| 1. |
- Chowdary, Pratima, et al.
(författare)
-
Modeling to Predict Factor VIII Levels Associated with Zero Bleeds in Patients with Severe Hemophilia A Initiated on Tertiary Prophylaxis
- 2020
-
Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:5, s. 728-736
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection. Objectives: In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds. Methods: Sixty-three patients (median [range] age, 28 [7-59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the potentially effective trough level for that bleed type. Kaplan-Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach). Results: Kaplan-Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds. Conclusion: This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.
|
|
| 2. |
- Coppens, Michiel, et al.
(författare)
-
Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B) : 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial
-
Ingår i: The Lancet Haematology. - 2352-3026.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B. Methods: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 1013 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7–18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with ClinicalTrials.gov, number NCT03569891. Findings: The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54–27·99), after a lead-in period of 7·13 months (6·51–7·82). In the updated analysis comparing months 7–24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0–6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]). Interpretation: By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B. Funding: uniQure and CSL Behring.
|
|
| 3. |
- Pipe, Steven W., et al.
(författare)
-
Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
- 2023
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 388:8, s. 706-718
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. Conclusions: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile.
|
|
| 4. |
|
|
