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. Author manuscript; available in PMC: 2024 Oct 1.
Published in final edited form as: Lancet Respir Med. 2023 Sep 9;11(10):932–944. doi: 10.1016/S2213-2600(23)00297-7

NEW ROADMAPS TO ADVANCE A PIPELINE OF CYSTIC FIBROSIS CLINICAL TRIALS: A GLOBAL TRIAL NETWORK PERSPECTIVE

Nicole Mayer-Hamblett 1,2,3, John Paul Clancy 4, Raksha Jain 5, Scott H Donaldson 6, Isabelle Fajac 7, Christopher H Goss 1,2,8, Deepika Polineni 9, Felix Ratjen 10,11, Bradley S Quon 12, Edith T Zemanick 13, Scott C Bell 14,15, Jane C Davies 16,17, Manu Jain 18, Michael W Konstan 19,20, Natanya R Kerper 4, Tré LaRosa 21, Marcus A Mall 22,23,24, Edward McKone 25, Kelsie Pearson 1, Joseph Pilewski 26, Lynne Quittell 27, Jonathan H Rayment 12, Steven M Rowe 4, Jennifer Taylor-Cousar 28, George Retsch-Bogart 29,*, Damian G Downey 30,*
PMCID: PMC10982891  NIHMSID: NIHMS1978358  PMID: 37699421

Summary

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with CF (pwCF) has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population now divided by CFTR modulator eligibility. A robust pipeline of nucleic acid-based therapies (NABTs) initially directed towards the estimated ~10% of the CF population who are genetically ineligible for, or intolerant of, CFTR modulators is critically dependent on optimizing limited trial participant resources across multiple development programs and will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire CF population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. This perspective will lay the foundation for clinical trial strategy and community partnership that must deviate from precedent to advance the future pipeline of CF therapeutics.

Introduction

Since the approval of the first therapy indicated for cystic fibrosis (CF) in the early 1990s (1), the pipeline of regulatory approved CF therapies has progressively expanded due to the feasibility of conducting clinical trials able to generate substantial evidence for the safety and clinical efficacy of a new therapy (2–4). This includes trials for supportive or “symptomatic” therapies addressing pathogenic events downstream of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, most prominently muco-active therapies and antimicrobials (1, 5–8), and trials for variant-specific modulator therapies aimed at restoring and/or augmenting CFTR protein function (9–14). Pivotal placebo-controlled clinical trials for these therapies demonstrated meaningful improvements in lung function, respiratory symptoms, and/or the frequency of pulmonary exacerbations. The cumulative successes of prior therapeutic development programs have contributed to precedent informing the clinical trial design and outcomes necessary to establish “substantial” efficacy of subsequent therapies, often requiring more than one pivotal trial. However, to advance the current pipeline of novel CF therapies amidst evolving standard of care and clinical needs, the CF research community is faced with a new challenge for which precedent can no longer be relied upon and alternative roadmaps must be envisioned.

The widespread uptake of highly effective CFTR modulators has caused a fundamental shift in clinical trial strategy that will need to meet the needs of a newly dichotomous CF patient population now divided by those able to and not able to benefit from these modulators(15). For the minority of the population who are not genetically eligible for CFTR modulators (<10%, and in which Black, Indigenous and People of Color [BIPOC] are overrepresented as compared to the general CF population(16)), a full pipeline of nucleic acid-based therapies (NABTs) broadly aimed at the restoration of defective CFTR function in the lung holds promise and is progressing in clinical trials(17). These efforts must be thoughtfully scaled due to the limited population size in order to facilitate testing of multiple therapeutic options, even though smaller trials may fall short of reaching prior benchmarks for substantial clinical efficacy simply due to feasibility. Symptomatic therapy trials will proceed across the entire CF population but will likely face enrollment challenges due to a growing number of healthier people with CF (pwCF) with more mild and stable pulmonary disease conferred by highly effective modulator therapies and who subsequently have active work, family and school lives less conducive to pauses for research participation(18). In this healthier group, the efficacy of a new therapy is also becoming more difficult to measure and it may be more challenging to establish a given treatment effect as clinically meaningful. Furthermore, meeting the therapeutic needs of the entire CF population will not only depend on a robust sponsor-driven pipeline, but will also be critically dependent on clinical trials informed by the research priorities of the CF community. As the trial landscape becomes more complex, global partnership to efficiently address these priorities is imperative to urgently address the needs of our CF community(18, 19).

In March 2023, international experts convened for a CF Therapeutic Development Research Workshop to discuss strategies across clinical trial networks that support the continued advancement of new therapies and partnerships needed to envision and execute studies relevant to research priorities across the world-wide CF community. The aim of this perspective is to expand on the key messages from this workshop (Table 1) and in particular, provide new CF clinical trial roadmaps that must now deviate from established and familiar precedent.

Table 1.

Panel: Key Messages from the Global Scientific Community Focused on Strategies to Support the CF Therapeutic Pipeline

  • The number and breadth of therapeutic trials with development efforts focused on the limited population of individuals with CF ineligible for, or intolerant of or non-responsive to, CFTR modulators is extensive and successful completion of multiple clinical development programs will depend on
    • Increasing the number of participants willing and able to participate in therapeutic trials through community engagement, education, and equitable methodology and infrastructure for communication of trial opportunities,
    • Increased prioritization of therapies as they enter and progress through the therapeutic pipeline with global alignment across CF clinical trial networks, balancing the communities needs with the need to support the interests of multiple engaged sponsors pursuing therapeutic indications in CF, and
    • Innovative trial designs that streamline clinical development programs including maximizing the use of external control and natural history data.

  • Efforts to expand therapeutic development to individuals residing in low- and middle- income countries (LMICs), many of whom are disproportionately affected by lack of access or eligibility for CFTR modulators due to a higher prevalence of non-F508del mutations, is critically contingent on strategies and advocacy to ensure equitable access to therapies that achieve regulatory approval. Investment in strategies to ensure comparable diagnosis, standards of care and outcomes in these countries will be essential to facilitate expansion of clinical trial development efforts to the global community.

  • Development of new therapies to benefit those without modulators will likely require continued contributions from those on modulators, such as to help establish early phase safety of new therapies, despite new challenges gauging interest in trial participation and assessing clinical efficacy signals in a population benefitting from highly effective modulators.

  • Advancement of alternative clinical outcomes to establish the clinical efficacy of a new therapeutic agent will be needed particularly when including the population of those with CF on highly effective CFTR modulators with more mild and stable pulmonary disease.

  • Successful clinical development of new symptomatic therapies may be enabled through supporting proposed indications and trials which combine populations from multiple diseases that share key features with those of the CF population.

  • There remains an important need for investigator-initiated studies to address research questions that will not be investigated by industry-sponsored trials.

  • The complexity of evaluating research questions that align with the priorities of the CF community amidst a dynamic and incompletely characterized population with changing disease manifestations in response to highly effective CFTR modulators highlights the need for increased global partnership.
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Advancing a Therapeutic Pipeline for the Modulator-Ineligible Population with CF

The demand for clinical trials to advance therapies for those ineligible, intolerant, or non-responsive to CFTR modulators has never been greater and is paralleled by a growing sponsor-driven therapeutic pipeline focused on this population. In order to advance multiple therapeutic options, clinical trial strategies must consider the entire pipeline , as what is optimal for a single sponsor’s development program may not be optimal for the success of the broader pipeline. Figure 1 provides a schematic of the many types of trials currently or soon to be available, particularly for those who are ineligible for CFTR modulators. These include therapeutic trials for variant-specific NABTs, such as antisense oligonucleotides (ASOs) aimed at targeting challenging splice and nonsense variants present in approximately one-third of the modulator ineligible population, and variant-agnostic NABTs inclusive of inhaled CFTR mRNA and viral vector based CFTR gene delivery therapies(20, 21). In parallel, symptomatic therapy trials are moving forward across multiple mechanisms of action. Development of these symptomatic therapies may be pursued exclusively in those without modulator access, across the entire CF population, or in some cases, with indications not specific to CF such as bronchiectasis and non-tuberculous mycobacterium (NTM). In most cases, eligibility criteria for CF symptomatic therapy trials (e.g., capped percent predicted forced expiratory volume in one second [ppFEV1] <90%, ability to produce sputum, bacterial detection and exacerbation history) will more frequently be met by those not benefitting from highly effective CFTR modulators. The breadth and depth of the clinical trial pipeline in relation to the small size of the patient population for which development will be pursued is a new, but not unsurmountable challenge as long as openness exists to pursue prioritized, innovative, and resourceful approaches throughout clinical development as discussed further below. Engagement of key stakeholders including the CF community, regulators, sponsors, and research teams will be needed early and often as programs develop.

Figure 1. Overview of current and near-term trial options for pwCF ineligible for CFTR modulators.

Figure 1.

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As a case example for the regional challenges of population size to fuel the trial pipeline, in the 2021 U.S. CF Foundation Patient Registry there were only 1100 of 1613 adults with CF currently genetically ineligible for modulators and who would meet initial eligibility for early phase trials (age ≥ 18 years and with ppFEV1 ≥40% or greater and not post lung transplant). Accessibility and willingness to participate in a clinical trial is a critical factor when considering feasible trial sizes that can be successfully enrolled contemporaneously across a full pipeline, and less than 50% of these 1100 have prior documented experience in a research study and a subset of these (less than 25% overall) in a recent clinical trial (2015 – 2022). The unique perspectives of individuals identifying as BIPOC and/or of Hispanic ethnicity must also contribute to inclusive trial recruitment strategies across the entire CF population since a disproportionate number (approximately 40%) of pwCF within minoritized populations are genetically ineligible for CFTR modulators(26, 29). There are many potential paths (arrows) to re-enter the pipeline after initial trial participation with several unknowns (represented by “?”) regarding the willingness and eligibility of participants to enroll in a clinical trial after completion of a prior trial, particularly in the setting of NABTs. Trial sponsors may be hesitant to enroll subjects who have previously participated in a NABT trial since this history could confound safety monitoring and there may be the potential to develop an immune response from exposure to a prior genetic therapy that could limit potential benefit of future genetic therapies(15). Most genetic therapy trials will require long term safety follow-up studies, including up to 15 years duration for gene editing therapies(82, 83). It will be essential to enable co-enrollment in several clinical trials during this time despite potential complications with attributing safety events.

Pipeline Prioritization and Community Engagement to Support the Parallel Advancement of Multiple Therapies with Limited Trial Participants

The current CF therapeutic development landscape which pairs a robust pipeline of new therapies with a more limited population of trial participants, particularly in pwCF ineligible for CFTR modulators, supports a greater need for prioritizing which therapies should enter and progress through the pipeline. It is recognized however that perspectives on prioritization will differ across the various stakeholders in the CF community, including pwCF, clinical care providers, research teams, sponsors, and clinical trial networks. CF clinical trial networks across the globe, including the CF Foundation’s (CFF) Therapeutics Development Network (CFF TDN; https://www.cff.org/researchers/therapeutics-development-network), the European Cystic Fibrosis Society (ECFS) Clinical Trials Network (CTN; https://www.ecfs.eu/ctn), and the Cystic Fibrosis Canada Accelerating Clinical Trials (CF CanACT; https://www.cysticfibrosis.ca/our-programs/clinical-trials-network), have established a unified scientific review process which enables network-specific prioritization in response to the growing pipeline (Figure 2). Key goals of prioritization processes implemented by clinical trial networks are (1) to serve as a guide for clinical sites to select studies when resource or trial participant capacity is limited, and (2) ensure the entry and progression of only those trials with sufficient preliminary data and scientific rationale to suggest a prospect for benefit with acceptable risk, combined with high potential for successful completion. It is essential that any prioritization approach best values the contributions of individual trial participants and is transparent to both industry partners and the CF community to the extent that this process directly influences the trial pipeline. Ultimately, prioritization must be preceded by extensive collaboration with sponsors that includes both researchers and CF community input to support the creation of feasible, scientifically meaningful trial protocols that offer the best potential for success.

Figure 2.

Figure 2.

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The CF Global Trial Network Scientific Review Process provides a streamlined mechanism to enable joint scientific review and prioritization of the CF therapeutic pipeline. Clinical trial networks, including the CFF TDN, ECFS CTN, and the CF CanACT, participate in a unified scientific review of the sponsor protocol and then independently assess the protocol’s priority within their respective network. Following independent priority review, an internal discussion among Network leadership occurs, after which a joint communication is sent to the Sponsor outlining the priority score of each network. CFF= Cystic Fibrosis Foundation; TDN= Therapeutics Development Network; ECFS= European CF Society; CTN= Clinical Trials Network; CanACT= Canada Accelerating Clinical Trials.

Prioritization alone will be insufficient to move the current pipeline forward. As indicated in Figure 1, increased engagement of the CF community in research trials, particularly among the population ineligible for CFTR modulators, will be essential to increase the pool of pwCF willing and able to participate in a clinical trial. Global disparities in modulator eligibility necessitate consideration for expanding trial opportunities and existing research infrastructure in regions with a predominance of individuals with mutations ineligible for modulators. Advocacy is necessary to expand therapeutic development and clinical trials to individuals residing in low- and middle- income countries (LMICs), many of whom are disproportionately affected by lack of access or eligibility for CFTR modulators or have yet to be diagnosed(22), to increase development opportunities, enable parallel progression of multiple therapeutic programs, and bring innovative therapies to pwCF living in these countries. Important caveats include the need for comparability of trial populations in terms of consistency in standard of care, standardization of protocol execution, and the stipulation that inclusion of persons with CF from LMICs in clinical trials must also include plans for future equitable access to therapies which achieve regulatory approval(23, 24). Achieving equitable access to new therapies is easily a predominant factor in the critical pathway for LMICs to achieve inclusion in future therapeutic development, and the value of community advocacy to achieve health equity cannot be understated. The CF drug development space must consider models achieved across other rare disease settings, such as the use of voluntary licenses to generic drug companies(24).

It is notable that less than half of the Unites States (U.S.) CF population ineligible for CFTR modulators have participated in any research study in the last several years, and significantly fewer in a therapeutic clinical trial (Figure 1). Because a disproportionate number of pwCF ineligible for CFTR modulators are BIPOC and/or Hispanic (24% and 25% recorded as non-white and Hispanic in the 2021 U.S. CF patient registry [CFFPR], respectively) as compared to the general CF population (9% and 10%, respectively), focused efforts toward research inclusion must adopt engagement strategies that recognize the impact of historical and on-going racism(16, 25). Inclusion of minoritized pwCF in clinical trials has been historically poor as in other disease settings and will require thoughtful and intentional behavior changes from research teams to alter this trend. Such actions must acknowledge the role of systemic racism throughout the broader healthcare system as a key factor that has led to decreased efforts by research teams to enroll BIPOC individuals and that has fostered mistrust and disengagement in research in those from marginalized groups (26, 27). The efforts of research teams to bridge these gaps will need to be substantial, beginning with trust building and open dialogue and supported by educational investments for pwCF, clinical and research teams (28, 29). Increased representation to ensure greater racial and ethnic diversity in trial leadership and research teams, possibly including engagement beyond existing trial networks, will also be essential to bridge the gap enabling trial designs that will be feasible and inclusive of individuals who have been disproportionately excluded in research.

Key Trial Design Considerations to Enable the Advancement of Multiple NABTs towards Late Phase Development

Clinical trials for NABTs will face challenges balancing speed and feasibility with the need to acquire sufficient data and evidence to meet the aims of each stage of clinical development. Development efforts for new therapies which are initially focused on the CF population ineligible for, and in some cases intolerant of or non-responsive to CFTR modulators promotes evaluation of safety and efficacy in those most urgently in need of these therapies, and for whom the greatest prospect for benefit exists relative to potential risks. Admittedly, the magnitude of benefit for these therapies may or may not reach that observed with highly effective modulators, and this remains a point for education and management of expectations across the community. To speed clinical development of these therapies, thoughtful consideration of expanding the development population may be necessary while also balancing the potential bias of the understudied and incompletely understood population of those under- or-unresponsive to modulator therapy (30, 31). Inclusion of modulator-treated individuals, particularly those with lack of perceived benefit, could play a role in providing early phase safety assessments, for instance in efficiently identifying target dose ranges prior to exhausting limited trial participants from the modulator ineligible population. Defining modulator responsiveness remains a complex clinical question however, and prospect of future benefit in comparison or addition to modulator therapy remains unclear. Including modulator-treated CF participants is clearly contingent on the willingness of participants on CFTR modulators to participate in future clinical trials(32), and transparent disclosure of the risks inherent to different NABT strategies which may be greater than those observed with modulators. Prior to approval of the modulator elexacaftor/tezacaftor/ivacaftor (ETI), modulator-treated pwCF were eligible and participated in an early phase trial of an inhaled lipid nanoparticle CFTR mRNA therapy without need for modulator discontinuation in order to investigate the additive effects of such a therapy(33). Scientifically, the partial restoration of CFTR function achieved with ETI (~40 to 50%) (34) may justify inclusion of modulator-treated patients. However, whether it is ethical and appropriate to include modulator-treated subjects in early phase trials of future NABT strategies is currently unresolved and requires further discussion. It would be difficult to envision inclusion of modulator-treated participants in trials requiring withdrawal of modulator therapy which carries independent safety concerns(35, 36), except in the instance for which comparable or greater benefit is expected from an alternative NABT approach with no increased safety concerns. With regards to development population expansion, regulatory guidance currently precludes investigation of new therapies in pediatric cohorts until prospect for benefit has been established in adults(37), but revisiting this guidance to enable expansion of a development population to adolescents, particularly for later phase efficacy trials may be warranted in this setting. Prior Phase 2 clinical trials of an adeno-associated virus (AAV)-based CFTR genetic therapy and a non-viral CFTR gene therapy have included adolescent CF trial participants 12 and older(38, 39). Expansion of other inclusion criteria (e.g. lower ppFEV1 thresholds ) may be another pathway for increasing eligibility but must be balanced by the potential for increased adverse events with unclear treatment attribution. It will be critical to seek the input of the CF community when evaluating the potential for expanding the eligibility of the population for development of a new CF therapy, particularly when this approach will have a more direct impact on speed and feasibility.

A dynamic guidance strategy will be needed to optimize ‘go/no go’ decisions for the progression of NABTs from early to late phase development. It will be imperative to prioritize ‘need to know’ versus ‘nice to know’ outcomes in early phases to feasibly progress multiple trials through the pipeline without taxing limited trial participant resources(40). Premature expansion of early phase clinical trials to better assess clinical efficacy in the absence of clear biologic efficacy data may be counterproductive to pipeline optimization and ensuring completion of multiple early phase programs. At the same time however, mechanisms must be in place to enable agile expansion of early phase trials to begin assessing clinical efficacy when meaningful biological efficacy has arisen, for instance to include additional participants at a given dose cohort. The need for Data Safety Monitoring Boards (DSMBs) and specialized scientific review committees (SRCs) with genetic therapy expertise to support critical interim and ad hoc reviews for safety and biologic efficacy, respectively, will grow as the pipeline of early phase NABT trials expands. Scientific experts including the U.S. CF Foundation’s Genetic Therapy Working Group (GTWG) have established guidance to serve as an initial roadmap spanning pre-clinical to early phase clinical trial milestones indicative of supporting pipeline progression(41). The scientific review and prioritization of protocols provided across CF global clinical trial networks (Figure 2), and safety oversight by DSMBs including the CFF DSMB with over two decades of experience, provides the essential vantage point to support the conduct of multiple, right-sized trials with appropriate safety surveillance.

Concerted efforts must begin now to plan for multiple late phase NABT trials progressing in parallel. It is likely that the primary assessments of clinical efficacy will rely on familiar endpoints including changes in ppFEV1 and patient reported outcome measures (PROMs) including the CFQ-R (respiratory domain, RD), which require smaller sized trials than those needed to evaluate pulmonary exacerbations(18). For NABTs, it is reasonable to assume a 5% benchmark for average effect in ppFEV1 to ensure sufficient benefit that will outweigh increased risks that may be associated with these therapies. While the average trial size to detect a 5% difference in ppFEV1 in a placebo-controlled trial is reasonably small and not more than about 100 participants under multiple scenarios (Table 2), rapidly recruiting a trial of this size in the modulator ineligible population will be challenging. Considerations include multiple competing therapeutic trials in the pipeline combined with the potential for a diminishing eligible patient population over time resulting from participation in a prior NABT trial (Figure 1). Innovative trial designs to streamline development efforts now include the increased use of master protocols and platform trials which enable the parallel evaluation of multiple therapies in a single protocol, with features that include use of a shared placebo group(42). Adaptive platform trials have the potential to significantly reduce sample size requirements across the trial pipeline by standardizing interim futility evaluations that could lead to early termination of therapies with low likelihood of demonstrating efficacy, thereby reallocating future participant resources to other trial arms(43). Although the use of master protocols and platform trials with the above features are gaining traction in multiple disease settings including oncology, infectious disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (44), these trial approaches represent unique challenges with respect to both achieving sponsor contractual consensus and, more specifically for the pipeline of NABTs, a one size fits all approach for trial design. However, a key attribute of master protocols is the use of a shared placebo or control group which minimizes overall sample size burden. In the setting of NABTs and rare diseases, the Food and Drug Administration (FDA) recently approved the AAV9 virus-based gene therapy Zolgensma® (onasemnogene abeparvovec-xioi) for spinal muscular atrophy based on small open label, single arm trials with reference to comparative clinical endpoint data from natural history data(45). The use of external controls is considered most appropriate for settings in which it is not feasible to conduct traditional placebo-controlled trials and when the treatment effects are expected to be substantial, such as for genetic therapies in which the benefits will likely need to significantly outweigh the associated risks to be viable candidates for development. The use of external controls is a likely pathway for future CF clinical trials to establish evidence of efficacy, and eventually safety, of NABTs(46, 47). Preliminary proof of concept work has begun in CF to establish the statistical validity of the use of external controls as a comparator in lieu of a concurrent placebo group(48). A paradigm shift in CF clinical trial design will be motivated by the unprecedented scenario poised by the full NABT pipeline in relation to small development population size, and as described above, a likely need to rely less heavily on traditional, large placebo-controlled trials(49). A critical window of opportunity now exists to build the infrastructure to support more innovative trial design roadmaps being used in other rare disease settings, including those reliant on external controls. The quality, representation, and comparability of control data in the context of standard of care must be evaluated however, in addition to the establishment of secure data sharing methods to enable patient-level data accessibility.

Table 2.

(a) Sample size calculations for a randomized, controlled trial and change in ppFEV1. Note that standard deviation (SD) estimates for the change in ppFEV1 are generally stable over time so these estimates apply independent of duration of the trial. Careful consideration will be necessary to inform the baseline lung function eligibility criteria for a given trial, balancing enrichment for a population that may have more perceived room for improvement with the need to enable a more expansive development population (e.g., by not having an upper limit of 90% for ppFEV1 as an eligibility criteria). (b) Sample size calculations for a one-year randomized, placebo-controlled trial and reduction in rate of CF pulmonary exacerbations (PEx). PEx rate of 1.0/year reflects rates in the absence of CFTR modulators and 0.3 reflects expect rates in the presence of CFTR modulators. Sample size estimates based on ppFEV1 variability and PEx rates from(9, 10).

(a)
Total Sample Size – ppFEV1 Endpoint (assuming one-sided 0.025 α)
80% Power 90% Power
Treatment Effect
(Active – Control)		 SD=6 SD=8 SD=6 SD=8
3% 126 224 170 300
4% 72 126 96 170
5% 46 82 62 108
7% 24 42 32 56
10% 12 22 16 28
(b)
Total Sample Size – PEx Endpoint (assuming one-sided 0.025 α)
80% Power 90% Power
Treatment Effect
(Rate Ratio)		 Placebo Rate
0.3/yr		 Placebo Rate
1.0/year		 Placebo Rate
0.3/yr		 Placebo Rate
1.0/year
0.5 316 104 426 140
0.55 406 136 548 182
0.6 536 178 722 240
0.65 728 242 978 326
0.7 1028 344 1380 460
0.75 1532 514 2054 688
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CF registries have been used to support multiple post-marketing regulatory requirements(50), but now may need to be mobilized to support the drug applications themselves. Further, carefully designed prospective observational studies in the modulator ineligible cohort, including assessment of novel endpoints, have the potential to augment registry data for this same purpose, providing research quality contemporary control data (51). Community engagement to inform appropriate consent which enables data sharing across key stakeholders, including regulators and sponsors, will be necessary to realize use of these data for therapeutic development purposes.

New Approaches to Advance the Development of Symptomatic Therapies across the CF Population

While therapies that have the potential to address the underlying defects of CF are of high priority, symptomatic therapies may provide more immediate benefit with less long-term safety risks. The clinical development of symptomatic therapies is undergoing its own paradigm shift to ensure the successful evaluation of therapies across multiple classes of action that have the potential to improve outcomes in those with persistent need, regardless of CFTR modulator use. Importantly, new approaches for defining optimal clinical trial populations and outcome measures that can work together to achieve regulatory thresholds for establishing substantial clinical efficacy will be needed. In terms of defining an optimal development population, speed and feasibility associated with pursuing development in broader patient populations must be balanced with identifying a sub-population with the greatest likelihood of demonstrating clinical benefit. There is compelling rationalization to pursue development efforts in populations without access to modulators who have significant prospect for benefit, contingent on regional commitments for future access. Similarly, while the benefits of developing symptomatic therapies in modulator ineligible or intolerant populations includes potential for greater treatment effects as compared to those on modulators, the potential for clinically important, albeit likely more modest, benefit in those on modulators must also be considered. The pursuit of indications that will apply to the broadest CF population will ensure the attainment of therapeutic benefit for all with CF while significantly increasing the size of the enrollment population, thereby reducing development barriers. However, to support a more heterogenous patient population for clinical development, it will require a reframing of the level of evidence needed for establishment of “substantial” efficacy.

Identifying those on modulators who are candidates for future symptomatic therapy trials is not only complicated by changing care patterns and willingness of pwCF to enroll in future trials(32), but also uncertainty with how modulator-treated lung disease will progress and potentially respond to novel symptomatic therapies as normalization has not been fully achieved and residual disease persists . Ongoing international studies aim to characterize long term clinical outcomes and inform distinct phenotypes in those on highly effective modulators, including PROMISE(52–54), BEGIN (NCT04509050), RECOVER (NCT04602468), and Modulate-CF (NCT04732910)(34, 55), and will be critical to enrich future clinical trials of additive symptomatic therapies(15). For example, those with residual mucus plugging after ETI may be an ideal population to enrich trials for future muco-active therapies. Another approach to address therapeutic development needs could include inclusion of CF populations in trials for -non-CF populations with similar disease characteristics, including non-CF bronchiectasis (NCFB). Further evaluation of the clinical comparability of these populations will be needed through further study. Historically, some symptomatic therapies approved for CF have not been efficacious in NCFB populations including dornase alfa, nebulized aztreonam, and inhaled mannitol(56, 57). In contrast, perceived benefit and widespread use of azithromycin and hypertonic saline has transitioned beyond CF care(58). Through careful specification of eligibility criteria for trial participants in the CF and NCFB populations, with potential to enrich for criteria such as exacerbation history as in the phase 3 trial for brensocatib (NCT04594369),and matching their clinical characteristics to the drug mechanism under investigation, it is possible this approach may be successful. As shown in Table 3, workshop participants felt that patient selection based upon certain phenotypic features (particularly ongoing sputum production and need for antibiotic interventions) and exclusion of certain underlying causes of NCFB (e.g., COPD, aspiration, traction) could lead to greater uniformity in treatment responses between groups, supporting a combined trial approach. Combining populations for therapeutic development is not new to CF, which has benefitted from the broader indication development of inhaled amikacin for Mycobacterium avium complex (MAC) lung disease(59) and more recently through the ongoing FORMaT platform trial (NCT04310930) enrolling both CF and non-CF participants to evaluate multiple therapeutic options for the treatment of Mycobacterium abscessus (MABS).

Table 3. Considerations for combining CF and NCFB disease populations for CF therapeutic development.

Summarized responses from workshop attendees surveyed regarding considerations when combining CF and NCFB populations for clinical trials of symptomatic therapies. Table indicates rank order of preferences in which more than 50% of respondents felt that consideration is important. NCFB=non-CF bronchiectasis; NTM=non-tuberculous mycobacterium; IV= intravenous; FEV1=forced expiratory volume in one second.

Hydrators/Muco-active Therapies Anti-inflammatories Inhaled antimicrobials NTM therapies
Target Characteristics within the CF population

  1. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  2. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  3. Requires IV antibiotics at least yearly

  1. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  2. Requires IV antibiotics at least yearly

  3. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  1. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  2. Requires IV antibiotics at least yearly

  3. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  1. Persistent NTM infection
Target Characteristics in the NCFB population

  1. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  2. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  3. Multi-lobe involvement by CT scan or x-ray

  4. Requires IV antibiotics at least yearly

  1. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  2. Requires IV antibiotics at least yearly

  3. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  1. Produces mucopurulent sputum on a regular basis (at least 3X/week)

  2. Requires acute antibiotic interventions (oral, inhaled or IV) at least twice yearly

  3. Requires IV antibiotics at least yearly

  4. Continues to perform airway clearance and use other inhaled maintenance therapies daily

  1. Persistent NTM infection
Recommended Sub-populations to Exclude in NCFB population

  1. Traction bronchiectasis in setting of fibrosis

  2. Bronchiectasis associated with chronic aspiration

  3. Bronchiectasis associated with active mycobacterial disease

  4. Bronchiectasis due to COPD

  5. Bronchiectasis due to immune deficiency or connective tissue disease

  1. Traction bronchiectasis in setting of fibrosis

  2. Bronchiectasis associated with chronic aspiration

  3. Bronchiectasis associated with active mycobacterial disease

  4. Bronchiectasis due to COPD

  5. Bronchiectasis due to immune deficiency or connective tissue disease

  1. Traction bronchiectasis in setting of fibrosis

  2. Bronchiectasis associated with chronic aspiration

  3. Bronchiectasis associated with active mycobacterial disease

  4. Bronchiectasis due to COPD

  5. Bronchiectasis due to immune deficiency or connective tissue disease

  1. Traction bronchiectasis in setting of fibrosis
Novel/Unique and Common Endpoints to Consider

  1. Lung clearance index

  2. Mucociliary clearance

  3. FEV1

  4. HRCT/imaging

  5. Sputum analytes (e.g., rheology, etc)

  1. Mucociliary clearance

  2. Lung clearance index

  3. Pulmonary exacerbation rate

  4. FEV1

  5. Sputum analytes (e.g., rheology, etc)

  1. Mucociliary clearance

  2. Sputum analytes (e.g., rheology, etc)

  3. Pulmonary exacerbation rate

  4. FEV1

  5. Lung clearance index

  6. HRCT/imaging

  1. Sputum microbiology

  2. HRCT/imaging

  3. Research biomarkers (e.g., urine tests)
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Equally as important as defining the optimal development population for a new symptomatic therapy is alignment in clinical efficacy endpoints and thresholds for efficacy that will meet the needs of diverse regulatory bodies. An example where a priori harmonization was achieved across regulatory agencies for a phase 3 development program is the RESPIRE phase 3 trials of ciprofloxacin dry powder for inhalation in non-CF bronchiectasis(60). Importantly, the current clinical trial landscape cannot support customized clinical trials of the same therapy in different regions to meet the needs of each regulatory body, but rather it must support harmonized clinical trials that will meet the needs of multiple regulators across the globe(13). Sponsor-agnostic regulatory interaction with key stakeholders will be necessary to envision a new, globally re-aligned architecture for regulatory packages that are sufficient and feasible for demonstration of clinical efficacy, transparently deviating from precedent established prior to the establishment of CFTR modulators. Precedent for clinical efficacy has been disrupted by multiple factors. First is the reduced frequency and potential for treatment benefit in pulmonary exacerbations, defined by currently accepted regulatory definitions(10, 61), in pwCF using highly effective modulators. This change will affect both the relevance and feasibility of using exacerbations as an outcome in future clinical trials (Table 2). Most specifically, this change may profoundly impact trials of anti-inflammatories for which exacerbation reduction was the greatest benefit in CF and NCFB (e.g., macrolides)(62). Further, ceiling effects with validated PROMs, as observed with the CRISS and CFQ-R RD in individuals using highly effective modulators, will negatively affect the ability of these outcomes to capture changes in respiratory symptoms and quality of life in response to a new therapy(54, 62). Most recently, >50% of participants in the SIMPLIFY clinical trial, which enrolled participants using ETI treatment for at least 90 days, had a maximal CFQ-R-RD score of 100(63). Lastly, demonstrating a substantial increase in lung function in those using highly effective modulators, for which the median ppFEV1 in adults in the U.S. CFFPR is now 79.5%(64), will be much more difficult.

Primary endpoints for late phase clinical trials using clinical outcomes reflecting how patients “feel, function, and survive” will provide the most streamlined path towards broad regulatory approval. Historically these have included pulmonary exacerbations, PROMs(65), and ppFEV1 as an accepted surrogate endpoint for survival(66). Therapies with more modest benefits in ppFEV1, for example lumacaftor/ivacaftor, have been more reliant on secondary efficacy endpoints including reductions in pulmonary exacerbations to substantiate clinical efficacy(11, 67). However, as noted above, this strategy is no longer feasible for many CF-specific development programs. The role for PROMs as a primary rather than secondary efficacy endpoint may become more prominent when the effect of a therapy on ppFEV1 is expected to be minimal. However, based on ceiling effects of current PROMs in modulator-treated pwCF, newer “fit for purpose” endpoints capturing clinical benefits from the perspective of pwCF and specific to a clinical development program and a particular context of use and/or indication may become increasingly important to consider in early phase development(68) Gathering appropriate data and gaining regulatory input to validate the use of such an endpoint will be critical before use in later phase development. The level of evidence needed to validate and support use of a new fit for purpose endpoint is unclear and could require data from multiple studies to substantiate. There are ongoing efforts across ECSF-CTN and CF Europe supporting the development of new PROMs across a CF population now benefiting from CFTR modulators including the PRO-CF(69). Additionally, there is an increased need to assess the utility of existing PROs to determine their sensitivity among pwCF to detect clinically meaningful changes in response to a new therapy, including for instance the St. George Respiratory Questionnaire (SGRQ) used for regulatory approvals in asthma and COPD and utilized across trials for non-CF bronchiectasis(70).

With the expectation of a pipeline of therapies with more modest, yet potentially clinically important, effects on pulmonary disease progression in the presence of CFTR modulator therapies, there will be an increased need for other outcomes to substantiate clinical efficacy such as lung clearance index (LCI) and imaging endpoints which may be sensitive to detect effects in the growing population with high lung function but still at risk for progressive lung disease. Without investment in these and other more sensitive markers of pulmonary disease, we risk failing to detect the efficacy of new therapies that may impact longer term disease progression even in the presence of more mild disease. It must be recognized that the path towards establishing new outcomes as surrogate endpoints that could serve as primary evidence for clinical efficacy is complex and dependent on clear evidence of epidemiologic association with established meaningful outcomes of disease progression; such associations must also include definitions of the minimally clinically important differences corresponding with therapeutic-induced changes(40). Minimum clinically meaningful effect sizes are beginning to be defined both for LCI and imaging, with context to both CFTR modulators(71–73) and a symptomatic therapy, hypertonic saline(74–76). There will also be an even greater need to elevate the importance of key secondary endpoints including microbiology and other biomarkers for biologic efficacy to enhance and support primary clinical outcome measures. Thus, it will be critical to build a scientific body of evidence for their use in therapeutic development through continuation of prospective observational and natural history studies and clinical trials that define meaningful clinical change in these outcomes. Regulatory engagement and alignment across global agencies will be needed to promote more flexible, consistent and necessary use of emerging clinical outcomes to adapt to the evolving CF landscape.

Complementing the Therapeutic Pipeline with Trials to Support Priorities of the CF Community

With a growing CF population with divergent therapeutic needs, it becomes even more critical to recognize that not all of these needs will be fulfilled by a sponsor driven drug pipeline. The James Lind Alliance Priority Setting Partnership (JLA PSP) in CF (https://www.jla.nihr.ac.uk/priority-setting-partnerships/cystic-fibrosis/) first established the top 10 CF research priorities in 2017(77), including input from more than 600 pwCF, family members, and care providers and representing more than 30 countries. The top research priority at this time, prior to the approval of ETI, was studying effective ways to simplify treatment burden, and this priority has remained in the top 10 priorities in a recent refresh to reflect the changing CF landscape(78). This priority exemplifies the necessity of complementing a robust therapeutic pipeline with studies to support the continued optimization of care, which paradoxically now includes the exciting potential to reduce or withdraw certain chronic CF therapies most particularly among those benefiting from highly effective CFTR modulators. The SIMPLIFY study recently reported results from two randomized, controlled trials demonstrating that short-term discontinuation of either hypertonic saline or dornase alfa resulted in no clinically meaningful changes in lung function, LCI, or respiratory symptoms(63). The trial design addressed challenges of conducting a non-blinded study with adoption of a 6-week study design with attention to protocol adherence in order to maximize interpretability of study results.(79) The results of two ongoing 12-month studies, a pragmatic clinical trial CF-STORM being conducted in the United Kingdom (EudraCT 2020– 005864–77), and real-world observational study HERO-2 conducted in the U.S. (NCT04798014) will be important to assess the longer-term impact of discontinuation of therapy. As future and perhaps more complex priorities regarding treatment simplification must be addressed, including the optimal timing of initiation of chronic symptomatic therapies in young children established on ETI and the role for chronic anti-pseudomonal therapies, envisioning an internationally partnered strategy to tackle these questions will become even more important.

Collaboration across clinical trial networks to address CF community priorities through investigator-initiated studies can include not only multinational studies but also the conduct of parallel or complementary studies across countries. Globally conducted investigator-initiated studies are complex and require substantial infrastructure and investment(80). Contract research organizations (CROs) with international coordinating experience are likely necessary in this setting and to enable shared data and specimen repositories. Challenges with the execution include the need to satisfy multiple regulatory bodies and ethics committees, contracting and ensuring consistent data sharing and material transfer agreements, creation and alignment of standard processes and operating procedures, supporting multiple languages across all study documents and in data collection, and accounting for differences in standard of care. One major opportunity of such a complex effort is the potential for coordinated data and specimen repositories to drive international research efforts, as evidenced by the recent COVID-19 Antibody Responses in CF (CAR-CF study) which collected blood samples from thousands of people with CF across Europe, Canada, and the U.S. to evaluate SARS-CoV-2 infection (EudraCT Number: 2021-003277-55, NCT05745948)(81). Importantly, efforts to include LMICs in investigator-initiated research efforts is an important gateway to build research experience at both the site and participant level, and a necessary step for future consideration in sponsor driven research.

Summary

Poised with a strong therapeutic pipeline and unwavering commitment to address the rapidly evolving clinical needs of all pwCF, regardless of use of CFTR modulators, there is an urgent need to shift from traditional clinical trial designs built on successful precedent to new roadmaps for clinical development that will balance feasibility with achieving sufficient evidence for establishment of clinical efficacy and safety. Efforts to build research partnerships with LMICs to expand the therapeutic options for every individual with CF is of critical importance. The input of the CF community will be paramount for devising necessary strategies for research inclusion and engagement, defining meaningful new outcomes to aid in the assessment of clinical efficacy, and informing research priorities that extend well beyond the advancement of new therapeutics. Strengthening alignment and partnership to tackle the increasingly complex clinical development landscape is a shared commitment across our collaborative CF trial networks as we continue to advance and optimize care for all pwCF.

Acknowledgments

The authors wish to thank the CF Foundation for funding the workshop and individuals with CF who participate and contribute to clinical research efforts across the globe. It is their dedication and engagement that will be critical to drive the future of CF clinical trials. NMH was supported by National Institutes of Health (NIH) grants P30 DK 089507 and UL1 TR002319. SHD was supported by NIH grant P30 DK065988 and the Cystic Fibrosis Foundation. ETZ was supported by the Cystic Fibrosis Foundation (002884121). MAM has been supported by grants from the German Federal Ministry of Education and Research (82DZL009B1) and the German Research Foundation (CRC 1449 project #431232613). CHG was supported by the National Institutes of Health (NIH) grants P30 DK 089507, UL1 TR000423 and the Cystic Fibrosis Foundation. MWK was supported by National Institutes of Health (NIH) grants P01HL128192 and UL1TR002548, and the Cystic Fibrosis Foundation. DP was supported by the Cystic Fibrosis Foundation (002805121). SMR was supported by the CFF and NIH grants P30DK072482 and UL1TR003096. SCB was supported by the CFF (BELL1480 and BELL19A0) and National Health and Medical Research Council (NHMRC), Australia (APP1102494). JCD is supported through the National Institute for Health and Care Research through the Imperial Biomedical Research Centre, the Brompton Clinical Research Facility and a Senior Investigator Award. Her team receives funding from the CF Trust as part of their Clinical Trials Accelerator Platform.

Role of the Funding Source

The views provided in this perspective represent those of the authors and not the sponsor of the workshop.

Declaration of Interests

GRB reports grants and contracts from Vertex Pharmaceuticals and the CFF. SHD reports contracts from Calithera, CFF, NIH, Vertex Pharmaceuticals, 4D Molecular Therapeutics, Chiesi USA, consulting fees from Polarean, 501 Ventures, Enterprise Therapeutics, Boehringer Ingelheim, fees for advisory boards for Innova Healthcare and Boehringer Ingleheim, travel fees from Enterprise Therapeutics, CFF, and participation on a board for Abbvie. SB reports grants from National Health and Medical Research Council (Australia), Medical Research Futures Fund (Australia), and the CFF, and honorarium from Vertex Pharmaceuticals. JTC reports grants and contracts from CFF, Vertex Pharmaceutics, Eloxx, and 4DMT, and consulting fees from Vertex Phamaceuticals, Insmed, and 4DMT, participation on a DSMB for Abbvie, and serving on advisory boards for CFF, American Thoracic Society (ATS), Journal of CF, Lancet Resiratory, and Emily’s Entourage. FR reports grants from Vertex Phamaceuticals and consulting fees from Vertex Phamaceuticals and Calithera. LMQ reports no conflicts. IF reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, and Vertex Pharmaceuticals, honorarium from Vertex Pharmaceuticals, participation on boards for AbbVie, Boehringer Ingelheim, Kither Biotech, and Vertex Pharmaceuticals, and support to their institution from the European Cystic Fibrosis Society. RJ reports grants from CFF, consulting fees from Boehringer Ingelheim and Recode Therapeutics, honorarium from Vertex Pharmaceuticals, and travel support from CFF. DP reports grants from the CFF, NIH, and Aclaris Pharmaceuticals, travel support from CFF, and board participation for Vertex Pharmaceuticals and Translate Bio. JD reports grants from UK Cystic Fibrosis Trust, CFF, CF Ireland, EPSRC, and NIHR, honoraria from Vertex Pharmaceuticals, Boehringer-Ingelheim, Eloxx, Algipharma, Abbvie, Arcturus, Enterprise Therapeutics, Recode, LifeArc, Genentech, and Tavanta, and serves as deputy editor for the Journal of CF. MAM reports grants from the German Research Foundation, the German Ministry for Education and Research, the German Innovation Fund, Vertex Pharmaceuticals, and consulting fees from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense, and Vertex Pharmaceuticals, and honoraria from Vertex Pharmaceuticals, travel support from Boehringer Ingelheim and Vertex Pharmaceuticals, and participation in boards for Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, and Vertex Pharmaceuticals. NK reports no disclosures. BQ reports grants from CFF, CF Canada, Vertex Pharmaceuticals, and Gilead Sciences, honoraria from Vertex Pharmaceuticals, travel support from CFF. EM reports grants from Vertex Pharmaceuticals, honoraria from Vertex Phamaceuticals, travel support from Menarini, board participation for CF Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. DD reports grants from Chiesi Farmaceutici, CFF, consulting fees from Vertex and Insmed, honoraria from Chiesi and Gilead, travel support from European CF Society and CFF, board participation for Momab and CSL Behring, and support for the European CF Society as director of the Clinical Trials Network (CTN). MJ has no reported disclosures. JHR reports grants from CF Canada, CFF, Vertex Phamaceuticals, Canada Foundation for Innovation, and Canadian Institutes of Health Research, consulting fees from Sanofi, and travel support from Vertex Pharmaceuticals. KP reports no disclosures. EZ reports grants from NIH, Vertex Pharmaceuticals, CFF, consulting fees from CFF, travel support from CFF, Vertex Pharmaceuticals, European CF Society, participation onboards for CFF and Vertex Pharmaceuticals. CHG reports grants and contracts from CFF, NIH, and the Food and Drug Administration, consulting fees from Enterprise Therapeutics, honoraria from Gilead Sciences and Vertex Pharmaceuticals, travel support from Vertex Pharmaceuticals and Enterprise Therapeutics, board participation for Novartis, stock options for Air Therapeutics, and leadership roles for the ATS. JPC reports employment at the CFF. NMH reports grants from CFF, NIH, and FDA, consulting fees from Enterprise Therapeutics, and DSMB membership for the NIH. SMR reports grant funding from Vertex Pharmaceuticals, Galapagos/Abbvie, Eloxx, Synspira, Translate Bio, Arcturus, Astra-Zenica, and Ionis, and consulting income from Vertex Pharmaceuticals, Synspira, Renovion, Cystetic Medicines, and Arcturus; all personal conflicts to SMR were resolved or ended in 2022 or before. MWK reports grants from NIH and CFF, consulting fees from AbbVie, AzurRx, Cystetic Medicines, EnBiotix, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Mylan, PBM BC Holdings, board participation for AbbVie, CFF, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Sionna, and Vertex, and committee membership for CFF.

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