Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec (CSL222) vs. extended half-life Factor IX therapies for severe or moderately severe hemophilia B
Bibliographic record
Abstract
Introduction Etranacogene dezaparvovec (CSL222) gene therapy for haemophilia B delivers Factor IX (FIX) Padua via an AAV5 vector and demonstrated superior efficacy at 24 months in reducing bleeds vs. a 6-month lead-in period of prophylaxis with FIX products in the HOPE-B clinical trial.In the absence of head-to-head comparisons of CSL222 vs. FIX products, indirect treatment comparisons (ITC) can be used. This study aims to compare the efficacy of CSL222 vs. prophylaxis with rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results. Method Phase 3 pivotal trials were used: HOPE-B for CSL222 (24-month data), PROLONG-9FP for rIX-FP, B-LONG for rFIXFc, Paradigm 2 for N9-GP. Outcomes of interest were annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds and FIX consumption. Unanchored inverse probability of treatment weighting method with individual patient data (IPD) from HOPE-B and PROLONG-9FP was used to compare CSL222 vs. rIX-FP. Unanchored matching-adjusted indirect comparison with IPD from HOPE-B was used to compare vs. rFIXFc and N9-GP. Factor ranking was conducted with haematology experts to prioritise baseline variables to be adjusted in ITCs. Results CSL222 demonstrated statistically significantly lower ABR, AsBR and AjBR vs. rIX-FP; rate ratio (RR) [95% confidence interval of the RR] for each outcome: 0.19 [0.09, 0.41], 0.08 [0.03, 0.23] and 0.09 [0.03, 0.25], respectively. Similar results were observed vs. rFIXFc and N9-GP. RRs [95% CI] for ABR, AsBR and AjBR for CSL222 vs. rFIXFc were 0.14 [0.08, 0.25], 0.13 [0.03, 0.59] and 0.15 [0.03, 0.65], respectively. RRs [95% CI] for ABR and AsBR for CSL222 vs. N9-GP were 0.24 [0.07, 0.82] and 0.13 [0.03, 0.57], respectively. N9-GP did not report AjBR. CSL222 demonstrated significantly higher % of patients with no bleeds vs. rIX-FP and rFIXFc; odds ratios [95% CI]: 17.60 [4.77, 64.88] and 5.65 [1.75, 18.21], respectively). CSL222 had significantly lower FIX consumption than all comparators. Conclusion CSL222 offers patients with severe or moderately severe haemophilia B a single dose treatment option that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies. ITCs supported results from HOPE-B trial. Publication History Article published online: 20 February 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.010 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".