Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - HIT-CF (Personalised Treatment For Cystic Fibrosis Patients With Ultra-rare CFTR Mutations (and beyond))

Teaser

HIT-CF Europe is a research project which aims to provide better treatment and better lives for people with cystic fibrosis (CF) and rare mutations. Cystic Fibrosis (CF) is a major chronic autosomal recessive genetic disorder that affects many organs and with lung failure as...

Summary

HIT-CF Europe is a research project which aims to provide better treatment and better lives for people with cystic fibrosis (CF) and rare mutations.
Cystic Fibrosis (CF) is a major chronic autosomal recessive genetic disorder that affects many organs and with lung failure as the main cause of death.New mutation class-specific drugs are currently only being clinically tested in patients with well-described, very common mutations. As a result, market authorization and reimbursement of these drugs is only granted in these specific subsets of patients. Nevertheless, other patients with less common mutations might also benefit from them.

At present, no drugs are on the market or in development for patients with ultra-rare CFTR mutations and these patients are also not included in the clinical trials organised by companies (small number of patients with each mutation pose challenges in designing adequate and well controlled studies). However, based on small-scale experiments in intestinal organoids derived from patients with ultra-rare CFTR mutations, we know a fraction (>15%) of these ultra-rare CFTR mutants do respond in in vitro assays to particular CF drugs.

Organoids are cell cultures that grow in a culture dish, and look similar to the organ from which they are derived. Intestinal organoids can therefore also be called mini-intestines. To make intestinal organoids for the HIT-CF Europe project, rectal tissue samples (biopsies) will be obtained. This procedure is not painful and will take 5-10 minutes. Because organoids are made from stem cells, they contain the same mutations as the person from whom the biopsies are derived. The drug candidates target the basic defect of CF, and the organoids will be used to test on which mutations the drugs have a positive effect.
The ultimate goal of HIT-CF Europe is to develop a path for access to therapies for individual patients or patient groups who show positive response to the therapy in an organoid test and pave the way for organoid-based personalized medicine.

Work performed

Complete document packages for the HIT-CF Organoid Study including the Study Protocol, Informed Consent Forms, Clinical Trial Agreement, Material Transfer Agreement and Standard Operating Procedures were generated.
Ethics approval for the HIT-CF Organoid Study has been obtained in 8 countries and patients have been included from 11 countries in Europe. Regarding ethics and governance, a large empirical study of the perspectives of both patients and professionals surrounding the ethics and governance of (long-term) storage of organoids in biobanks and their use in both clinical and broader research applications, has been completed.

In regards to regulatory approval, the consortium had both informal and formal interactions with EMA: preparatory discussions and meetings with Innovation Task Force (ITF) and Scientific Advice Qualification pre-discussion (SA). Contacts with European Reimbursement Authorities and with MoCA are established. Contacts with the FDA are currently being prepared.

The goal to reach a uniform protocol for organoid testing has been completed. The protocol has been implemented in the participating laboratories and measurements have reached outstanding standardisation, which make all the participating labs ready to start screening of the organoids in the next phase of the HIT-CF program. Initiation of drug screening by the three screening labs was achieved. Collection of organoids and screening is underway.

The patient representatives of CF Europe were involved in and heard out concerning the conceptualization and implementation of all aspects of HIT-CF. In the role of WP8 leader, CF Europe’s main responsibilities were communicating on and disseminating key messages about HIT-CF. As such, a professional project identity was created, including a project website and six-monthly newsletters. In addition, internal communication procedures were developed, with two-weekly recruitment updates and six-weekly calls with all consortium partners. Furthermore, a dissemination plan was drafted, including key performance indicators to monitor the dissemination of the output of the project. The strategy outlined in the dissemination plan guarantees that the key messages of the project are disseminated to the relevant stakeholders (general public, policy makers, patient and patient advocacy groups, scientific and medical community, regulatory and reimbursement decision makers and pharmaceutical industry) making use of the most appropriate communication methods. A Patient Liaison Officer (PLO) was appointed to ensure personal interaction with the patients. The PLO can be contacted via the contact form on the website or via direct mail. Via several dissemination tools (Facebook posts, workshops etc.), patient awareness was created which greatly supports patient recruitment.”

Final results

HIT-CF project aims 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.

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.

To achieve this, drug candidates of several companies will first be tested in the laboratory on patient-derived mini-intestines (organoids). Secondly, based on the reaction in the organoids, a smaller group of patients will be assigned to studies (clinical trials) with one of the drug candidates.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. HITCF 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.

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.

Website & more info

More info: https://www.hitcf.org/.