Page 33 - Haematologica March 2020

Future of hemophilia therapy
pain and other symptoms associated with joint and mus- cle bleeding (Figure 1). The second World War and related combat casualties were triggers for the improved prepara- tion of plasma, that contains all the coagulation factors (Figure 1). However, this form of replacement therapy was not widely available and of limited clinical efficacy. So, even until the 1960s, the life expectancy of patients with hemophilia was no more than 20-30 years.
A first step forward was the demonstration in 1964 by Judith Pool that cryoprecipitation of fresh-frozen plasma was able to concentrate FVIII (and also vWF and fibrino- gen) in the pellet (Figure 1). But the most significant advance was seen in the 1970s with the industrial manu- facturing and commercial availability of freeze-dried plas- ma concentrates of FVIII for HA and of the coagulation factors (II, VII, IX, X) of the so called prothrombin com- plex (PCC) for HB and the corresponding rare coagu- lopathies (Figure 1). The main advantages of these prod- ucts was storage in simple refrigerators, reconstitution in small amounts of fluid, and no need for a drip to adminis- trate blood, plasma and cryoprecipitate. Their availability, at least in European and North American countries and Japan, was the success story of the 1970s because they allowed home care and self-treatment. Some countries, such as Sweden, were also pioneers in using these prod- ucts to develop prophylactic treatment of hemorrhages instead of only treating episodic bleeding events.10 Our demonstration in 1977 that the synthetic drug desmo- pressin (DDVP) was clinically efficacious as a non-transfu- sional form of FVIII replacement in mild HA and vWD contributed to further progress in the field.10
However, the 1980s threw a dramatic shadow on this favorable scenario when a large proportion of patients treated with factor produced from very large plasma pools developed serious or fatal blood-borne viral infections such as hepatitis and HIV/AIDS.11 Fortunately, this gloomy decade was accompanied by rapid progress in molecular medicine that not only clarified the genetic basis of the coagulation defects but also, and most importantly, led to the therapeutic production in the 1990s of recombinant coagulation FVIII and IX (Figure 1). Moreover, the addition of virucidal or virus-removal steps to the manufacturing process made plasma-derived coagulation products safer, such that no bloodborne viral infections have been report- ed since the late 1980s - early 1990s.11 The wider availabil- ity of safer and more effective therapies for hemophilia care attracted more attention among researchers and resulted in progress in what had so far been the rather hopeless management of a dire complication of HA: the development in at least one-third of patients of alloanti- bodies that make them refractory to replacement therapy, because the coagulant activity contained in FVIII replace- ment products is neutralized by specific inhibitors (and more rarely for FIX).11,12 In the late 1990s, plasma concen- trates of activated factors of the prothrombin complex (APCC), as well as the production of activated factor VII (rFVIIa) by recombinant DNA technology, offered novel ways to bypass the coagulation defect associated with FVIII inhibitors, and thus to improve the management of acute bleeding and surgical interventions (Figure 1).11,13 It was also demonstrated that inhibitory alloantibodies could be eradicated in approximately two-thirds of cases through the induction of immune tolerance (ITI) by means of the long-lasting and highly expensive administration of large doses of plasma-derived or recombinant FVIII prod-
ucts, so that successful patients could resume replacement therapy and prophylaxis with efficacious outcomes.14,15 All this progress improved not only the pattern and quality of patients’ lives, but also led to substantial changes in their life expectancy, achieving figures very close to those of males without hemophilia in the general population;16-18 the figures are particularly encouraging if the ravages of the early years of uncontrolled HIV infection and AIDS are excluded.3,17 The late 1990s and the whole first decade of the third millennium were years of consolidation and rel- atively slow progress (Figure 1), mainly characterized by the refinement of recombinant factors. There was a con- tinuous improvement in the purity of these products, and the use of animal and human proteins during manufactur- ing and in the final formulation was avoided.
With this optimistic scenario of hemophilia care and of patients’ life-expectancy, particularly in comparison with other monogenic diseases such as cystic fibrosis, tha- lassemia and muscular dystrophy, in the first decade of the new millennium efforts were mainly addressed to the for- midable and still unresolved challenges of the global avail- ability and affordability of replacement therapy and to the more widespread implementation of prophylaxis.19-21 On the other hand, relatively little effort has been made to develop new therapeutic products. In contrast, multiple new therapies designed to address the challenges and the gaps in the standard treatments are now being developed.
Recent progress in hemophilia therapy
Prophylaxis as standard of care
Primary prophylaxis of bleeding episodes became the evidence-based standard of care following the random- ized clinical trial of Manco-Johnson et al.,22 who demon- strated that this preventive regimen was clearly superior to the episodic management of bleeds, because it reduced the rate of their occurrence and also achieved a marked reduction in joint damage. A subsequent randomized study by Gringeri et al.23 confirmed and strengthened this evidence, so that prophylaxis became the undisputed standard of care in countries that could afford it. Additional and important advantages were a much improved patient quality of life, including less hospitaliza- tions and days lost from school and work, and an improved social life. However, the implementation of pro- phylaxis met some obstacles,20,21 in addition to that of affordability.24 The degree of adherence was often less than optimal, particularly in children and adolescents, owing to the burden created by the need of 2-3 or more weekly intravenous injections. This not only interfered with the patients’ quality of life, but also created problems of vein access, with the related frequent need to resort to ports or other central venous access devices.20,21
Extended plasma half-life coagulation factors
Frequent intravenous injections are necessary due to the relatively short plasma half-life of replaced coagulation factors (range 10-14 hours for FVIII, 18-22 hours for FIX). Thus, starting from the 2010s, attempts were made to engineer these factors by recombinant technology, with the goal of obtaining medications that remained in the cir- culation longer and thus reducing the number of intra- venous injections. Two main techniques were introduced: (i) coagulation factor fusion to proteins like the Fc part of
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