Toshko Lissitchkov

Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors.

Summary.  Background: Hemophilic patients with factor VIII (FVIII) and FIX inhibitors suffer from frequent bleeding episodes and reduced quality of life. Objectives: To evaluate whether secondary prophylaxis with activated recombinant factor VII (rFVIIa) can safely and effectively reduce bleeding frequency as compared to conventional on‐demand therapy. Methods: Thirty‐eight male patients entered a 3‐month preprophylaxis period to confirm high baseline bleeding frequency (mean ≥ 4 bleeds per month). Twenty‐two patients were randomized 1:1 to receive daily rFVIIa prophylaxis with either 90 or 270 μg kg−1 for 3 months, followed by a 3‐month postprophylaxis period. Results: Bleeding frequency was reduced by 45% and 59% during prophylaxis with 90 and 270 μg kg−1, respectively (P < 0.0001); however, there was no significant difference detected between doses. The majority of this reduction was maintained during the postprophylaxis period. Although all types of bleed were similarly reduced, the effect was most pronounced for spontaneous joint bleeds. Patients reported significantly fewer hospital admissions and days absent from work/school during prophylaxis as compared to the preprophylaxis period. No thromboembolic events were reported during prophylaxis. Conclusion: Clinically relevant reductions in bleeding frequency during prophylaxis as compared to conventional on‐demand therapy were achieved without raising safety concerns. These results provide evidence for the concept of secondary rFVIIa prophylaxis in inhibitor patients with frequent bleeds.

Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART)

The benefits of routine prophylaxis vs. on‐demand treatment with factor VIII products have not been evaluated in controlled clinical trials in older patients with hemophilia A.

Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re‐evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow‐up, investigator‐assessed complete response (CR) rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non‐responders. However, patients with objective response or a CR experienced a significantly longer OS than non‐responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first‐line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Background Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. Methods In this phase 1 dose‐escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. Results No thromboembolic events were observed during the study. The most common adverse events were mild injection‐site reactions. Plasma levels of fitusiran increased in a dose‐dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose‐dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Conclusions Once‐monthly subcutaneous administration of fitusiran resulted in dose‐dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605.)

Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.

A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.

Novel, human cell line-derived recombinant factor VIII (human-cl rhFVIII; Nuwiq®) in adults with severe haemophilia A: efficacy and safety

Nuwiq® [human cell line‐derived recombinant factor VIII (human‐cl rhFVIII)] is a new generation rFVIII protein, without chemical modification or fusion to any other protein, produced in a human cell line.

Prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII) in adults with severe haemophilia A.

Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults.

PK-guided personalized prophylaxis with Nuwiq(®) (human-cl rhFVIII) in adults with severe haemophilia A.

Nuwiq® (human‐cl rhFVIII) is a 4th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell‐line.

Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: An interim analysis of a Phase III trial

Fibrinogen concentrate is the preferred choice for fibrinogen replacement in congenital fibrinogen deficiency. This study investigated hemostatic efficacy of a new plasma‐derived, double virus‐inactivated (using two dedicated virus inactivation/elimination steps) human fibrinogen concentrate for on‐demand treatment of bleeding episodes (BEs) and surgical prophylaxis.

Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: Randomized comparison with active control in congenital fibrinogen deficiency

Essentials Congenital afibrinogenemia causes a potentially life‐threatening bleeding and clotting tendency. Two human fibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study. Bioequivalence was not shown for AUCnorm, which was significantly larger for the new HFC. Increases in clot strength were comparable, and no thromboses or deaths occurred in the study.