Abstract
Background
Methods
Results
Conclusions
1. Introduction, background and definitions
1.1 Cystic fibrosis and the cystic fibrosis transmembrane conductance regulator
1.2 Symptom-based therapy and CFTR-based therapy with CFTR modulators
- Rowe S.M.
- Heltshe S.L.
- Gonska T.
- Donaldson S.H.
- Borowitz D.
- Gelfond D.
- et al.
1.3 CFTR modulators
1.4 Theratype definition
2. Potential applications of theratyping to research and care
2.1 Use of patient-derived model systems for drug discovery/early development
2.2 Evaluation of modulator efficacy on rare variants not captured in clinical trials or traditional drug development
2.3 Selecting subjects/enrichment for clinical trials
2.4 Optimizing modulator selection (‘personalized medicine’) when choices exist
2.5 Use of theratyping for regulatory purposes
2.6 Examining the benefit of CFTR modulators in individuals with CFTR-related disorders
3. Preclinical model systems to test CFTR therapies
Model system | Source | Level of advancement | Most common uses |
---|---|---|---|
Transient CFTR expression in heterologous cell lines | Established cell lines | High | Characterize CFTR variants and CFTR biology |
Stable CFTR transduction in cell lines | Established cell lines | High | HTS screening, evaluate common and rare CFTR variants in standardized system |
Human bronchial airway epithelial (HBE) planar cultures | Lung explant | High | Validation of CFTR modulation in primary human cells, assess downstream effects (e.g. mucocilary clearance, airway surface liquid height) |
Rectal organoids | Rectal biopsy | Moderate | Validation of CFTR modulation in primary human cells, and patient-specific responses to modulators (fluid secretion) |
Duodenal enteroids | Duodenal biopsy | Low | Similar to rectal organoids above |
HBE planar cultures from brush | Bronchial brush | Low | Similar to HBEs from lung explant, and patient-specific responses to modulators (ion transport) |
Human nasal epithelial (HNE) planar cultures from brush | Nasal brush | Low | Similar to HBEs from lung explant, and patient-specific responses to modulators (ion transport) |
HNE spheres | Nasal brush | Low | Similar to HBEs from lung explant, and patient-specific responses to modulators (fluid transport) |
Induced pluripotent stem cells (iPSCs) | Blood | Low | Differentiation into CFTR-expressing epithelial cells and tissues |
3.1 Transient CFTR expression in cell lines (e.g. lipid/DNA, electroporation, viral transduction)
3.2 Stable CFTR transduction in cell lines (e.g. FRT, HEK, 3T3, CFBE41o-, MDCK cells)
3.3 Primary HBE planar cultures grown at air-liquid interface (from explant lung tissue obtained at the time of lung transplantation)
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A. 2011 Nov15;108(46):18843–8. [Epub 2011 Oct 5. PubMed PMID:21976485; PubMed Central PMCID: PMC3219147].
3.4 Gastrointestinal organoids and enteroids
- Sato T.
- Vries R.G.
- Snippert H.J.
- van de Wetering M.
- Barker N.
- Stange D.E.
- et al.
- Sato T.
- Stange D.E.
- Ferrante M.
- Vries R.G.
- Van Es J.H.
- Van den Brink S.
- et al.
- Sato T.
- Vries R.G.
- Snippert H.J.
- van de Wetering M.
- Barker N.
- Stange D.E.
- et al.
- Sato T.
- Stange D.E.
- Ferrante M.
- Vries R.G.
- Van Es J.H.
- Van den Brink S.
- et al.
3.5 HNE planar cultures grown at air-liquid interface (primary nasal cells obtained from CF individuals by nasal brushings)
- Pranke I.M.
- Hatton A.
- Simonin J.
- Jais J.P.
- Le Pimpec-Barthes F.
- Carsin A.
- et al.
- Pranke I.M.
- Hatton A.
- Simonin J.
- Jais J.P.
- Le Pimpec-Barthes F.
- Carsin A.
- et al.
3.6 HNE cell spheres
3.7 Studies of CF-affected epithelia derived from iPSCs
- McCauley K.B.
- Hawkins F.
- Serra M.
- Thomas D.C.
- Jacob A.
- Kotton D.N.
- Firth A.L.
- Dargitz C.T.
- Qualls S.J.
- Menon T.
- Wright R.
- Singer O.
- et al.
- Konishi S.
- Gotoh S.
- Tateishi K.
- Yamamoto Y.
- Korogi Y.
- Nagasaki T.
- et al.
3.8 Comparing model systems
Model system | Dynamic range | Sensitivity/specificity | PPV/NPV b PPV and NPV have not been systematically assessed, as unresponsive variants in preclinical models have generally not been studied in clinical trials. However, some populations with CFTR variants unresponsive or less responsive to specific CFTR modulators in preclinical model systems have been examined in clinical trials (e.g. ivacaftor monotherapy in F508del homozygous CF adults, ivacaftor/lumacaftor in F508del/minimal function CF adults [23,24]). These studies have generally confirmed that variants unresponsive/poorly responsive to modulation in vitro are poorly responsive in vivo. However, some variants studied in transient or stable expression systems have not aligned with clinical findings (e.g. G970R CFTR variant response to ivacaftor in stably transduced FRT cells compared with results from clinical trials [6,17]. Of note, VX770 studies of this variant in rectal organoids did correlate with absent/low clinical response [39]). | Precision/accuracy | Portability |
---|---|---|---|---|---|
Transient CFTR expression in heterologous cell lines | Large | Mod to high | Moderate | High | High |
Stable CFTR transduction in cell lines | Large | Mod to high | Mod to High | High | High |
HBE planar cultures (explants) | Moderate | High | High | High | Moderate |
Rectal organoids | Large | Sens. high Spec. unk | Mod to High | Moderate | Low |
Duodenal enteroids | Moderate | Unknown | Unknown | Unknown | Low |
HNE planar cultures (brush) | Small | Moderate | Unknown | Unknown | Moderate |
HNE spheres | Small | Moderate | Unknown | Unknown | Moderate |
iPSCs | Unknown | Unknown | Unknown | Unknown | Low |
4. Linking pre-clinical testing to clinical outcomes
Clinical outcome measure | Comments |
---|---|
CFTR biomarker | Genotype group changes in sweat chloride (and NPD, but more limited number of studies) during modulator clinical trials have correlated with CFTR responses from many preclinical model systems [ [5] ,[18] ,[19] ,60 , 61 , 62 ]. ICM measurements of G551D CFTR activity have correlated with benefit for patients treated with ivacaftor [
Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation. PLoS One. 2013 Jul 26; 8 ([Print 2013. PubMed PMID: 23922647; PubMed Central PMCID: PMC3724869])e66955 [63] ], or F508del CFTR activity in homozygous patients treated with lumacaftor/ivacaftor [[64] ]. This biomarker is most valuable for demonstrating modulator bioactivity.
Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2018; 197: 1433-1442 |
FEV1 | Genotype group changes in FEV1 during modulator clinical trials have correlated with CFTR responses from many preclinical model systems, including heterologous expression systems, HBE cells, rectal organoids, and HNE cells [ 5 , 6 , 7 , 8 ,
Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014 Jul 15; 190 ([PubMed PMID: 24927234; PubMed Central PMCID: PMC4226057Van Goor Missense mutations 2016 JCF]): 175-184 9 ,[24] ,[36] ,[39] ,[49] ,[50] ]. Change in FEV1 over time (i.e.: FEV1 trajectory) compared with untreated patient registry controls has been assessed in open label studies of ivacaftor in G551D CF patients and lumacaftor/ivacaftor in F508del CF patients. Both analyses have demonstrated reductions in FEV1 decline trajectory [
Sermet-Gaudelus I. Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators. Sci Rep. 2017 Aug 7; 7 ([PubMed PMID: 28785019; PubMed Central PMCID: PMC5547155]): 7375 [65] ,[66] ]. This outcome measure is the gold standard for pulmonary drug development, but has limitations in young patients, and those with early and advanced lung disease.
Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017 Feb; 5: 107-118 |
Multiple breath washout/lung clearance index (MBW/LCI) | The use of MBW/LCI has been limited to studies in young people with CF and those with preserved lung function, including ivacaftor in CF subjects with gating and the R117H mutations, and lumacaftor/ivacaftor in F508del homozygotes. Genotype group changes in LCI during modulator treatment have aligned with CFTR responses in many preclinical model systems [ 67 ,
VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017 Jul; 5 (Epub 2017 Jun 9. [PubMed PMID: 28606620]): 557-567 68 , 69 ]. This outcome measure is most valuable in early lung disease and potentially younger CF subjects.
Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med. 2013 Oct; 1 ([Epub 2013 Sep 10. PubMed PMID: 24461666]): 630-638 |
Nutrition/Growth | Genotype group changes in BMI during modulator clinical trials have aligned with CFTR responses from many preclinical model systems for ivacaftor and lumacaftor/ivacaftor [ [5] ,7 , 8 ,
Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014 Jul 15; 190 ([PubMed PMID: 24927234; PubMed Central PMCID: PMC4226057Van Goor Missense mutations 2016 JCF]): 175-184 9 ,[67] ,
VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017 Jul; 5 (Epub 2017 Jun 9. [PubMed PMID: 28606620]): 557-567 [68] ]. In contrast, tezacaftor/ivacaftor produced similar F508del CFTR correction and potentiation in vitro, but did not demonstrate weight/BMI benefits in F508del homozygous adults relative to placebo [[70] ]. Ivacaftor has been demonstrated to be associated with increased linear growth [[71] ]. Growth is a valuable outcome measure (typically a secondary efficacy endpoint in modulator clinical trials), particularly in pediatric studies. |
Risk of acute pulmonary exacerbation (APEx) | The data for this endpoint is less developed than that for other outcome measures. When included in clinical trials, genotype group changes in risk of APEx during modulator clinical trials have generally aligned with CFTR responses from many preclinical model systems [ [5] ,[9] ,[70] ]. The frequency of APEx is typically not included in crossover trials, which have been necessary for studies in rare CFTR variant groups (e.g. subjects with non-G551D gating mutations). Furthermore, many CFTR modulator trials in young CF patients do not have a placebo group, limiting assessment of APEx risk. Monitoring APEx can be complicated by variable definitions, and is most valuable outside of the young pediatric age group (since they are poorly defined in this population). |
Microbiology | Detection of CF pathogens has only been carefully assessed in open label studies of ivacaftor in subjects with highly responsive CFTR vairants (e.g. gating mutations) [ [8] ,
Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med. 2014 Jul 15; 190 ([PubMed PMID: 24927234; PubMed Central PMCID: PMC4226057Van Goor Missense mutations 2016 JCF]): 175-184 [72] ]. The results of these studies have been mixed, and thus the relationship regarding the modulation of CFTR variants in preclinical model systems to CF microbiology is unknown. Changes in the detection of known CF pathogens is an important secondary outcome measure in clinical trials of CFTR modulators, but is limited in younger patients or patients with mild disease who fail to expectorate.
Restoring cystic fibrosis transmembrane conductance regulator function reduces airway Bacteria and inflammation in people with cystic fibrosis and chronic lung infections. Am J Respir Crit Care Med. 2017 Jun 15; 195 ([PubMed PMID: 28222269; PubMed Central PMCID: PMC5476912]): 1617-1628 |
Patient Reported Outcomes (PROs) | PROs are typically included in CFTR modulator trials, and are an important secondary efficacy endpoint. The Cystic Fibrosis Quality of Life Questionnaire Revised (CFQ-R) has most commonly been included in modulator clinical trials, frequently demonstrating significant improvements in the respiratory domain that exceed the minimal clinically important difference (MCID). [ [5] ,[9] ,[68] ,[73] ]
Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015 Jul; 3 ([Epub 2015 Jun 9. PubMed PMID: 26070913; PubMed Central PMCID: PMC4641035]): 524-533 |
5. Regulatory considerations for theratyping
- Davies J.
- Sheridan H.
- Bell N.
- Cunningham S.
- Davis S.D.
- Elborn J.S.
- et al.
- •A solid understanding of the drug's mechanism of action and consequences of specific CFTR defects intended to be targeted
- •An established drug risk/benefit profile based on an existing efficacy and safety data
- •Adequate characterization and standardization of the specific theratype system
- •Reasonable evidence based on existing clinical data that achieving a predetermined theratype response threshold would be likely to predict clinical benefit
6. Summary and future directions
6.1 Short term
- •Standardize conditions for growth and testing in preclinical model systems used to evaluate CFTR modulators. This is most advanced for stable cell lines expressing missense mutations, HBE cells grown in planar cultures, and rectal organoids. This is least advanced for duodenal enteroids, brushed HNE cells, and iPSCs.
- •Develop Standard Operating Procedures for preclinical testing and therapeutic trials of modulators in individuals with CF (including those with common and rare CFTR variants). These data should be centralized in data repositories for potential support of regulatory expansion of CFTR modulators.
- •Perform standardized testing of available CFTR modulators, examining CFTR missense mutations in transiently transfected model systems as well as the better established stably expressing model systems (e.g. FRT, HEK, MDCK, CHO, CFBE41o- cells). Clarifying what background cell lines are most informative to characterize rare mutations that translate to human subjects could accelerate future theratyping efforts.
- •Define clinically relevant thresholds for CFTR responses in all pre-clinical systems, including CF donor-derived and stably transduced cellular models.
6.2 Medium term
- •Test the predictive nature of preclinical model systems simultaneously (both independently and compared with one another) in individuals who have been prescribed CFTR modulator therapies, examining assay sensitivity, specificity, PPV and NPV. Clear input from clinical researchers and regulators will be needed to define what constitutes a meaningful response in the laboratory, what constitutes a clinical response, and to determine experimental thresholds for clinical response or nonresponse.
- •Capture data centrally and in common format(s) from individual labs/investigators testing CFTR modulators in CF donor-derived model systems. This includes both in vitro and in vivo studies.
- •Perform inter-laboratory and repeated measure validation for model systems.
6.3 Long term
- •Conduct prospective studies of theratyping strategy to predict, select or optimize CFTR modulator therapy regimen.
- •Accumulate real world data from patient registries to determine the relationship between CFTR modulator responses from preclinical testing with long term outcome measures, including pulmonary exacerbation risk, lung function trajectory, microbiology, CF co-morbid conditions (e.g. diabetes, bone disease, mental health), and mortality/progression to lung transplant. This goal comes with inherent challenges because of differences in adherence to prescribed therapies, age and disease state at start of treatment, and stage of comorbid conditions.
Conflict of interest statement
Acknowledgements
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☆The content of this White paper was developed from a Theratyping Workshop supported by CFFT in April 2017. Participants in this workshop included.
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