In this phase 1 study, a chemically modified RNA interference therapy designed to target antithrombin was administered to participants with hemophilia A or B. Antithrombin levels decreased and the ...generation of thrombin increased.
Background:
Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators.
Aim:
To assess the ...effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*.
Patients and methods:
Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) - with deferiprone, and 8 (17.3%) - with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA.
Results:
In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 - 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014.
Conclusion:
A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.
Patients with transfusion-dependent β-thalassemia were randomly assigned to receive luspatercept (a binder for TGF-β family member ligands) or placebo. During any 12-week period, a greater percentage ...of patients in the luspatercept group than in the placebo group had a reduction of at least 33% (70.5% vs. 29.5%) or at least 50% (40.2% vs. 6.3%) in the transfusion requirement.
Background
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.
...Objectives
To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.
Patients/Methods
In this open‐label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once‐monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient‐reported outcomes (exploratory).
Results
The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean SEM) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean standard deviation 69.4 16.3 days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (−9.2 2.9) and physical health (−12.3 3.9) domain scores suggested clinically meaningful improvement.
Conclusions
Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim of the study: To assess serum sclerostin in transfusion-dependent beta-thalassaemia patients versus healthy controls and to examine its associations with bone mineral density, bone metabolism ...markers and beta thalassaemia alterations.
Material and methods: Sixty-two transfusion-dependent beta-thalassaemia (TDßT) patients and 30 healthy controls were evaluated for serum sclerostin, osteocalcin, beta-cross laps, osteoprotegerin and serum level of receptor activator of nuclear factor kappa-Β ligand (sRANKL). Bone mineral density was measured at the lumbar spine and femoral neck. Thalassaemia characteristics were collected from the patients' medical records.
Results: A significantly higher sclerostin level (median 565.50 pmol/L) was observed in the transfusion-dependent beta-thalassaemia patients vs. the healthy controls (median 48.65 pmol/L, p < .001). Sclerostin showed significant associations with the Z-scores at the lumbar spine and femoral neck, osteocalcin, beta-cross laps, osteoprotegerin, sRANKL, pretransfusion haemoglobin, liver iron concentration and female gonadal state. Significantly higher levels of sclerostin were observed in splenectomized TDßT patients and in those with fragility fractures. Age, sex, body mass index, disease severity, serum ferritin, cardiac T2* and male gonadal state did not show significant associations with sclerostin.
Conclusion: Sclerostin may play a role in the bone pathophysiology of beta-thalassaemia patients and could serve as a marker of severe osteoporosis.
KEY MЕSSAGES
Serum sclerostin is more than 10-fold higher in adult patients with transfusion-dependent beta-thalassaemia compared to healthy controls.
Serum sclerostin is negatively associated with bone mineral density and the bone synthesis markers and positively with the bone resorption indices.
Serum sclerostin is significantly associated with pre-transfusion haemoglobin, liver iron concentration, splenectomy status and fragility fracture events in adult patients with transfusion-dependent beta-thalassaemia.
Serum sclerostin could serve as a marker of severe osteoporosis in beta-thalassaemia patients.
Background: Ineffective erythropoiesis and anemia are pathognomonic features of β-thalassemia, leading to red blood cell (RBC) transfusion dependence in patients with more severe genotypes and ...consequently increased morbidity and mortality. The phase 3 BELIEVE study showed that luspatercept reduces transfusion burden in transfusion-dependent patients with a manageable safety profile (Cappellini MD, et al. HemaSphere 2022;6S3:171-172; Viprakasit V, et al. HemaSphere 2022;6S3:2664-2665). Patients who continued to benefit from luspatercept at completion of the BELIEVE study or who needed to complete post-treatment follow-up could roll over to the phase 3b long-term follow-up study (LTFU; NCT04064060) to continue receiving treatment or complete post-treatment follow-up, respectively. Patients receiving luspatercept were monitored for continued efficacy and safety.
Methods: The aim of this analysis was to evaluate long-term safety and efficacy of luspatercept in patients who rolled over to the LTFU study. This analysis included patients randomized to luspatercept during BELIEVE (luspatercept group) and those randomized to placebo who crossed over to receive luspatercept after unblinding (crossover group). Response was defined as ≥ 33% reduction from baseline in RBC transfusion burden during any 12-week interval over the entire treatment period of the combined studies. The data cutoff was Jan 2, 2023.
Results: At the closure of the BELIEVE trial, 127/224 (56.7%) patients from the luspatercept group and 67/92 (72.8%) patients from the crossover group had transitioned to the LTFU study with the intention to continue luspatercept. At data cutoff, treatment was ongoing for 138 patients, 90 in the luspatercept group and 48 in the crossover group. Median (range) total treatment duration over the combined studies was 229.1 (1.7-336.1) weeks for the luspatercept group and 221.2 (6.1-230.7) weeks for the crossover group; 98 patients had completed 288 weeks (> 5 years) of treatment at data cutoff, all of whom had been randomized to luspatercept.
In the luspatercept group, 180/224 (80.4%) patients had achieved response, continuing the trend showing an increasing proportion of responders with longer duration of treatment observed at previous data cutoffs (Figure A). Response in the crossover group was similar with 71/92 (77.2%) responders. Patients in the luspatercept and crossover groups had median (range) reductions in transfusion burden of −17.75% (−100.0 to 33.3) and −19.05% (−100.0 to 20.8), respectively, from baseline to week 145-192, equating to mean reductions of 6.78 RBC units (SD 7.27; n = 120) and 6.85 RBC units (SD 6.78; n = 50), respectively.
Liver iron concentration in the luspatercept group was reduced with long-term treatment at each timepoint compared with the baseline (mean decrease of 2.80 mg/g dry weight dw at week 144 from median 8.97 range, 1.1-31.9 at baseline n = 24; mean decrease of 0.45 mg/g dw at week 192 from median 7.75 1.4-35.5 at baseline n = 27; mean decrease of 1.48 mg/g dw at week 240 from median 5.65 1.0-42.0 at baseline n = 20). Mean changes from baseline in overall serum ferritin levels (last 24-week level for each patient prior to their efficacy cutoff) were −376.27 μg/L for luspatercept and +43.09 μg/L for crossover.
In the combined studies up to data cutoff, 59.4% of luspatercept patients and 47.8% of crossover patients discontinued treatment. The most frequent reason for treatment discontinuation was the patient's personal decision to withdraw (luspatercept: 23.7% in BELIEVE and 33.5% in the combined studies; crossover: 14.1% in BELIEVE and 28.3% in the combined). Discontinuation due to an adverse event (AE) in the combined studies was similar to experience from BELIEVE (luspatercept: 10.3% BELIEVE and 12.5% combined; crossover: 4.3% BELIEVE and 7.6% combined). One patient (0.4%) discontinued luspatercept and transitioned to a commercially available treatment. The frequency of treatment-emergent AEs in the combined studies was also consistent with previous experience from the BELIEVE trial (Figure B).
Summary: These long-term data from the LTFU study show that erythroid responses and safety results in both the luspatercept and crossover groups were consistent with previous clinical experience from the BELIEVE trial. Patients receiving long-term luspatercept treatment experience durable clinical benefit with no new safety concerns.
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
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