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LENA Report Summary

Project ID: 602295
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 2 - LENA (Labeling of Enalapril from Neonates up to Adolescents)

Project Context and Objectives:
All aspects of the LENA project are focused on comprehensively answering one simple question: How can we provide a safe, effective, and age-appropriate formulation of enalapril for children in Europe?
The LENA project acknowledges the current shortcomings of paediatric drug development and aims to develop an orally administered, age-appropriate formulation of enalapril for use in neonates and infants. The development process will include investigator-driven trials that will collectively generate all necessary data for devising a paediatric-use marketing authorization (PUMA). The project will therefore conclude with a completely tested product ready for broad dissemination to the paediatric population in the European Union (EU) member states.
The LENA consortium consists of partners with expertise and experience in paediatric enalapril formulation development (Stoltenberg 2010; Hermes 2012), enalapril/enalaprilat assay development (Ramusovic 2012b), pharmacokinetic/pharmacodynamic (PK/PD) modelling of enalapril (Ramusovic 2012a), management of HF, recruitment of paediatric populations for clinical studies, and management of complex conditions in clinical trials. Basing the project on the partners’ past research and expertise will save considerable cost and time compared to developing an entirely novel formulation, assay, model, or PK clinical study. The partners will collaborate with selected small- and medium-sized enterprises (SMEs) with proven expertise in the field of preclinical and paediatric drug development. The LENA project will be overseen and advised by an independent Ethical and Scientific Advisory Board (ESAB) and patient data will be evaluated by an independent Data and Safety Monitoring Board (DSMB), both of which will be fully constituted after successful approval of this proposal.

This project aims at fully utilizing the expertise and experience of the consortium members to achieve the following objectives:
• Objective 1: Develop a novel age-appropriate solid drug formulation of enalapril for use in neonates and children, and provide bioavailability data by age group within the paediatric population
• Objective 2: Demonstrate via investigator-driven bridging studies that this novel drug formulation is effective and clinically safe in the paediatric population
• Objective 3: Consolidate data from the investigator-driven studies to lay the groundwork for a PUMA application to transform off-label into on-label use of enalapril
• Objective 4: Disseminate information and provide outreach to clinicians, parents, and patients
• Objective 5: Gather epidemiological data to facilitate the optimal distribution, marketing and pricing of enalapril in the European Union member countries

Project Results:
Work performed since the beginning of the project and the main results achieved so far:
The LENA project has made significant progress towards its aims in the second reporting period. With effective project and scientific management and the commitment of the LENA partners, the project has achieved most of its objectives and technical goals for the second period with relatively minor deviations. After successful negotiations, the consortium received a positive decision from PDCO (decision number P/0176/2015) about the Paediatric investigation plan. This was published on 07 August 2015 EMA by “decision on the agreement of a paediatric investigation plan for enalapril (maleate)” by document EMA/43439/2015. A LENA GxP infrastructure has been built for the paediatric clinical trials to guarantee that the LENA results are obtained under GCP and GCLP conditions.
Therefore, the LENA results will sustain audit processes by the legal authorities once data are submitted to the European Medicines Agency (EMA) for approval. The orodispersible minitablets (ODMTs) containing enalapril have been produced under GMP conditions; they are stable and were administered successfully to paediatric patients with heart failure. Final analysis and reporting of documentation of the standard of care for children with DCM across Europe and the consensus-forming process demonstrated a high acceptance among paediatric cardiologists of the use of enalapril in the paediatric population. The LENA consortium developed successfully three LENA paediatric study protocols and received their approval subsequently for all clinical sites in 5 European countries. As recruitment started, it quickly appeared that the ODMTs delivered on the promise to parents: patients were highly satisfied with the ODMTs, and ODMTs were a much better treatment choice than the liquids, capsules or crushed tablets currently available on the market. Moreover, the medical staff members very much liked the ODMTs. With carefully arranged preparation and training of the clinical sites, the LENA paediatric study protocols were correctly performed at the clinical sites. On the basis of an innovative active learning tool (simulation study) for LENA-specific training, high quality study performance (especially for PK/PD sampling at all LENA clinical sites) was achieved. Thus, one-third of the paediatric patients envisaged in the LENA trials have been recruited. Only one patient has dropped out so far. It already appears that enalapril ODMTs will have the chance of being the first choice for treating heart failure in neonates, infants and younger children rather than the on-label available captopril, which is currently used in more than 90% of neonate and infant cases, according to the European survey results. In summary, the LENA enalapril ODMT would be a substantial step forward in the safe and effective treatment of children with heart failure.

Potential Impact:
The expected final results and their potential impact and use (including the socio-economic impact and the wider societal implications of the project so far):
The LENA project will provide the first orodispersible mini-tablet for neonates up to adolescents and will have an impact on European families. A minitablet is convenient and easy to handle, and its use will increase adherence to treatment. Many parents are unable to cope with complicated instructions for the preparation and use of extemporaneous drug formulations for their children, causing non-adherence and impeding the effective use of medications. Parental non-adherence induces feelings of guilt regarding their child. As a last resort, some parents give up their job in order to care for their children and ensure medication compliance, impacting the economic well-being of the family. Thus, mini-tablets will alleviate the socioeconomic burden of disease for the family. Such easy-to-use technologies are promising and can increase adherence to medications. These seemingly small but innovative steps can have a great positive effect on European families.

The LENA project may lead to licensing of the first long-acting ACE inhibitor for use in the treatment of neonates (impact on European treatment guidelines). To date, only the short-acting ACE inhibitor captopril is licensed for young patients and must be administered at least thrice a day. Enalapril is used only once or twice a day and thus will increase adherence to and the compliance of parents and children with treatment regimes.

The concepts addressed by the LENA project may be extended to other drugs. Numerous off-patent and patented drugs are candidates to be re-formulated as minitablets such as hydrochlorothiazid, diazepam, vitamin K, and sildenafil. The LENA project may be regarded as a proof-of-concept project for the European pharmaceutical industry to explore minitablets as a novel technology for convenient solid formulations for use in neonates and young infants. This can shift the paradigm of age-appropriate formulations from liquid to solid in the very young, offering many advantages with regard to drug stability and ease of administration. LENAs minitablets are an ideal medicine for children with limited access to clean potable water in developing countries because water is not necessary to administer the minitablets. With the data obtained in clinical trials of mini-tablets for neonates, infants, and young children, and the application of the LENA protocol to other drugs, LENA can strengthen the pharmaceutical industry as well as the small- and medium-sized enterprises (SMEs) of the European Union, which can then become more competitive and increase their economic power by offering novel and superior products. Since elderly patients also have problems swallowing tablets, enalapril minitablets might be beneficial to them as well. This would most likely significantly increase the economic impact of the LENA project.

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