Pillar 02 · Biophysics & Trials · Scale 06: Population Registries
Global CF Registries & 10-Year ECFSPR Trajectory
Longitudinal demographic surveillance across five official ECFSPR Annual Data Reports (57,288 registered individuals across 40 European countries in 2024) alongside multi-registry modulator eligibility gaps in the United States, Canada, the United Kingdom, and Australia.
Multi-Registry Surveillance
Multi-registry CFTR modulator eligibility (2024–2025)
Independent patient registries in North America, Europe, and Australasia track CFTR modulator eligibility and uptake. Each registry operates under distinct inclusion thresholds and regulatory approvals; cross-registry pooling or summing into a global percentage is mathematically and clinically invalid.
United States · CFFPR (2024)
89.6% prescribed of 29,314 eligible by age & genotype (26,277 individuals). Overall 92.3% have an eligible genotype. 8.0% ineligible across all approved modulators in 2024 (down from 61.4% in 2015).
CFF Patient Registry 2024 Annual Data Report, pages 8, 58.
Canada · CCFR (2024)
3,087 on elexacaftor/tezacaftor/ivacaftor (1,004 children, 2,083 adults). 7.6% not eligible by age & genotype. 152 rare mutations approved in July 2024.
Canadian CF Registry 2024 Annual Data Report, page 38.
United Kingdom · UKCFR (2024)
11,381 registered (93% annual review). 80.3% on Kaftrio at annual review (8,830 active modulator users). 12.4% have never used a modulator.
UK CF Registry Annual Data Report 2024, pages 8, 9, 47.
Australia · ACFDR (2025)
Adults (n=2,326): 85.6% prescribed, 5.8% ineligible. Pediatric (n=1,473): 75.0% prescribed, 11.5% ineligible. Under 6 years: 18.0% ineligible.
Australian CF Data Registry Annual Report 2025, pages 5, 39, 68.
Europe · ECFSPR (2024)
Continental mapping of EMA eligibility criteria and national reimbursement across participating countries. Triple combination is the primary modulator in both children and adults.
ECFSPR Annual Data Report 2024, Chapter 9, pages 81–88.
Track B · Answer Tier T2 Verified Pipeline (T-0009 & T-0010)
ECFSPR 10-Year Demographic Trajectory (2014–2024), 5-Tier Denominator Cascade & Epistemic X-Ray
Interactive extraction across 185 standardized rows from five official ECFSPR Annual Data Reports (2020–2024, plus 2014 and 2019 historical benchmarks). Audited on a 100-cell random sample (100.0% accuracy, Wilson 95% CI [0.9630, 1.0000]) and guarded by a cryptographically frozen 60-claim evaluation harness (60/60 correct verdicts; 10/10 out-of-scope abstentions).
Dimension 1 · Longitudinal Cohort Trajectory (2014–2024)
Registered PwCF
57,288
scope: all_registered
Adults (≥18 yr)
56.6%
n = 32,277 (alive_end_of_year)
Follow-up Age (Median / IQR)
20.8 yr (11.1-33.8)
scope: alive_end_of_year
At Least One F508del Allele
80.1% (43,330)
scope: seen_during_year
Living with Lung Transplant
2,380 (4.4%)
scope: alive_end_of_year
Registered Deaths & Age at Death
276 (0.50%)
median: 36.5 yr (24.0-49.0)
Dimension 2 · 2024 Five-Tier Denominator Scope Cascade
Five distinct population denominators govern a single ECFSPR report year. Conflating these tiers is caught as contradicted by the T-0010 claim harness.
5. Seen & Never Transplanted (seen_never_transplanted)
51,294 ( of registered)
Chapter 4+ Clinical Outcome Denominator: Excludes transplanted individuals to prevent lung allograft confounding of FEV1, microbiology, and nutrition.
Dimension 3 · 2024 Country Stratification (Table 1.1, Page 12)
Inspect national cohort counts and active clinical follow-up across 16 participating European registries in 2024.
Cohort
All Europe (40 countries)
Registered N
57,288
Seen During Year
54,241 (94.7%)
Continental ECFSPR total across 40 participating countries (Table 1.1, page 12).
Epistemic Provenance X-Ray · Answer Tier T2 Grounding
Official ECFSPR Annual Reports ↗
Year Quote: People with CF registered in the ECFSPR: 57,288; Seen during year (*): 54,241; Alive on 31/12 (**): 53,988; Mortality cohort (***): 55,199
Denominator Quote: From chapter 4 onwards, only people with CF seen during the year and who have never had a transplant are considered for the analyses (total number 51,294).
Country Quote: Total registered: 57,288; Total seen during the year: 54,241 (ECFSPR 2024 Table 1.1, page 12).
Descriptive registry epidemiology — research, not medical advice. Cross-sectional median age at death is not individual projected survival, and national registry cohorts are never pooled across incompatible definitions.
T2 Receipt · ECFSPR 185-Row Audit (100/100) & Frozen 60-Claim Harness Proof
Primary Source & Audit: Five official ECFSPR Annual Data Reports (2020–2024; 2024 PDF SHA-256 2c2ceca3da7aa8a8dc8ce8eb2c4fbef9df94a8bbbd7ff997ba73d6c53efbd29a), 185 standardized rows, 100-cell random audit (100/100 = 100.0%, Wilson 95% CI [0.9630, 1.0000]), 60-claim frozen benchmark (60/60 correct verdicts; 10/10 out-of-scope abstentions).
Ledger Lock Hash: 4ee7fcc1c002159041ec3c480bed1c5666adb8cc52c8d5ca65a6eb128c243b40 (verified in data/evidence.lock.json).
GitHub Proof: cf-research/tools/registry-extract/ecfspr_v0_1_audit.json ↗ · eval_set_60.lock.json ↗
The Non-Pooling Imperative: Summing these distinct cohorts into a single global percentage is scientifically invalid due to differing reporting criteria (annual review completion vs. encounter records vs. year-end status) and asynchronous regulatory dates.
The Curative Imperative: The persistent ~6–12% unserved denominator primarily represents Class I nonsense mutations (W1282X, G542X), canonical splice defects, and structural deletions producing zero targetable protein. Small-molecule modulators cannot restore conductance without a protein substrate; advancing universal restoration requires genetic therapies and alternative conductance bypass.
Track B · Clinical Equity & Translation
Interactive Global Registry Variant Theratyping & Diagnostic Equity Explorer
Examine non-pooled national registry denominators (CFFPR, CCFR, UKCFR, ACFDR, ECFSPR), newborn screening sensitivity across diverse ancestries, and in vitro organoid (FIS) theratyping pathways.
National Registry Denominator
Patient Ancestry (Newborn Screening Disparity)
Screening Assay / Mutation Panel
Eligible & Prescribed
89.6%
26,277 of 29,314 eligible
Unserved Denominator
8.0%
Modulator ineligible
Screening Sensitivity
64.2%
35.8% potential false negatives
Sweat Chloride Status
45 mmol/L
Intermediate (30-59 mmol/L)
Organoid Theratyping
350 AUC
Partial Theratyping Rescue
In plain words: why non-pooled data and genetic equity matter
When headlines report that '90% of people with CF have treatments,' they hide two critical realities. First, national registries use different rules: summing them creates false statistics. Second, standard newborn genetic panels were designed primarily around common European mutations like F508del. In Hispanic, Black, Asian, and Indigenous families, standard panels miss between 25% and 47% of CF-causing variants, delaying diagnosis and access to care. Modern Whole-CFTR gene sequencing and patient-derived organoid testing (HIT-CF Europe, NCT02392234) ensure every person is diagnosed early, regardless of heritage.
Independent research, not medical advice. Computational registry synthesis grounded in official national registry annual reports (CFFPR, CCFR, UKCFR, ACFDR, ECFSPR), ClinicalTrials.gov NCT02392234, and Dekkers et al. (JCF 2022, DOI: 10.1016/j.jcf.2022.06.002). Never combines national denominators. Sensei Ewok CF Lab does not make clinical recommendations.
Track B · Answer Tier T2 Verified Pipeline (T-0211)
Interactive Genotype-to-Modality Eligibility & Clinical Trial Pathway Finder
Explore how CFTR variant classes (Class I–VII) map to approved small-molecule modulators (CFFPR, ECFSPR, CCFR, UKCFR, ACFDR) versus investigational mRNA replacement, splice-switching ASOs, and alternative conductance bypass trials.
Step 1 · Select CFTR Functional Variant Class
Molecular Defect & Mechanism
No Approved Modulators
Class I · No Synthesis / Premature Stop & Null
Premature termination codons (PTCs), frameshifts, or canonical splice-junction disruptions lead to nonsense-mediated mRNA decay (NMD) or severely truncated polypeptide fragments that are degraded immediately. Zero functional CFTR protein reaches the apical membrane.
Approved Small-Molecule Modulator StatusIneligible across all approved small-molecule modulators (elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor, lumacaftor/ivacaftor, ivacaftor). Small-molecule potentiators and correctors require a translated protein substrate to exert allosteric rescue.
Global Registry Denominator ImpactRepresents the core of the ~6–12% unserved denominator in international registries (CFFPR 2024: 8.0% ineligible across all approved modulators; ECFSPR 2024: ~7.7% of seen pwCF carry two non-targetable alleles; CCFR 2024: 7.6% not eligible).
Clinical Trial Pathways & Investigational Modalities
Emerging Curative & Bypass Approaches
NCT05668741 ↗
Phase 1/2 Dose Escalation
A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF)
Modality: Inhaled mRNA Replacement (LNP Aerosol)
Encapsulated full-length CFTR mRNA delivered via aerosolized lipid nanoparticles to airway epithelial cells, bypassing genomic premature stop codons entirely to express wild-type CFTR.
- Inhaled full-length CFTR mRNA replacement (VX-522, NCT05668741)
- PTC translational readthrough (small molecules + eRF1/eRF3 inhibitors)
- Nonsense-mediated mRNA decay (NMD) attenuation cocktails
- Dual-AAV split-intein base editing and Prime Editing
- Alternative conductance bypass: ENaC blockade (ETD001) & TMEM16A potentiators (ETX001)
Care Team Conversation Starter
Discuss with your accredited care team: (1) Verifying exact cDNA annotations for both alleles in the national registry; (2) Inhaled mRNA clinical trials (e.g. NCT05668741) and mutation-agnostic genetic therapy pipelines; (3) Expanded access biobanking programs.
Registry and Clinical Trial Grounding: ClinicalTrials.gov does not evaluate safety or efficacy of listed trials. The lab does not assess efficacy or recommend treatments. Research, not medical advice. Clinical trial eligibility depends on detailed inclusion/exclusion criteria, organ function, and investigator evaluation.
T2 Receipt · Genotype-to-Modality Mapping & Trial Surveillance Grounding (T-0211)
Primary Sources: CFTR2 Database (DOI: 10.1038/ng.2745); ECFSPR Annual Data Report 2024 (Chapter 9 & Table 1.1); CFF Patient Registry 2024 Annual Data Report (pages 8, 58); ClinicalTrials.gov official protocols NCT04043806 (VX-445 long-term safety, Phase 3), NCT05668741 (VX-522 inhaled mRNA in LNP, Phase 1/2), and NCT06429176 (SPL84 splice-switching ASO, Phase 2a).
Ledger Lock Hash: 4ee7fcc1c002159041ec3c480bed1c5666adb8cc52c8d5ca65a6eb128c243b40 (verified in data/evidence.lock.json).
GitHub Proof: cf-research/tools/trial_atlas/snapshot.json ↗ · cf-research/sources/catalog.yaml ↗
Track B · Biomarker Concordance & Curative Horizon
Sweat Chloride vs. ppFEV1 Non-Linear Sigmoidal Concordance Explorer
Explore why 10%–15% wild-type CFTR function captures the steepest therapeutic rescue, and why individual spirometry scatters around the population mean.
Benchmark Regimen & Functional Tiers:
Cohort Mean ΔppFEV1
Clinical & Diagnostic Zone
Population vs Individual Scatter
Track B · Community & Care Partnership
Questions for Your CF Care Team: Registries & Long-Term Health Planning
Connecting national registry surveillance, demographic trends, and unserved variant equity to your individual care journey.
Understanding Population Data vs My Individual Path
“How do national registry demographic benchmarks (like median age at death or modulator uptake rates) relate to my individual health status and long-term care goals?”
Why this matters: Registry metrics describe broad population cohorts from previous decades; they do not predict your individual life trajectory or the benefits of modern multidisciplinary care.
Confirming Registry Enrollment & Genetic Cataloging
“Are my annual health encounter data enrolled in our national CF registry, and are both of my CFTR variants completely and accurately recorded in the database?”
Why this matters: Accurate variant cataloging in registries ensures you are counted in epidemiological surveillance and notified when variant-specific trials or therapies emerge.
Navigating Unserved Variant Support & Health Equity
“If our mutations currently sit in the unserved ~6–12% denominator without approved modulators, what expanded access, clinical trials, or specialized support pathways are available to our household?”
Why this matters: Care teams can connect families with rare or unserved genotypes to specialized research registries, theratyping programs, and patient advocacy resources.