Special Issue "Outstanding Advances in Hemophilia Therapies"
A special issue of Journal of Clinical Medicine (ISSN 2077-0383).
Deadline for manuscript submissions: closed (31 January 2017)
Dr. Massimo Morfini
Italian Association of Haemophilia Centres (AICE), Italy
Since 2010 a multitude of new recombinant clotting factor concentrates (CFC) have been produced by various pharmaceutical companies. In order to improve the biocompatibility of CFC with the recipients, human embryonic kidney (HEK) cells have been transfected with FVIII or FIX genes and even with Fc of IgG. Another protein-fused FIX concentrate derived from Albumin and FIX co-expression. The cellular recycling mechanism of Albumin and Fc by means of FcnR enabled a half-life increase of both rFIX-Albumin and FIX-Fc fused. Other substantial results have been achieved by Pegylation of rFVIII/IX molecules or by modification of the FVIII molecule in order to increase the affinity with the carrier, the VWF. Also, improvements in the immunoaffinity purification procedures determined more homogeneous and probably less immunogenic FVIII concentrates. The new Extended Half-Life (EHL) CFC will address the issue of reducing the interval between bolus administration during prophylaxis, i.e., the venous access which is the biggest obstacle to implementation of prophylaxis in children. On the other hand, the EHL CFC pose some other issues: first of all, their immunogenicity, with the new fused or PEGylated proteins, which is completely exogenous for the recipients. The outcomes of the randomized clinical trial, SIPPET, published recently in N. Engl. J. Med., decisively established that old generation rFVIII concentrates are significantly more immunogenic than the plasma derived concentrates. Studies of EHL CFC on previously untreated patients (PUPs), requested by EMA, are now in progress and we hope their incidence proves lower than that scored by SIPPET: 44.5% of PUPs seroconverted against rFVIII. The efficacy of EHL CFC as shown in phase III studies to date seems to be very good: The annualized bleeding rate (ABR) decreased dramatically during prophylaxis with respect to on demand treatment. Pharmacokinetics of EHL CFC, especially of new rFIX concentrates, improved significantly. A single dose PK study of current vs. the new EHL CFC is recommended in order to verify the true advantages of switching to the new concentrates, as the variability of PK outcomes is very large among hemophilia patients. The PK characteristics of EHL CFC will also determine the cost of therapy. Pharmacoeconomics will further take into account the improved PK and efficacy. Probably, issues of immunotolerance induction (ITI) will be better addressed in the future, as well as primary, secondary and tertiary prophylaxis of hemophilic arthropathy. The mechanism of physiopathology of arthropathy is now better known due to the introduction of humoral biomarkers of inflammation. Early detection of arthropathy is now possible by prospective evaluation of joints through ultrasonography. Recent progress in joint replacement by means of modern prostheses allows a better quality of life in elder hemophilia patients with severe joint damage. Also rare diseases, such as FVII deficiency, type III VWD, and Glanzmann’s disease have recently received much more attention and ministrations than in the past. Most recently, new clinical trials started on gene therapy of both hemophilia A and B and we hope that the success of previous pivotal trials carried out in UK, will be validated worldwide.
Dr. Massimo Morfin
Prof. Giovanni Di Minn
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- Extended half-life concentrates
- Albumin-fused rFIX, Fc-fused rFVIII
- Fc-fused rFIX
- PEGylated rFIX/rFVIII
- rFVIII single chain
- FVII deficiency
- Glanzmann’s thrombasthenia
- Hemophilic arthropathy
- Total joint replacement
- Gene therapy