaining the research element of the
study in detail. AKUS was featured on national UK TV (BBC Two) Incredible Medicine: Dr
Weston's Casebook, which highlighted Nick Sireau’s story, the AKUS and DevelopAKUre.
• Media work
The AKUS maintained one-on-one contact with interested journalists. AKUS produced and
distributed several press releases about DevelopAKUre. The DevelopAKUre project has been
featured on local radio and TV. AKUS worked with partners to get press releases translated and
distributed locally. AKUS and the AKU research have also been featured in national media and
numerous online magazines.
• Online comminutions
AKUS maintains regular online communications on the following platforms:
‒ The DevelopAKUre microsite –
‒ The AKU Society website –
‒ Facebook –
‒ Twitter –
‒ LinkedIn –
‒ YouTube –
‒ PatientsLikeMe –
‒ RareConnect -
Excepting scientific publications, a full list of dissemination events of the project, numbering
approximately 250 separate activities, is provided in Deliverable 12.3 the Dissemination Report.

Potential Impact:
Exploitable Foreground and Plans for Exploitation
Notwithstanding the standard rules of collaborative projects funded by the EC Framework
Programmes, as set out in Articles 26 – 29 of Annex II to the Grant Agreement, the Consortium agreed
that all parties to the Grant Agreement granted Sobi an exclusive, royalty-free and assignable license,
with the right to sublicense, right under any Foreground to research, develop, manufacture, promote,
market, distribute and sell any nitisinone product to AKU patients.
To demonstrate the commitment to this strategy, Sobi have applied for a patent regarding the results
of the SONIA 1 study, which defines the dosing of nitisinone. At the end of the project, the final results
of the SONIA 2 study are not yet known, and these will define the ultimate direction of the commercial
strategy. If successful, Sobi intends to apply for marketing authorisation, in which case the commercial
exploitation plan, as set out below, will apply.
2.2.1 Commercial exploitation plan
The aim of this exploitation strategy is to create a new state-of-the-art by providing nitisinone as a
licensed treatment to AKU patients in the EU and worldwide. A license to use nitisinone as the
treatment for AKU will result in a new commercial venture for Sobi, which will contribute to the
objectives of the IRDiRC to obtain 200 new treatments for rare diseases by 2020. Sobi will exploit this
license to generate revenue for the company, helping create jobs and brand value. This is summarised
EU market size
Current estimates are that AKU affects one in every 250,000 people, apart from in Slovakia where it
affects one in every 19,000. This indicates that the market size should be around 2,275 patients, based
on an EU population of 502M in 2011 (Eurostat), and a Slovakian population of 5.44m in 2010. AKUS
knows of 450 AKU patients in the EU, so there are still many unidentified patients, which the new
AKU societies set up in Germany, the Netherlands and Belgium will identify with support from the
AKU Society as the principal group. AKUS has launched a new online community for AKU patients
in the EU and worldwide via its website that includes a patient identification campaign. The AKU
Societies identify on average 30-50 new AKU patients in the EU each year. This number will most
likely increase significantly if nitisinone is approved, as doctors refer patients for treatment
Market exclusivity in the EU
According to the EU orphan drug legislation of 2000, nitisinone will be granted market exclusivity for
AKU within the EU for 10 years if marketing authorisation is successful. This would provide a
significant incentive for Sobi to distribute nitisinone to AKU patients in a sustainable manner.
Marketing authorisation EU
If the project is successful and regulatory approval secured, Sobi will take on the legal and regulatory
responsibilities of being the marketing authorisation holder (MAH): ensuring the quality of the product
and that the overall risk/benefit of keeping the product on the market is positive. The estimated time
for review of the Marketing Authorization by EMA is approximately one year, which means nitisinone
may be approved for treatment by late 2020, in time for the IRDiRC deadline of 2020.
Exploitation in non EU countries
We will also, in parallel, and in partnership with the NIH, develop a regulatory strategy for the US.
Other territories may also be exploited and will be investigated by Sobi.
Distribution and implementation
Sobi already has a strong distribution network for nitisinone (under the brand name Orfadin®) for HT-
1, which it will use as the basis for its distribution of nitisinone for AKU. The overall roll-out period
will be about a year depending on the future processes within the EU. Patients will be able to access
nitisinone either through their general practitioners or metabolic specialists or, in countries which have
them, through dedicated AKU reference centres. The UK has set up an AKU Reference Centre at the
RLUH. France has an AKU programme at HNEM. Slovakia has a National AKU Centre at NIRD.
Italy has an AKU reference centre in Tuscany. We have also been involved in setting up reference
centres in the Netherlands and Germany.
Pharmacovigilance and registry
Patient safety is crucial for the long-term exploitation of the project’s results. Sobi will adhere to all
post marketing safety commitments in accordance with internal Sobi SOPs (Standard Operating
Procedures) fulfilling external regulatory requirements. Sobi will fulfil this information from
healthcare providers and patients on adverse effects of nitisinone for AKU and to prevent harm.
Commercial revenue
Treatment will be long-term, thus providing financial incentives for Sobi as the Marketing
Authorisation Holder. Hence, Sobi will finance the launch of the product and the future prospect of
commercialisation of nitisinone in the treatment of AKU patients.
2.2.2 Other exploitation plans
Academic exploitation
The academic centres led on the analysis of patient samples taken during the clinical trials. They have
already published this work in 16 scientific publications, with many more, estimated at approximately
a further 15-20, after the results of the SONIA2 trial are available. Universities will use dedicated press
offices that will exploit the results of the study in order to gain positive press coverage for their
institutions and research teams. This additional brand recognition will increase their chances of raising
further funds for research. UniLiv and UniSi also have an active Erasmus agreement that will be further
exploited for students and teachers exchanges in future.
Clinical trial centre exploitation
If the project is successful, the trial centres will prescribe nitisinone to their AKU patients. This will
reduce the disease burden and decrease resources spent on AKU patients, such as for joint
replacements. Even if the project fails, the three hospitals will be able to exploit the results of this work
as they will have gained deeper understanding of AKU and will use this to develop new care guidelines
for their patients. It may also be possible for national centres, such as the RLUH, to offer the drug offlabel.
SME exploitation
NB will use the study data to investigate the use of novel biomarkers for bone degeneration in AKU
and extracellular matrix turnover, potentially creating a new commercial venture. NB will use the
project to raise its profile at trade events.
Patient organisation exploitation
AKUS and ALCAP will use the project results to provide up to date information to AKU patients and
families about the disease. If the project is successful, they will use the project results to inform patients
about nitisinone treatment and the expected benefits. They will publish the results on their websites
and inform patients directly across the EU. Through frequent contact with all patients during the trials,
they will continue to build the community of patients, helping them assist each other. They will use

knowledge from the project to help other rare disease patient groups work with Horizon 2020 and
Horizon Europe programmes, academia and industry to conduct clinical trials.
Contract research organisations exploitation
This project will further strengthen PSR’s experience and knowledge in the orphan drug field. They
will exploit this in their business development and PR.
2.2.3 Table B1: Applications for patents, trademarks, registered designs
Type of IP
Click on
(e.g. EP123456)
Subject or title of
Applicant (s) (as on
the application)
Patent NO N/A WO
2015/165972 A1
Nitisinone Dosing
Regimens for the
Treatment of
Swedish Orphan
Biovitrum International

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