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Hemophilias are rare bleeding disorders, usually inherited, and (as they are X-linked diseases) only occurring in males. There are two types of hemophilias: hemophilia A (clotting factor VIII deficiency) and hemophilia B (clotting factor IX deficiency). The incidence of hemophilia A is 4-6 times higher than that of hemophilia B. When injuries occur, clotting factors normally bind to platelets to stop bleeding, however in these diseases bleeding lasts longer than normal. Hemophilia requires lifelong management and treatment. However, most hemophilia patients can achieve a healthy lifestyle if they receive proper treatment and support for self-care.
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Background: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SQ) for prophylaxis of hemophilia B bleeding episodes. Objectives: To investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DalcA. Methods: This multicenter, Phase1/2a study (NCT03186677) was conducted in 11 males aged 12-65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX® and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SQ 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SQ 150 IU/kg DalcA for 6 days and Cohort 6 received IV 75 IU/kg and daily SQ 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD and anti-drug antibody (ADA) measurement. Subjects were monitored for safety endpoints for 30 days post-dosing. Results: DalcA demonstrated a 24-fold greater potency over BeneFIX® and longer mean residence time (33.8 hours). SQ bioavailability 8.2-20.3%, beta half-life 53.9-106.9 hours and Tmax 24-48 hours. A median 15.7% FIX activity level [IQR 14.9-16.6%] was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wt-FIX, occurred in 2 cousins. Conclusions: The data demonstrated that DalcA achieved protective FIX activity levels between 11-18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a Phase 2b trial to assess the safety and efficacy of 28 daily SQ doses of DalcA was performed.
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Of the various types of hemophilia, the most common of these lifelong bleeding disorders are due to an inherited deficiency of factor VIII or factor IX (Table 1). The genes for these blood coagulation factors lie on the X chromosome, and when mutated, they cause the X-linked recessive traits hemophilia A and B. Since these disorders are X-linked, they usually occur in males. Usually, the affected boy has inherited the mutant gene (XH ) from his carrier mother (X H/X ), but about 30 percent of cases arise from a spontaneous mutation, and there is . . .
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We tested the safety of a nonviral somatic-cell gene-therapy system in patients with severe hemophilia A. An open-label, phase 1 trial was conducted in six patients with severe hemophilia A. Dermal fibroblasts obtained from each patient by skin biopsy were grown in culture and transfected with a plasmid containing sequences of the gene that encodes factor VIII. Cells that produced factor VIII were selected, cloned, and propagated in vitro. The cloned cells were then harvested and administered to the patients by laparoscopic injection into the omentum. The patients were followed for 12 months after the implantation of the genetically altered cells. An interim analysis was performed. There were no serious adverse events related to the use of factor VIII-producing fibroblasts or the implantation procedure. No long-term complications developed, and no inhibitors of factor VIII were detected. In four of the six patients, plasma levels of factor VIII activity rose above the levels observed before the procedure. The increase in factor VIII activity coincided with a decrease in bleeding, a reduction in the use of exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months. Implantation of genetically altered fibroblasts that produce factor VIII is safe and well tolerated. This form of gene therapy is feasible in patients with severe hemophilia A.
The management of hemorrhagic episodes in patients with hemophilia B is in transition as a result of the availability of new products for replacement therapy. Although the basic principles of therapy have not changed, the new highly purified Factor IX concentrates, AlphaNine and Mononine, represent a break-through, as they appear to be safe in terms of viral transmission and thromboembolic side-effects. These products are now widely available, and although expensive, are regarded by some physicians as the preferred therapy for Hemophilia B. Less pure and less expensive Factor IX products, however, are also available and can be used safely in previously treated patients who have already been exposed to the hepatitis viruses.
Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe Hemophilia A
  • Da Roth
  • Ne Tawa
  • Jr
Roth DA and Tawa NE Jr (2001) Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe Hemophilia A. New England Journal of Medicine 344(23): 1735–1742.
USA: McGraw-Hill. Relevant Websites -This website, which is maintained by the national Hemophilia Foundation, has information on research funding and resources related to hemophilia
  • R Handin
Handin R (2001) Disorders of Coagulation and Thrombosis. In: Braunwald E (ed.) Harrison's Principles of Internal Medicine, 15th edn., pp. 751-758. USA: McGraw-Hill. Relevant Websites -This website, which is maintained by the national Hemophilia Foundation, has information on research funding and resources related to hemophilia. -This site, which is maintained by the National Institutes of Health, provides information on hemophilia.
  • L W Hoyer
Hoyer LW (1994) Hemophilia A. New England Journal of Medicine 330(1): 38-47.