In our HIT-CF project, we aim to bring personalised disease modifying therapies to cystic fibrosis (CF) patients with ultra-rare CFTR mutations, who could otherwise never get access to such treatment. Once we have proven our unique concept, the CF community can easily extend our state-of-the-art methodology to all CF patients such that HIT-CF will impact the entire CF field. We will achieve our goals by means of a randomised, double-blind, placebo-controlled, repeated-crossover, three-armed platform trial with prospectively defined meta-analysis to evaluate efficacy at group and individual level. HIT-CF is designed to enable access to the most relevant global drug products, and each trial arm will test a drug product candidate (a single compound or a compound combination) from one of our pharmaceutical consortium partners. The patients will be assigned to the specific trial based on the effect of the drug product candidates on cultured intestinal miniature organs (termed organoids) grown from rectal biopsies, instead of based on typical genotyping only. In parallel with this H2020 project, our pharmaceutical partners will obtain market approval of their drug product candidates for common (F508del or gating) mutations in the CFTR gene. Ultimately, our project will enable ‘managed’ off-label access to these therapies towards patient groups or individuals who show response to the therapy in a prospective intestinal organoid test. One of the major impacts of this project will be the innovative methodologies to acquire reimbursement for current and future off-label treatments of people with CFTR mutations. This will represent a real paradigm shift in CF treatment as it implements a new type of personalized medicine paradigm based on organoids, by shifting therapeutic trials from patients to the laboratory.

The objective of the current proposal is to advance the orphan drug OligoG CF-5/20 (OligoG) through a pivotal phase IIb clinical trial, to enable a new and improved therapeutic approach for the orphan disease cystic fibrosis by 2024. The study drug is an alginate oligosaccharide derived from seaweed. Several properties relevant to the treatment of CF have been demonstrated using in vitro and ex vivo model systems including release of stagnant mucus, disruption of bacterial biofilm and increased bacterial susceptibility to antibiotics. OligoG received an EU Orphan Drug Medicinal Product Designation in 2007 and an FDA Orphan Drug Designation February 2016, for the treatment of cystic fibrosis. The planned clinical trial will include approx 200 CF patients from approx. 35 European sites in coordination with the European Clinical Trial Network. The final study design, selection criteria, procedures and endpoints will be based on results from a recently finalized phase II study and will follow scientific advice and protocol assistance sought at the European Medicines Agency (EMA). A set of clinical and exploratory endpoints will be defined to assess the various effects of OligoG, comprising lung function assessed by spirometry and Lung Clearance Index (LCI) measurements, infection status assessed by frequency of pulmonary exacerbations and non-culture-dependent microbiology, and patient reported outcomes assessed by questionnaires, including standardised CF questionnaires (CFQ-R). A successful trial will enable preparation of international applications for conditional marketing authorisation (cMAA) throughout Europe and a New Drug Application (NDA) in the US, for the treatment of cystic fibrosis lung disease. In accordance with the work programme, a successful project will thus imply a new and improved therapeutic approach within cystic fibrosis available for CF patients by 2024.

Cystic fibrosis (CF) is a progressive life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leading to a dysfunctional CFTR protein. The disease affects over 70,000 patients worldwide and while many mutations are known, the F508del mutation affects 90% of all patients. The absence of CFTR in the plasma membrane leads to a dramatic decrease in chloride efflux, resulting in viscous mucus that causes severe symptoms in vital organs like the lungs and intestines. For CF patients that suffer from the life threatening F508del mutation only palliative treatment exist. PRO-CF-MED addresses the specific challenge of this call by introducing the first disease modifying medication for the treatment of the CF patients with F508del mutation. The PRO-CF-MED project has been designed to assess the potential clinical efficacy of QR-010, an innovative disease modifying oligonucleotide-based treatment for F508del patients. Partners within PRO-CF-MED have generated very promising preclinical evidence for QR-010 which allows for further clinical assessment of QR-010 in clinical trials. PRO-CF-MED will enable the fast translation of QR-010 towards clinical practice and market authorisation. PRO-CF-MED has the potential to transform this life-threatening condition into a manageable one.

Paediatric medicines development is embedded in the European policy, legislation and in the work of the pharmaceutical industry but currently the potential of this effort is not realised. The conect4children (c4c) project will address the critical problems with the design, implementation and operational conduct of paediatric clinical trials, for example the fragmented and redundant efforts between sponsors, sites and countries. This project will generate a sustainable infrastructure that optimises the delivery of clinical trials in children through: a) a single point of contact for all sponsors, sites and investigators; b) efficient implementation of trials adopting consistent approaches, aligned quality standards and coordination of sites at national and international level; c) collaboration with specialist networks; d) high quality input to study design and preparation through rigorous strategic and operational feasibility assessment and e) the promotion of innovative methodologies. The project will be managed according to IMI2 best practice with a dedicated communications effort. The clinical trials infrastructure will be setup, implemented and tested by implementing 3-4 industry and at least 1 non-industry proof-of-viability studies. Expert advice groups will promote innovative methodologies and engagement with regulators. The business model for a sustainable infrastructure will be based on the European landscape of paediatric networks and available trial sites, the evaluation of services needs of sponsors of all kinds, and will be informed by the proof-of-viability studies. Supporting activities will include: data management (data about the trials and the network, including performance metrics for network management and promotion; handling trial data for non-industry sponsors; support for common data dictionaries); education and training. The voices of children, young people and their families will be central to the network.