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P.M. Mannucci et al.
All in all, the main benefit of this first non-factor replacement antihemophilic medication is the feasibility of regular prophylaxis in patients with inhibitors, using the advantageous and user-friendly subcutaneous admin- istration route at weekly intervals or even less frequently. The high cost of emicizumab is an issue, but all the prod- ucts used so far to manage patients with inhibitors are very expensive, including the traditional bypassing agents and immune tolerance inductions (ITI). Furthermore, the licensing of emicizumab also for HA patients without inhibitors is an important alternative to the currently available options of SHL and EHL coagulation factors, with the advantage of the subcutaneous instead of the intravenous route of administration. Efficacy parameters, such as the ABR and the zero bleeding rates, appear to be better than those obtained with the EHL FVIII products, but since there have still not been any face-to-face com- parison studies between replacement and non-replace- ment products, this impression stems from indirect data.
A potential but still unexplored approach is the use of this non-FVIII product in young, previously untreated patients (PUP) with severe HA who, at high risk of devel- oping inhibitors following exposure to FVIII replacement, might be able to avoid this complication. Another definite advantage is the subcutaneous route of administration, which would promote early prophylaxis without the need for venous ports. Emicizumab may also help to prevent the intracranial hemorrhages that are relatively frequent in the early years of life. Potential disadvantages may mate- rialize in cases in which FVIII replacement is required to prevent or treat breakthrough bleeds, because the delayed FVIII inhibitors may develop in dangerous, high-risk cir- cumstances, such as at the time of major trauma or sur- gery. Thus, the use of emicizumab in PUP is still a subject of debate and warrants a specific study to evaluate the forementioned advantages and disadvantages of this approach.
Other unanswered questions and causes for concern remain (Table 4). It is still not known whether or not the FVIII-mimicking activity of emicizumab provides the same physiological benefits of the bona fide coagulation factor, such as the long-term preservation of joint and bone health and the optimal support of wound healing.52 In pivotal studies, a few patients developed thrombotic microangiopathies and other thromboses when inhibitor patients had a bleeding episode and were concomitantly treated with large and frequent doses of APCC.48 At least 23 deaths have been associated with the use of emicizum- ab, mostly in patients with inhibitors, but also in some without. The deaths occurred both in the context of the pivotal clinical studies and as a result of the expanded access, compassionate and post marketing use, as reported by the manufacturer53 and by the FDA Adverse Events Reporting System (FEARS).54 As emphasized by Aledort,55 more information on causality or chance association is needed to dissipate the uncertainty that surrounds these cases among consumers and care-givers.
Other non-factor therapies
Medications with mechanisms of actions other than that of emicizumab, and also mainly administered subcu- taneously, are currently at an advanced stage of clinical development. Concizumab, a monoclonal antibody against the anticoagulant protein TFPI, increases the potential for thrombin generation.56,57 A trend towards
lower bleeding rates was observed in patients with HA and HB with and without inhibitors, but the cases were too few to provide robust evidence of efficacy. Another anti-TFPI monoclonal antibody is PF-06741086, currently undergoing a phase II trial (NCT02974855).58 Fiturisan is a compound that interferes with RNA, and that decreases the plasma concentrations of antithrombin.59,60 In early clinical studies, this agent, given subcutaneously at pro- gressively higher dosages and even at monthly intervals, was accompanied by the progressive decrease in plasma antithrombin paralleled by an increase in thrombin gener- ation and reduction of the ABR. Phase III studies of fitur- isan in patients with severe HA and HB with and without inhibitors are at the advanced phase of development,61,62 but the drug is as yet not licensed for clinical use. A fatal thrombotic event that occurred in 2017 in a patient with severe HA during a phase II study63 led to the FDA tem- porarily stopping the study, but some protocol and guide- line changes have allowed it to be restarted and to move this product forward to phase III studies; these are current- ly ongoing. On the whole, it is still too early to truly understand the role of these additional non-factor prod- ucts in the scenario of hemophilia care, but potential advantages are their use not only in HA but also in HB and other inherited coagulation disorders, with or without inhibitors. Another advantage is that they can be adminis- tered at intervals that are as widely spaced as once a month.59,60
Gene therapy
As we have seen, within the already positive scenario that developed at the beginning of the third millennium in terms of almost normal life expectancy, a new era of huge innovation in hemophilia therapy is currently underway.64 A recent study attempted to identify the main players involved in this almost miraculous progress. These include outstanding and dedicated physician-scientists, patient advocates and consumer organizations, but also more and more pharmaceutical companies involved in the hemo- philia market.64 With this background, are there still rea- sons and incentives for further progress? The main thrust stems from patients, who want to be cured! For them, cure means to be free of spontaneous bleeds, because the ideal zero rate has not been fully achieved with the avail- able weaponry.65 Thus, the ideal goal is gene therapy, preferably with a single therapeutic intervention of life- long duration.
The first vector associated with curative gene transfer in animal models of hemophilia was the adeno-associated virus (AAV), and, so far, AAV vectors are the only tools used to achieve therapeutic levels of FVIII and IX in hemo- philia patients.66-70 Historically, the first study involved ten patients with severe HB at the Royal Free Hospital in London, UK, who received single but increasing doses of an AAV8 vector, some of them with a current follow up of 9-10 years.71,72 They continue to have stable expression of the transgene, with plasma levels ranging from 2% to 5%, and a 90% reduction in bleeding episodes.72 Among the six additional ongoing studies in HB,73 impressive results were obtained in the SPK-9001 phase I-II study, of partic- ular interest because it used an AAV8 vector expressing the gain-of-function FIX Padua gene mutation.74 The 15 patients who received a single infusion of this vector attained mean plasma levels of FIX of 33.7% (range 14.3- 76.8%) over a period of at least 52 weeks.74 According to
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