Periodic Reporting for period 2 - HIT-CF (Personalised Treatment For Cystic Fibrosis Patients With Ultra-rare CFTR Mutations (and beyond))
Okres sprawozdawczy: 2019-07-01 do 2020-12-31
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.
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.
Slightly more than 500 patients were so kind to donated rectal tissue to the consortium. The organoids derived from these biopsies were biobanked and studied by HIT-CF. Beginning 2021 two studies on the ethics and governance of using patient-derived organoids for public and private scientific research will be published by the consortium. In the meantime, already ~30% of the patients recruited in the HIT-CF organoid study have given their written consent for using their organoids for academic and commercial research outside HIT-CF. The consortium is considering to generate, in consultation with laboratories outside the consortium, electronic informed consent forms to also offer the remaining patients this unique opportunity.
The primary and secondary organoid screening for the PTI compounds are finished. Delays due to the covid pandemic were mitigated by re-organising multiple other linked tasks. In this way, we were able to select in time the 52 patients for the CHOICES trial (the first of two HIT-CF managed clinical studies). Any other preparations HIT-CF could do to start the CHOICES trial were also performed. Once the PTI drug product and the related information for the regulatory agencies arrives at our CRO, Julius Clinical, preparations can start to recruit the first patients. Unfortunately, the merger of PTI with Yumanity Therapeutics (announded 23th of December 2020) is causing severe delays in the kick off of CHOICES. The HIT-CF team is currently looking into the best way to get the PTI drugs to the selected patients.
The primary organoid screening for the ELOXX compound, ELX-02, is also finished. Even at this early stage, it is clear that there are people with CF caused by rare stop mutations who respond to the Eloxx drug, which is great news. These organoid screening activities did experienced delays due to the covid pandemic and the associated prioritisation of tasks to prepare for the CHOICES trial. However, these delays are not on hampering the critical path to recruit patients for the HIT-CF trial in time. Indeed, the consortium has to wait till ELOXX has finalised their running phase 2 clinical trials targeting cystic fibrosis patients with a G542X mutation on one or both alleles.
Data from the secondary screen, which will now be performed in next reporting period, will be used to select 26 people for our second HIT-CF managed clinical trial. At ELOXX's discretion, we hope to start our HIT-CF study with ELX-02 in early 2022.
The primary and secondary organoid screening for the PTI compounds are finished. Delays due to the covid pandemic were mitigated by re-organising multiple other linked tasks. In this way, we were able to select in time the 52 patients for the CHOICES trial (the first of two HIT-CF managed clinical studies). Any other preparations HIT-CF could do to start the CHOICES trial were also performed. Once the PTI drug product and the related information for the regulatory agencies arrives at our CRO, Julius Clinical, preparations can start to recruit the first patients. Unfortunately, the merger of PTI with Yumanity Therapeutics (announded 23th of December 2020) is causing severe delays in the kick off of CHOICES. The HIT-CF team is currently looking into the best way to get the PTI drugs to the selected patients.
The primary organoid screening for the ELOXX compound, ELX-02, is also finished. Even at this early stage, it is clear that there are people with CF caused by rare stop mutations who respond to the Eloxx drug, which is great news. These organoid screening activities did experienced delays due to the covid pandemic and the associated prioritisation of tasks to prepare for the CHOICES trial. However, these delays are not on hampering the critical path to recruit patients for the HIT-CF trial in time. Indeed, the consortium has to wait till ELOXX has finalised their running phase 2 clinical trials targeting cystic fibrosis patients with a G542X mutation on one or both alleles.
Data from the secondary screen, which will now be performed in next reporting period, will be used to select 26 people for our second HIT-CF managed clinical trial. At ELOXX's discretion, we hope to start our HIT-CF study with ELX-02 in early 2022.
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.
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.