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Potential for Advances in the Treatment of Hemophilia A

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - XXIV Congress of the International Society on Thrombosis and Haemostasis (ISTH)/ 59th Annual Scientific and Standardization Committee (SSC) Meeting

Amsterdam, The Netherlands / June 29-July 4, 2013

Amsterdam - Current treatment for patients with hemophilia A, the most common hereditary coagulation disorder, involves intravenous injection of human factor VIII given on demand in response to a bleeding event or as a prophylactic therapy. Recombinant FVIII (rFVIII) concentrates have good efficacy, tolerability, and safety profiles, but their use can be limited by the development of alloantibodies that inactivate the infused coagulation factor and by the need for multiple and frequent infusions to manage a bleeding episode. After 20 years of experience with rFVIII, recombinant DNA technology is being extended to further enhance replacement therapy. Bioengineering strategy has been directed at producing novel rFVIII therapeutics with increased production efficiency, increased potency, prolonged plasma half-life, and reduced antigenicity/immunogenicity or increased resistance to inactivation. A number of these factors are in clinical trials, demonstrating promise for replacement therapy and prophylaxis. Attempts to find a cure continue and are focused on gene therapy.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Since rFVIII became available in the 1990s, many approaches to improving the formulation have been explored. Advances in the manufacturing process have led to the production of highly purified and stable rFVIII products with minimized risk of viral contamination, several of which are in late-stage clinical trials for prophylaxis and on-demand treatment of bleeding in patients with hemophilia A.

Enhanced Purification Technology

Building on the currently available rFVIII formulated with sucrose (rFVIII-FS; Kogenate), a new full-length protein with a longer half-life, has been studied in 2 clinical trials in previously treated patients with severe hemophilia A. BAY 81-8973 is produced from the same gene expression construct and BHK cell line but displays a glycosylation pattern more similar to native FVIII. It is manufactured by a new process that eliminates the use of animal- or human-derived proteins in the fermentation and purification steps, and has a new nanofiltration step, all in an effort to further reduce immunogenicity and the potential for any pathogen transmission. The results of the LEOPOLD I trial, presented by Dr. Kapil Saxena from Boston Hemophilia Center, demonstrated that the pharmacokinetic profile of BAY 81-8973 was at least non-inferior to that of rFVIII-FS, showing a significantly higher AUC, t1/2, and MRTiv and a lower clearance (abstract PB 4.37-2). “There are a number of new steps in the manufacturing process designed to make BAY 81-8973 more effective than rFVIII-FS,” Dr. Saxena commented, citing the addition of heat shock proteins, “which result in better folding and unfolding of the protein, which should reduce the protein aggregates and improve rFVIII expression efficiency over rFVIII-FS.” he suggested. In 62 men who received the agent in prophylaxis (20-50 IU/kg 2-3 times/week) for 12 months, the median annualized number of total bleeding episodes per patient was 1.0. The incidence of treatment-related adverse events was low (≤7%), hemostasis was maintained, and no patient developed inhibitors during the trial.

A new rFVIII protein manufactured without the use of animal- or human-derived raw materials, turoctocog alfa (N8), is expressed by a modified (B-domain truncated) human FVIII gene in CHO cells (Thim L et al. Haemophilia 2010;16:349-59). Turoctocog alfa has been shown to be safe and effective in treatment of bleeding episodes and in prophylaxis in two Phase III clinical trials (Kulkani R et al. Haemophilia 2013 Sep;19(5):698-705, Lentz SR et al. Haemophilia 2013 Sep;19(5):691-7). Dr. Margareth C. Ozelo, INCT do Sangue Hemocentro UNICAMP, University of Campinas, São Paulo, Brazil, described how data from 210 trial patients who received turoctocog in prophylaxis were used to construct a model to predict FVIII coagulant activity (FVIII:C) (abstract PA 2.06-5). This revealed that the risk of experiencing a bleeding episode decreased with increasing FVIII:C. FVIII:C levels >10% were associated with the lowest risk of spontaneous and traumatic bleeding in both adult and pediatric patients. Further studies are likely indicated.

PEGylated rFVIII

A major focus of current bioengineering strategy is on extending rFVIII half-life, which could reduce the dose and frequency of injections needed for prophylaxis. One approach under investigation is sustained delivery through chemical modification of rFVIII with polyethylene glycol (PEGylation). These new products include N8-GP (glycoPEGylated rFVIII), BAY 94-9027, a B-domain-deleted rFVIII covalently linked to a single 60 kDa PEG moiety and BAX 855, a full-length longer-acting rFVIII developed to increase the half-life of antihemophilic factor [recombinant] plasma/albumin-free method (rAHF-PFM; Advate). In a Phase I prospective, open-label trial in 19 previously treated patients age 18 years or older with severe hemophilia A, the half-life of BAX 855 was approximately 1.5-fold higher compared with rAHF-PFM (Bevan D et al. Haemophilia 2013, 19 (Suppl.2), 10-82. PO 053). BAY 94-9027 showed a similar half-life increase in Phase I of 19 h vs. 13 h for rFVIII-FS (Coyle T et al. Haemophilia 2012, 18 (Suppl. 3), 1-208. FP-MO-03.2-3).

For these products there is a need to identify reliable activated partial thromboplastin time (aPTT) assay reagents that can be used for clinical monitoring of FVIII:C. In a US study that compared 5 widely used commercial aPTT reagents for evaluating BAY 94-9027 activity, ellagic acid aPTT reagents were found to be most suitable for evaluating potency and for use in clinical laboratories for monitoring FVIII:C after infusion (abstract PA 2.11-5). Prolonged clot time and poor precision were seen in silica-based aPTT assays, possibly due to interference with contact activation on the silica surface by the PEG moiety. Validation of a new highly selective modification-dependent activity assay (MDAA)  for measurement of BAX 855 in normal human and VIII-deficient plasma was also reported (abstract PA 2.11-5). This concept of specifically capturing potency of PEGylated rFVIII before measuring its activity could be used to determine whether a PEGylated protein is still intact.

Fusion Protein Technology

Another strategy to extend the half-life of rFVIII is fusion to another protein with a much longer half-life such as the fragment crystallizable (Fc) region of an immunoglobulin (IgG). In a pivotal Phase III study in 165 subjects, once to twice weekly prophylactic regimens with a long-lasting rFVIIIFc product (Eloctate) resulted in low ABR with 98% of bleeding episodes controlled with 1 or 2 injections, reported Dr. Johnny Mahlangu from University of the Witwatersrand, Johannesburg, South Africa (abstract OC 37.2). The results of the A-LONG study confirmed the long-lasting characteristics of rFVIIIFc, with a terminal half-life of 19 h vs. 12 h for rAHF-PFM. “The extended PK profile confirmed in this study creates new opportunities for managing patients,” Dr. Mahlangu predicted.

Data from the A-LONG study have been used to compare projected prophylactic consumption and effects on bleeding of newer, long-acting rFVIII over traditional short-acting rFVIII agents. Dr. Alec H. Miners from the London School of Hygiene and Tropical Medicine, UK reported the development of a new decision-analytic model which was able to show how an rFVIII product with a longer half-life has the potential to reduce the number of injections required and lower overall factor consumption, while achieving similar hemostatic effects (abstract PB 3.55-5). The model was applied to a hypothetical 30-year-old individual receiving 37.5 IU/kg of either short-acting rFVIII 3 times/week or rFVIIIFc twice weekly. Bleeding frequencies were similar with the 2 products (2 bleeds per year) but 33% less clotting factor was used with rFVIIIFc compared with short-acting rFVIII. Projected over 30 years, rFVIII use would be reduced by 4.6 million IU. “It is a no-brainer that you are going to use less clotting factor, but the extent of the difference is interesting,” Dr. Miners commented. He also cautioned that the results were based on “average individuals,” whereas “there isn’t one way of doing prophylaxis in the real world.”

Hope for a Cure

Gene therapy represents a potential cure for hemophilia A and B patients, with the possible continuous expression of a clotting factor gene following the administration of a viral vector carrying that gene. “It is clear that momentum in the field of gene therapy is building,” said Prof. Thierry VandenDriessche, Free University of Brussels (VUB), Belgium. In a state-of-the-art lecture, he explained that hepatocytes, skeletal muscle cells, and hematopoietic stem cells have all been shown to be capable of maintaining stable clotting factor expression levels and so are suitable target cells for gene therapy. “The Achilles heel of gene therapy is the gene delivery vector,” he noted. Lentiviral- and adeno-associated virus (AAV) based vectors are among the most promising. AAV-based gene therapy has been shown to produce long-term expression of factor IX (FIX) levels, but generating AAV FVIII vectors is more challenging, he explained.

Summary

There is a large pipeline of novel therapeutic agents for hemophilia A and new rFVIIIs offer the potential for improved quality of life and cost reduction associated with less frequent dosing. Factor replacement therapy still leaves patients vulnerable to bleeding events and gene therapy may hold potential for a cure, although it may be a number of years before the clinical success seen with FIX can be extended to FVIII, suggesting that additional investigation is needed.  

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