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KIEKIDS Report Summary

Project ID: 282559
Funded under: FP7-HEALTH
Country: France

Final Report Summary - KIEKIDS (Development of an innovative paediatric formulation of an antiepileptic agent for the treatment of absence epilepsy in children.)

Executive Summary:
The KIEKIDS project was dedicated to the development of an innovative paediatric formulation of an antiepileptic agent for a safe alternative treatment of absence epilepsy in children. Development of an age-appropriate formulation using a drug with identified and documented efficacy in the target population was regarded by the European Medicines Agency (EMA) to be amongst the highest priorities for the treatment of epilepsy.
For that purpose, the KIEKIDS project has gathered a very strong consortium of well trained and qualified partners from industry, academy, and hospital with extensive experience in drug development in clinical, pharmacological, data analysis, statistics, and regulatory areas.
The consortium was coordinated by the INSERM Unit 1129, a French public research organisation devoted to paediatric epilepsies and brain plasticity. This consortium, formed by INSERM Unit 1129, Advicenne Pharma, the CHUV (Centre Hospitalier Universitaire Vaudois) and ClinBay, rallies all the competencies required to manage a paediatric drug development from the designing of an adapted formulation up to market.
The consortium was able to perform the pharmaceutical development of a paediatric formulation for the treatment of childhood absence epilepsy (CAE) and progress in the conduct of a complete clinical programme, previously endorsed by a Scientific Advice and approval of a Paediatric Investigation Plan (PIP).
With its solid track record of clinical success in pharmaceutical and biotech companies, and its extensive expertise in absence epilepsy, this consortium was able to avoid the pitfalls of pharmaceutical drug development and is in a strong position to guarantee the commercial success of the product.

Project Context and Objectives:
Epilepsy is common chronic neurologic disorder that affects 1% to 3% of the population (Shneker and Fountain 2003). A significant proportion of epilepsy syndromes have their onset in childhood and adolescence and there is a great heterogeneity with respect to syndrome type, causes and prognoses.
Epilepsy syndromes in childhood differ from those in adults mainly by their occurrence in a structurally and functionally maturing brain, the occurrence of seizure/epilepsy types not seen in adults and the occurrence of seizures as part of age-dependent epilepsy syndromes. This is the case for the epilepsy syndromes with absence and/or myoclonic seizures, such as childhood absence epilepsy (CAE). This syndrome accounts for approximately 10-17% of the epilepsy cases in children (Tenney and Glauser 2013).
CAE is characterized by the occurrence of frequent typical absence seizures (peak manifestation between 6 and 7 years) in otherwise normal children. Typical absence seizures are brief (usually less than 10 seconds) with sudden loss and recovery of consciousness, and frequent, appearing 100 to 200 times a day. During adolescence, generalised tonic-clonic seizures (GTCS) may develop. Otherwise, absences usually remit or, more rarely, persist as the only seizure type (ILAE 1989).
A family history is common and in some cases it is transmitted by autosomal recessive inheritance (Shneker and Fountain 2003). There is a female predominance, more than two thirds of the children with CAE being girls (Jallon and Latour 2005).
An arbitrary upper age cut-off for the onset of absence seizures of 10 years has been established in clinical practice to define what is CAE (Loiseau, Duche et al. 1995; Sadleir, Scheffer et al. 2008) but it may be reasonable to classify patients with very frequent absence seizures (pyknolepsy), a pattern unusual after 11 years, as CAE regardless of their age (Tenney and Glauser 2013).
The symptoms and potential comorbidities (such as attentional deficits) associated with CAE may impact on the social life of these children, being often the cause of isolation and loss of self-esteem (Hills 2007). The patient’s quality of life may be affected, due to deficits in school performance, and social stigma.
Absence seizures being so brief, a child may have absence seizures for some time before they are noticed. The decline in a child’s learning ability may be the first sign of this disorder. Indeed, children may present dozens of episodes a day, which eventually interferes with school or daily activities.
Growing evidence indicates that children with CAE have a high rate of baseline attentional deficits unrelated to seizure frequency, along with long-term psychosocial difficulties and variable remission rates (Bouma, Westendorp et al. 1996; Wirrell, Camfield et al. 1996; Pavone, Bianchini et al. 2001).
An early age of appearance of absence seizures seems to be a factor of good prognostic. The fast disappearance of the absence seizures after prescription of an adapted treatment is also considered as a factor of favourable prognostic (Wirrell, Camfield et al. 2001).
The majority of children with CAE will remit with time. The remission rates, defined as the percentage of children having a terminal remission of at least 1 year, are in a wide range between 51 to 90% (Grosso, Galimberti et al. 2005; Valentin, Hindocha et al. 2007; Callenbach, Bouma et al. 2009). Their evaluation is greatly influenced by the classification criteria used.
The total duration of this syndrome cannot be predicted based on baseline and EEG characteristics. On the other hand, treatment of CAE is usually successful with a single medication and a quick response to therapy is a good prognostic sign (Callenbach, Bouma et al. 2009).
Approximately 40% of the patients develop GTCS at a later stage, generally 5-10 years after onset of the absence seizures (Tenney and Glauser 2013). Apparently, the occurrence of other seizure types does not influence outcome, although certain studies indicate that the presence of GTCS is a poor prognostic factor (Callenbach, Bouma et al. 2009).
Absence seizures persisting in adult life are rare (occurring approximately in 6% of the cases). In adulthood, absence seizures are often masked by the occurrence of other types of seizures more visible and that start first (Hirsh and Panayiotopoulos 2005). However, in occasional cases, absence seizures can remain extremely incapacitating (Panayiotopoulos, Koutroumanidis et al. 1997; Panayiotopoulos 2005).
The current strategy of treatment for seizures is to initiate a monotherapy with one of the anti-epileptic drugs commonly used as first-line treatment options (Glauser et al. 2010). In case of failure with this first step, most experts agree that a second monotherapy should be tried. If both monotherapies lose efficacy over time, a combination of 2 or even 3 anti-epileptic agents may be attempted. When pharmacological treatments fail or start losing efficacy over time, a ketogenic diet (a high-fat, low-protein, low-carbohydrate diet) is more and more often initiated (NICE epilepsy clinical guideline 2012). Such a strict diet is obviously not compatible with a syrup treatment.
In case of pharmacoresistant CAE, there is some evidence that vagal nerve stimulation is a good option and that it has similar or greater efficacy against generalised seizures as it does in localization-related epilepsy (Buoni, Mariottini et al. 2004; Holmes, Silbergeld et al. 2004; Ng and Devinsky 2004), but its use is off-label.
The currently available formulation of one of the first-line treatment options is not adapted to paediatric needs. The lack of an alternative formulation results in a more restricted use of the drug, considered to be a high priority for the treatment of absence seizures by the European Medicines Agency (EMA) in its revised list dated July 2010 for off-patent paediatric medicinal products (EMA/480197/2010). The need for additional pharmacokinetic and safety data in children was specifically emphasised in this revised list.
Consequently, it is clear that paediatric patients and their parents deserve an appropriate treatment based on the best possible formulation which should be adapted to the type of epilepsy, easy to administer, flexible, palatable and better tolerated, leading to improved compliance and therefore improved efficacy.
The main objective of KIEKIDS project was therefore to develop a sugar-free, age-appropriate, and flexible treatment of CAE.
1. Development and validation of an adapted paediatric free-sugar formulation (ADV6770)
2. Assessment of the pharmacokinetic profile of ADV6770.
3. Evaluation of the palatability and acceptability of ADV6770
4. Assessment of the safety and tolerability of ADV6770

Literature references:
Shneker, B. F. and N. B. Fountain (2003). "Epilepsy." Dis Mon 49(7): 426-478.
Tenney, J. R. and T. A. Glauser (2013). "The current state of absence epilepsy: can we have your attention?" Epilepsy Curr 13(3): 135-140.
Jallon, P. and P. Latour (2005). "Epidemiology of idiopathic generalized epilepsies." Epilepsia 46 Suppl 9: 10-14.
ILAE (1989). "Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy." Epilepsia 30(4): 389-399.
Glauser, T. A., A. Cnaan, et al, (2010) “Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy”. N Engl J Med 362:790-799.
Loiseau, P., B. Duche, et al. (1995). "Absence epilepsies." Epilepsia 36(12): 1182-1186.
Sadleir, L. G., I. E. Scheffer, et al. (2008). "Factors influencing clinical features of absence seizures." Epilepsia 49(12): 2100-2107.
Hills, M. D. (2007). "The Psychological and Social Impact of Epilepsy." Neurology Asia 12(Supplement 1): 10-12.
Bouma, P. A., R. G. Westendorp, et al. (1996). "The outcome of absence epilepsy: a meta-analysis." Neurology 47(3): 802-808.
Wirrell, E. C., C. S. Camfield, et al. (1996). "Long-term prognosis of typical childhood absence epilepsy: remission or progression to juvenile myoclonic epilepsy." Neurology 47(4): 912-918.
Pavone, P., R. Bianchini, et al. (2001). "Neuropsychological assessment in children with absence epilepsy." Neurology 56(8): 1047-1051.
Wirrell, E., C. Camfield, et al. (2001). "Prognostic significance of failure of the initial antiepileptic drug in children with absence epilepsy." Epilepsia 42(6): 760-763.
Grosso, S., D. Galimberti, et al. (2005). "Efficacy and safety of topiramate in infants according to epilepsy syndromes." Seizure 14(3): 183-189.
Valentin, A., N. Hindocha, et al. (2007). "Idiopathic Generalized Epilepsy with Absences: Syndrome Classification." Epilepsia 48(11): 2187-2190.
Callenbach, P. M. C., P. A. D. Bouma, et al. (2009). "Long-term outcome of childhood absence epilepsy: Dutch Study of Epilepsy in Childhood." Epilepsy Research 83(2–3): 249-256.
Hirsh, E. and C. P. Panayiotopoulos (2005). "Epilepsie-absences de l'enfance et syndromes apparentés". Les syndromes epileptiques de l'enfant et de l'adolescent. J. Roger, M. Bureau, C. Dravetet al. Montrouge, France, John Libbey: 315-336.
Panayiotopoulos, C. P. (2005). "Idiopathic Generalized Epilepsies: A Review and Modern Approach." Epilepsia 46: 1-6.
Panayiotopoulos, C. P., M. Koutroumanidis, et al. (1997). "Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic seizures, and frequent absence status." J Neurol Neurosurg Psychiatry 63(5): 622-627.
NICE Guideline. Epilepsies: diagnosis and management (update 2016).
Buoni, S., A. Mariottini, et al. (2004). "Vagus nerve stimulation for drug-resistant epilepsy in children and young adults." Brain and Development 26(3): 158-163.
Holmes, M. D., D. L. Silbergeld, et al. (2004). "Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes." Seizure 13(5): 340-345.
Ng, M. and O. Devinsky (2004). "Vagus nerve stimulation for refractory idiopathic generalised epilepsy." Seizure 13(3): 176-178.
Revised priority list for studies onoff-patent paediatric medicinal products EMA/480197/2010 (revised July 2010).

Project Results:
An innovative formulation of an antiepileptic drug for the treatment of childhood absence epilepsy (CAE) was developed in order to improve palatability, acceptability, safety and compliance of treatment in paediatric patients.
Prior to KIEKIDS project start, Advicenne had already performed preliminary feasibility studies in order to identify an adapted process for its industrial development and provided evidence for the difficulties to develop a stable form due to intrinsic physico-chemical properties associated with this antiepileptic drug.
In order to overcome those difficulties, several alternatives were investigated, including the use of different salts of the drug, as well as liquid and solid multi-particulate forms.
A granule formulation (ADV6770) was selected and optimised, addressing the following features as requested by neuro-paediatricians:
• Flexible age-adapted formulation affording accurate dosing
• Easy administration for all paediatric groups from 2 years old (avoiding monolithic forms) to 17 years old (avoiding too large volume for product intake)
• Tasteless formulation that should improve compliance and avoid adherence problems linked to bitter taste of the active compound and could possibly limit some gastrointestinal (GI) symptoms
• Sugar-free-formulation compatible with an adequate ketogenic diet.
From a quality stand-point, a pharmaceutical up-scaled process has been developed for the production of 5 kg product batches.
The analytical methods have been developed and validated for the different formulations evaluated and fully validated for the final formulation. They include:
• Assay and determination of related impurities.
• Physical form stability
• Dissolution testing
• Microbiological examination
Data have been gathered demonstrating stability of ADV6770 up to at least 18 months and further stability studies are ongoing. Compatibility with food and drinks at temperatures ranging 5-25°C has been demonstrated through studies mimicking in-use administration conditions.
The whole development plan was discussed with EMA’s Paediatric Committee (PDCO) and a Paediatric Investigation Plan (PIP) for ADV6770 was validated.
ADV6770 being a reformulated oral form of a well-known molecule, no additional non-clinical studies were performed. This was previously endorsed through a Scientific Advice by EMA’s Committee for Medicinal Products for Human Use (CHMP).
Considering that the existing data from published clinical trials already confirmed the efficacy of the drug for the treatment of CAE and that pharmacovigilance data provided useful short and long term efficacy and safety information confirming the well-established profile of the drug, the clinical studies of the development plan focused mainly on pharmacokinetic and palatability/acceptability objectives, but aimed also at collecting additional safety, efficacy and compliance data.
In order to support Phase I and Phase II studies, an HPLC-UV method was validated for determination of drug concentrations in plasma. The bioanalytical method was then adapted and validated in human saliva. Validation demonstrated that reproducibility, intermediate precision and selectivity of the method were satisfactory. Linearity of the response was also satisfactory. Drug stability in plasma and after 3 freeze-and-thaw cycles was demonstrated. There was no matrix effect regarding plasma and water/saliva.
The Phase I trial, consisting of three study parts, was organised and conducted in the Clinical Pharmacology facilities of the CHUV. The first study part compared different formulations against the commercially available reference formulation and against placebo in order to gather pharmacokinetic, pharmacodynamics, and safety data.
Two additional study parts were performed to compare successfully pharmacokinetic (including bioequivalence vs. the reference formulation), pharmacodynamic and safety data profile. Exploratory work was performed for saliva during the first two study parts, confirming a relatively good linear correlation between saliva and plasma however with a ratio below unity. Thus saliva concentrations allow to estimate mean plasma concentrations but not to make an accurate individual plasma prediction. Saliva is a good option to follow compliance.
The last study part confirmed the targeted good palatability for the optimised formulation, thus opening the door to its evaluation in Phase II study with paediatric patients.
The process to manufacture the optimised formulation is complex and challenging because of the sensibility of the Active Substance to environmental factors. Due to important issues during formulation development and scale-up, the planning was significantly delayed. As a consequence, the clinical batches for the Phase II study are expected to be available only in July 2017.
The Phase II study protocol and the regulatory documents were submitted, and approval for the clinical trial was obtained. The investigators are selected and ready to start study conduct in September 2017.
The French network of paediatric investigation in health products network (named RIPPS) involved in the Phase II study has evolved over the past few years and has founded a specific network for the research in paediatric epilepsy, called the Paediatric Epilepsy Research NEtwork (PERENE). Today, among the identified investigator sites from PERENE having initially agreed in participating, most of them have confirmed their participation to the study (20) and could include 5 children in average (between 2 and 10 patients per site) as shown by a feasibility evaluation (each site following between 15 and 30 patients per year).
In order to better adapt the study to the objectives of the global clinical investigation plan discussed with the PDCO and of the target indication, significant modifications were included with respect to the initial study plan presented in the FP7 dossier.
Indeed, the primary objective of the study was modified and it is now to evaluate the acceptability of the new formulation in the paediatric population, since it is the main concern for clinicians and for patients, and to evaluate the phamacokinetic profile as a secondary objective since it was already demonstrated during Phase I.
The adapted study design is a randomised, controlled, two period cross-over, open-label study, comparing ADV6770 the reference product in paediatric patients (2-17 years old), suffering from childhood absence epilepsy (CAE) and currently under treatment, either as monotherapy or in combination. The duration of both periods has been discussed and one month for each has been considered adequate.
The study objectives will allow the evaluation of the novel formulation against the reference drug :
• Primary objective: palatability of ADV6770 coated granules (instead of the determination of the pharmacokinetic profile of ADV6770)
• Secondary objectives:
o Acceptability (volume to swallow, easiness of administration, preference)
o Pharmacokinetics (average steady-state plasma concentration), using sparse collection approach
o Tolerability and safety
o Treatment compliance
o Effect sustainability
• Exploratory objectives
o Correlation concentration/effect
o Correlation concentration/safety issues
Palatability endpoint is evaluated using a single scale regardless of the child’s age. In the case of patients taking drug combinations it has been stressed that palatability should be evaluated before taking the second treatment.
The subjects will be distributed into three age-groups (2-5, 6-11 and 12-17 years inclusive). Subjects will be enrolled in order to be representative of each subset of age but an effort to increase recruitment in the extremities will be made compared to the extremely low prevalence in young children and adolescents. The enrolment objectives will be as follows: 10 % in the sub-set 2-4 years, 80 % in the sub-set 5-11 years and 10 % in the sub-set 12-17 years.
The KIEKIDS Ethical Committee has reviewed the Phase I data and the design, tools, and documents proposed for Phase II. It has no reservation to initiate the Phase II trial based on safety, on risk/benefit ratio, and on medical, technical and ethical considerations.
In conclusion, the consortium has achieved the pharmaceutical development of an innovative multi-particulate formulation for the treatment of CAE and provided pharmacokinetic bioequivalence, pharmacodynamics, safety and palatability data. The on-going clinical investigation plan, validate at the European level, will be completed by the end of 2018.
Potential Impact:
The direct impact of the KIEKIDS project will be the availability of an adequate paediatric formulation for the treatment of absence epilepsy, identified as a high priority by the EMA, with dedicated pharmacokinetic and safety data in children.
The ultimate goal of the KIEKIDS project is to obtain for ADV6770a Paediatric Use Marketing Authorisation (PUMA), allowing availability of this novel age-adapted formulation in all EU Countries. The marketing authorisation application is expected to be submitted by Advicenne in 2019.
The reported annual incidence of CAE varies from 0.7 to 8 per 100’000 persons in the general population and prevalence ranges from 0.1 to 0.7 per 1’000 persons.
In most instances, epilepsy requires a prolonged treatment during childhood and has a significant impact on medical and social aspects of patient’s life:
• Absence seizures are not predictable and they can occur at any time. They are consequently inconvenient and embarrassing for patients and family alike.
• Absence seizures also induce a negative impact on patient’s social behaviour, triggering isolation and loss of self-esteem.
• CAE is connected to learning disabilities and memory problems:
o Symptoms are overrepresented among children with CAE.
o Attention deficit disorders are emphasized during absence seizures.
o Adverse side-effects such as drowsiness and short attention impact education achievement.
o These symptoms are exacerbated by polytherapy.
Proposing an efficient treatment of childhood absence or myoclonic epilepsy would result in a significant improvement of the social conditions for these patients.
The need for a new paediatric formulation for treatment of childhood absence epilepsy was evaluated by a questionnaire addressed to neuro-paediatricians in Europe. The 20 neuro-paediatricians questioned in France (where the drug is only available as syrup) replied to the enquiry, as well as 6 other European neuro-paediatricians. All clinicians but one (who did not take a position) indicated a new formulation is required.
Their answers clearly confirmed the need for a formulation adapted to the whole paediatric population in terms of acceptable taste, sugar-free and age-adapted pharmaceutical formulation

Formulation needs expressed by European neuro-paediatricians

It was concluded that:
• 95 % of the neuro-paediatricians call for a formulation with an acceptable taste.
• 80 % of the neuro-paediatricians indicate that there is an important need for a formulation without sugar.
• 85% of the neuro-paediatricians request a formulation more adapted to older children and adolescents or high dosing schemes (>30 mg/kg).
• 35 % of the neuro-paediatricians request a formulation better adapted to young children
This allowed communicating with neuro-paediatricians about the new product, eliciting great expectations. Indeed, patients and clinicians are eagerly expecting this new product as a new treatment for Childhood Absence Epilepsy (CAE), a syndrome affecting approximately 40’000 children in Europe.
Scientific communication about the clinical programme has been performed through presentations at different congresses and symposia.
Intellectual property protection is being prepared through a patent covering the new formulation and several publications of clinical results are expected to be subsequently submitted, at least one for Phase I and one for Phase II..
Finally the KIEKIDS project has been mentioned in an article about paediatric medicines research in the EU:
• Ruggieri L, Giannuzzi V, Baiardi P, Bonifazi F, Davies EH, Giaquinto C, Bonifazi D, Felisi M, Chiron C, Pressler R, Rabe H, Whitaker MJ, Neubert A, Jacqz-Aigrain E, Eichler I, Turner MA, Ceci A; GRiP Consortium. “Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines”. Eur J Pediatr. 2015 Apr. 174(4):481-91.

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