New therapies for people with CF in the CFTR modulator world

Abstract

Editorial In this edition of the Journal, the outputs from two workshops provide an important framework for the future development of a pipeline for new CF therapies. The workshops considered drug development, clinical trial design, and regulatory pathways, in the evolving and challenging research environment that has developed with clinical use of CFTR modulation. CFTR modulation has led to improved health outcomes for patients with CF, although the benefits derived from CFTR modulation have also led to difficulties in the design of clinical trials for new medicines. Established trial endpoints may not be as sensitive to change in healthier populations, and new outcomes or biomarkers may be required. Patients may be less inclined to stop effective treatment for clinical trials, and this makes gold standard placebo-controlled trials more challenging. De Boeck et al. provides the summary of discussions from a workshop held in November 2019 that focused on drug trial design in the new era of CFTR modulation. The workshop included invited clinical experts as well as representatives from pharmaceutical companies, the European Medicines Agency (EMA), experts in Health Technology Assessment and patient organisations [1]. There were welcome discussions on trials and approaches to drug development for groups such as those with rare CFTR mutations and vulnerable groups such as infants and young children. Infants and young children require special consideration as they may derive the greatest benefit in the long term from early improvement of CFTR function, although early exposure may also increase the potential for greater harm given the developmental context. Measuring efficacy in uncooperative young children also presents many challenges, and there are time constraints to understanding longitudinal safety and outcomes. Regulatory requirements for drug development vary between different countries. These differences lead to barriers for drug development and contribute to reduced global access and increased costs associated with drug development. Harmonization between regulatory authorities should provide agreement on the technical and marketing requirements for therapeutic products. This requires cooperation between the regulatory authorities working with pharmaceutical companies to achieve an agreed pathway for the ethical development of new therapies and reduce both duplication of effort, and the time taken to bring a product from bench to bedside across different jurisdictions. Globally there are those who are living without access to new CFTR modulation, or other new medicines, because of regulatory issues as well as the cost of these expensive treatments. Mayer–Hamblett et al. reflect the discussions and outcomes from a workshop of invited international experts on clinical trials and trial networks that was held in October 2019 associated with the North American CF meeting [2]. The workshop focused on the development of new therapies for CF and discussed the challenges and approaches to regulatory requirements in the post CFTR modulator environment including treatments for rare mutations. The workshop highlighted the crucial importance of clear communication between all stakeholders. The workshop also provided strategies for the development of new anti-infective, anti-inflammatory and other symptomatic treatments, as well as for the development of new cellular therapies that would be impacted by the availability of CFTR modulation. Regulatory authorities have started to find solutions to some of the challenges raised in both the workshops. The Food and Drug Administration (FDA) in 2017 took the step of approving the potentiator ivacaftor for an extended list of CFTR mutations based on laboratory studies rather than specific clinical trial evidence. The premise for this decision was that clinical trials for many rare CFTR mutations would not be feasible, and that cell models of functional CFTR responses were generally predictive of the clinical benefits [3]. This approach will need careful consideration and agreement on which cellular approaches are required, and for which therapies they are appropriate in the future, but this has certainly opened a new door for drug development and regulatory approval. During the peer review process, an issue arose around the terminology used in both manuscripts. This led to considerable debate between the authors, the reviewers and the journal, and given the strong opinions around the terminology, it may be worthwhile to reflect on this debate. Both manuscripts initially used the term “highly effective CFTR modulators” to identify the exceptional outcomes from two CFTR modulators currently in clinical use. The two CFTR modulators include ivacaftor in patients with CFTR gating mutations [4], [5], and the triple combination elexacaftor, tezacaftor and ivacaftor (Trikafta™) in patients aged 12 years and older who are either homozygous [6] or heterozygous for F508del-CFTR [7]. Two other CFTR modulator therapies in clinical use, Orkambi™, and Symdeko™ (also known as Symkevi™), are associated with more modest improvement in CFTR function and clinical outcomes [8], [9]. Given this background, and the growing common usage of this terminology, why should there be any concern about the use of “highly effective CFTR modulator” to differentiate these drugs in the scientific literature? Drugs are classified based on their pharmacological effects, their chemical structures, molecular targets or specific drug actions, and the recognised classification of “CFTR modulators” fits nicely within this approach. As clinicians and scientists, we describe and compare specific drugs in terms of their potency, effect or toxicity and such comparisons and discussion are critical in developing appropriate clinical use. To date, however the classification of drugs has not included adjectives that describe them. New CFTR modulators are in development and, like other new drugs, may end up being equivalent or may be more, or may be less effective for specific outcomes compared with the various current clinically available CFTR modulators. If we start to differentiate within the CFTR modulator class in the scientific world by the term “highly effective’, what will we use to set the bar to achieve this accolade, and could there be consequences to doing this? How will we account for variation in effects on different outcomes or between individuals? Naming or labelling things is a very powerful tool that is well recognised in the advertising world. In the clinical trial setting there has been concern around the explosion in the use of acronyms for naming clinical trials and the risks that positive sounding trial acronyms pose with regards to the therapeutic misconception [10]. The language of science should be clear and objective while still providing the opportunity for creative thought, but the labelling of drugs as “highly effective” as part of their classification feels close to leaving objectivity behind. The global SARS-CoV-2 pandemic emerged after both workshops. The pandemic has led to substantial impacts on health and on the global economic outlook. It is likely that there will be repercussions felt across all sectors of the economy, including drug development and support for clinical research. What this means for CF research and the pipeline of new treatments for CF specifically, or indeed for how clinical trials will be conducted, or new therapies may be reimbursed in the future, remains to be seen. The pandemic however has prompted urgent collaboration globally to develop vaccination and treatments to combat COVID-19, the disease caused by SARS-CoV-2. In June 2020, a great start was made in regulatory harmonization with a meeting chaired by the FDA and EMA under the auspices of the International Coalition of Medicines Regulatory Agencies (ICMRA,) which brought together experts from over 20 countries and 28 regulatory authorities. The meeting led to broad agreement on the data required from laboratory, animal and human research as well as aspects of Phase 3 clinical trials aimed at the rapid development and regulatory approval for vaccines for COVID-19. We can only hope that this example of global collaboration will lead to a more established pattern of harmonization and more rapid development of other important medicines in the future. The outputs from the two workshops have provided a very helpful start in setting the scene for clinical development of new treatments for CF in the CFTR modulator era. There were some issues however that may benefit from further consideration in the future. The high cost of new treatments and reimbursement remains a considerable concern for CF care. This of course is a thorny global issue for all areas of health worldwide, and while there are no easy solutions, we need to keep reconsidering the issues and chip away at the problem. The other major area that deserves further thought includes trials and regulatory pathways for new medicines in vulnerable groups such as pregnant or lactating mothers, those with solid organ transplants, and those with severe liver disease. These groups are almost always excluded from clinical trials and regulatory packages although clinicians and patients may choose to use the medicines once they are generally approved. There has been some encouraging progress recently with the 2018 FDA guidance on the issue of trialling and monitoring medicines during pregnancy and lactation. Future collaboration and communication between regulatory authorities, pharmaceutical companies, clinicians and patient groups will be needed to consider how best to establish the clinical use of new CF medicines for these very challenging populations. There has been enormous improvement and exciting development in CF care especially with CFTR modulation, but much work remains to be done to ensure equitable access to safe and appropriate use of medicines for all people with CF in the future.