This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative ...hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.
Key Points
A fusion protein comprising factor IX and the dimeric Fc domain of IgG1 has a half-life that is five times as long as that of native factor IX, allowing prophylactic injections to be spaced as far as ...2 weeks apart while maintaining levels of factor IX that are sufficient to prevent bleeding.
In patients with severe hemophilia B, recurrent bleeding leads to painful hemarthroses, disabling hemophilic arthropathy, and other sequelae.
1
,
2
Prophylactic replacement of coagulation factor IX is associated with improved clinical outcomes
3
–
7
; however, the relatively short half-lives of currently available factor IX products necessitate frequent intravenous injections (two or three times weekly) to maintain protective levels (at or above 1 IU per deciliter).
8
,
9
The frequency of injections is a considerable burden, cited by patients as a key deterrent to undertaking prophylactic treatment.
10
Various strategies to reduce this burden and improve the treatment of hemophilia B are under investigation, . . .
Romiplostim is a Food and Drug Administration (FDA)-approved therapy for immune thrombocytopenia (ITP). Biosimilar is a biological product that has no clinical meaningful difference from an existing ...FDA-approved reference product. It has a potential of lowering health-care-related cost. Biosimilar of romiplostim can be made available to patients with ITP at a low cost and can be beneficial in providing the best therapy. Thus, the efficacy and safety of biosimilar romiplostim (ENZ110) was compared with innovator romiplostim (Nplate) with respect to platelet response in patients with chronic ITP. This was a prospective, multicenter, randomized, and double-blind clinical trial. Patients with chronic ITP, aged 18–65 years, were enrolled in a study and were randomized to receive either ENZ110 or Nplate in a 3:1 ratio for a treatment period of 12 weeks, respectively. After completion of the treatment period, the patients were followed-up for one week to evaluate the platelet response and to monitor the adverse events (AEs). Over the duration of 12 weeks, platelet response of > 50 × 10
9
/L was achieved in 85.3% patients treated with ENZ110 and in 75.0% patients treated with Nplate in per protocol population. In intent-to-treat population, 83.8% patients with ENZ110 and 76.9% patients with Nplate achieved a platelet response of > 50 × 10
9
/L. In the ENZ110 group, 111 AEs were recorded in 66.7% patients, while 18 AEs were reported in 61.5% patients in the Nplate group. The study demonstrated non-inferiority with comparable efficacy and safety between biosimilar romiplostim and innovator romiplostim in patients with chronic ITP.
Trial registration number and date of registration
: CTRI/2019/04/018614.
Purpose
Hemophilia B is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor IX (FIX) clotting activity. This study evaluated safety and efficacy of nonacog alfa, a ...recombinant human blood coagulation FIX replacement product, in males aged 12–65 years with hemophilia B (FIX activity ≤ 2%) with or without inhibitors in India.
Methods
In this multicenter, open-label, post-approval phase 4 study, participants were treated for up to 8 weeks, with up to a 4-week screening period and a subsequent post-treatment 28-day safety observation period. Intravenous nonacog alfa 40 IU/kg (range 13–78 IU/kg) was administered at intervals of 3–4 days, in accordance with the approved local product document.
Results
A total of 25 participants were enrolled and completed the study. No participants developed FIX inhibitors during the study, experienced treatment-related adverse events (AEs) or serious AEs, or developed a thrombotic event and/or hypersensitivity reaction. No participants experienced bleeding events requiring on-demand treatment with nonacog alfa. Seventeen bleeding episodes (16 spontaneous and 1 traumatic) were reported in 10 participants; all occurred post treatment, with the exception of a minor gum-bleeding event, and were managed without treatment. The mean (SD) annualized total factor consumption (TFC) per patient was 224,582 (75,527) IU; the mean (SD) annualized TFC by weight per patient was 3639 (573) IU/kg.
Conclusion
Nonacog alfa was safe and effective for the prevention of hemorrhagic episodes in Indian males with congenital, severe hemophilia B. No participants developed FIX inhibitors, and no new safety signals were reported.
Purpose
Hemophilia A is an X-linked congenital disorder, characterized by factor VIII (FVIII) deficiency. Globally, India has the highest population of patients with hemophilia, and there is a clear ...unmet need for appropriate and effective treatment for this patient population. This multicenter, open-label, post-approval study evaluated the safety and efficacy of moroctocog alfa in patients with moderate or severe congenital hemophilia A in India.
Methods
Intravenous moroctocog alfa was administered 30 ± 5 IU/kg 3 times weekly for bleeding prophylaxis, according to the local product document. Participants were treated for up to 8 weeks, with an up to 4-week screening period and a subsequent post-treatment, 28-day safety observation period. Patients continued in the study until at least 24 exposure days or a period of up to 8 weeks on moroctocog alfa.
Results
A total of 50 participants were enrolled, and 48 (85.7%) completed the study. No participants developed FVIII inhibitors during the study. The mean (SD) annualized bleeding rate during moroctocog alfa prophylaxis was 0.79 (2.0) with a median (range) of 0.00 (0.0, 6.8). The mean (SD) annualized total factor consumption (TFC) per participant was 287,432 (93,866) IU; the mean (SD) annualized TFC by weight per participant was 4176 (858) IU/kg. Moroctocog alfa was well tolerated with no reported treatment-emergent adverse event-related dose reductions, discontinuations, or serious adverse events.
Conclusion
Moroctocog alfa was safe, effective, and well tolerated in Indian participants with congenital moderate to severe hemophilia A. No participant developed FVIII inhibitors during the study.
In a developing country like India, with limited resources and access to healthcare facilities, dealing with massive hemorrhage is a major challenge. This challenge gets compounded by pre-existing ...anemia, hemostatic disorders, and logistic issues of timely transfer of such patients from peripheral hospitals to centers with adequate resources and management expertise. Despite the awareness amongst healthcare providers regarding management modalities of bleeding patients, no uniform Patient Blood Management (PBM) or perioperative bleeding management protocols have been implemented in India, yet. In light of this, an interdisciplinary expert group came together, comprising of experts working in transfusion medicine, hematology, obstetrics, anesthesiology and intensive care, to review current practices in management of bleeding in Indian healthcare institutions and evaluating the feasibility of implementing uniform PBM guidelines. The specific intent was to perform a gap analysis between the ideal and the current status in terms of practices and resources. The expert group identified interdisciplinary education in PBM and bleeding management, bleeding history, viscoelastic and platelet function testing, and the implementation of validated, setting-specific bleeding management protocols (algorithms) as important tools in PBM and perioperative bleeding management. Here, trauma, major surgery, postpartum hemorrhage, cardiac and liver surgery are the most common clinical settings associated with massive blood loss. Accordingly, PBM should be implemented as a multidisciplinary and practically applicable concept in India in a timely manner in order to optimize the use the precious resource blood and to increase patients' safety.
The performance of surgery and invasive procedures in patients with haemophilia is currently facing new challenges globally. The first is the appropriate application of low‐dose protocols of clotting ...factor concentrates (CFC) achieving adequate perioperative haemostasis in resource constraint environments. The increasing availability of CFC through humanitarian aid programmes allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half‐life CFC that are increasingly available in many countries represent valuable alternatives to standard half‐life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half‐life factor IX. Third, in the era of recently introduced non‐factor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low‐dose administrations of CFC or bypassing agents. Additional factor VIII or bypassing treatment has proven to be safe and effective in association with emicizumab for major surgeries, and it was effectively given at low doses in association with fitusiran. No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.
Introduction
Factor replacement therapy in treatment of haemophilia A is complicated by the production of neutralising antibodies known as inhibitors. The formation of inhibitors is multifactorial ...being associated with both genetic and environmental factors.
Aim
To document the prevalence of inhibitors in severe haemophilia in the community where most patients receive only infrequent episodic replacement therapy and evaluate the factors which could be contributing to it.
Methods
Community based camps were conducted in different parts of the country. Patients were assessed through a structured questionnaire and blood samples were obtained for laboratory evaluation of inhibitors and defined immunological parameters.
Results
Inhibitors were present in 87/447 (19.5%) of the evaluated patients. High‐titre inhibitor (>5 Bethesda Units BU) was identified in 31 (35.6%) patients. HLA DRB1‐13‐positive cases (RR = 2.04; 95% CI 1.06‐3.911; P = 0.033) had an increased risk of inhibitor formation which was retained in the high‐titre subset. A decreased risk of inhibitor formation was noted with heterozygous IL4‐590 C/T allele (RR = 0.22; 95% CI 0.108‐0.442: P = 0.000). There were no significant correlations between any of the evaluated environmental factors and the development of inhibitors in this study.
Conclusion
The overall prevalence of inhibitors in patients with severe haemophilia A is similar to that reported among patients receiving regular replacement therapy. The data from this study, limited by its retrospective and cross‐sectional study design, would suggest that genetic rather than environmental are more likely to impact the development of inhibitors.
New treatment possibilities and modalities are now available globally for patients with haemophilia requiring surgery or invasive procedures.
The first is the appropriate application of low‐dose ...protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resources constraint environments. The increasing availability of CFC through humanitarian aid programs allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported.
Second, extended half‐life CFC that are increasingly available in many countries represent valuable alternatives to standard half‐life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half‐life factor IX.
Third, in the era of recently introduced nonfactor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low‐dose administrations of CFC or bypassing agents. Additional factor VIII/IX or recombinant activated factor VII has proven to be safe and effective in association with emicizumab for major surgeries and it was effectively given at low doses in association with fitusiran (including activated prothrombin complex concentrate). No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents.
PDF
