Personalised Treatment For Cystic Fibrosis Patients With Ultra-rare CFTR Mutations (and beyond)

Project Information

HIT-CF

Grant agreement ID: 755021

DOI

10.3030/755021

Project closed

EC signature date 28 November 2017

Start date 1 January 2018

End date 30 June 2025

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

€ 6 701 365,00

EU contribution

€ 6 701 365,00

Coordinated by

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Periodic Reporting for period 5 - HIT-CF (Personalised Treatment For Cystic Fibrosis Patients With Ultra-rare CFTR Mutations (and beyond))

Reporting period: 2024-07-01 to 2025-06-30

Summary of the context and overall objectives of the project

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 from the beginning of the project to the end of the period covered by the report and main results achieved so far

Slightly more than 500 patients were so kind to donate rectal tissue to the consortium. The organoids derived from these biopsies were biobanked and studied by HIT-CF. Two studies on the ethics and governance of using patient-derived organoids for public and private scientific research have been published by the consortium.
The primary and secondary organoid screening have been finished for all CF modulating compounds included in the project. This allowed us to select in time the patients for the CHOICES trial. The CHOICES trial is a trial using CF drug products that were originally owned by Proteostasis Therapeutics. In the meantime, Fair Therapeutics has the rights to market these compounds for CF. Consequently, Fair therapeutics was invited to join the consortium to take over the role of Proteostasis Therapeutics.

Following earlier delays due to a rejected Clinical Trials Information System (CTIS) application, the consortium addressed all regulatory requirements. A second CTIS submission was approved, and national approvals were obtained. All preparations for the CHOICES trial were finalized: all clinical trial sites were activated, laboratory kits and Investigational Medicinal Product (IMP) were distributed, and the trial officially started in M78 with the enrollment and randomization of the first patient. In total, 46 patients were screened and 41 patients were enrolled and randomized. Last Patient Last Visit (LPLV) was achieved in M90. The Clinical Study Report is currently in preparation.

Primary and secondary organoid screening for the ELOXX compound, ELX-02, has also been completed. Meanwhile, ELOXX has put the development of ELX-02 for CF patients on hold. So, it makes no sense to perform a clinical trial with ELX-02. Nevertheless, the data generated are proving to be of greatest use for patients whose organoids do not respond to CFTR modulating drugs. Indeed, companies with Advanced Therapy Medicinal Products for CF patients are queuing up to recruit this kind of patients for their clinical trial. In this regard, the consortium is in close collaboration with Recode therapeutics, which has a mRNA-lipid nanoparticle technology platform that could potentially cure CF patients.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The 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 organoid 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 have first been tested in the laboratory on patient-derived mini-intestines (organoids). Secondly, based on the reaction in the organoids, a smaller group of patients has been assigned to a study (clinical trial) with one of the drug candidates. We will achieve our goals by means of a randomised, double-blind, placebo-controlled, repeated-crossover 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. The patients have been assigned to the trial based on the effect of the drug product candidates on cultured intestinal miniature organs 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.

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