The More Recent History of Hemophilia Treatment

Abstract

The availability first in the 1970s of plasma-derived and then in the 1990s of recombinant clotting factor concentrates represented a milestone in hemophilia care, enabling not only treatment of episodic bleeding events but also implementation of prophylactic regimens. The treatment of hemophilia has recently reached new landmarks. The traditional clotting factor replacement therapy for hemophilia has been substituted over the last 10 years by novel treatments such as bioengineered factor VIII and IX molecules with extended half-life and non-factor treatments including the bispecific antibody emicizumab. This narrative review is dedicated to these newer therapies, which are contributing significantly to improving the long-term management of prophylaxis in hemophilia patients. Another section is focused on the current state of gene therapy, which is a promising definitive cure for severe hemophilia A and B.

Keywords

hemophilia - history - therapy

The hemophilias are X chromosome-linked bleeding disorders, resulting from the deficiency or dysfunction of coagulation factor VIII (FVIII, hemophilia A) or factor IX (FIX, hemophilia B).[1] These rare inherited disorders (the prevalence of hemophilia A and B is 1:5,000 and 1:30,000 male live births, respectively) and are clinically relevant, with symptoms being loosely commensurate with the degree of plasma factor deficiency.[1] [2] People with hemophilia are at risk of spontaneous bleeding, and trauma and surgical interventions can provoke uncontrolled bleeding.[3] [4] [5] The main sites of spontaneous bleeding are joints and muscles; if these bleeds are not treated adequately, chronic damage to the musculoskeletal system can ensue, with consequent severe handicap and disability.

An early reference to a bleeding condition highly suggestive of hemophilia dates back to the second century AD. The Babylonian Talmud exempted male infants from circumcision if they had two brothers who had already died of excessive bleeding from the procedure. Albucasis, an Arabic physician who lived in the 10^th century, described a family with males who died from bleeding after minor injuries. The first modern description of hemophilia appears to be that by Dr. John Conrad Otto, a physician from Philadelphia, who in 1803 described an inherited bleeding disorder in several families in which only males, called bleeders, were affected, and in which transmission occurred via unaffected females. The word “hemophilia” appeared, however, for the first time in an essay written in 1828 by the German physician Johann Lukas Schonlein and his student Friedrich Hopff. Hemophilia B was distinguished from the more common hemophilia A in 1952, and was often initially denoted as Christmas disease after the surname of the first boy described with the condition. The first description of the genetics of hemophilia was published in 1820 by Nasse.[6] [7] Hemophilia is occasionally called “the royal disease”, because several members of royal families across the whole of Europe were affected by this affliction, which they inherited from Victoria, Queen of England from 1837 to 1901, who was a hemophilia B carrier.[8] Queen Victoria's eighth son Leopold had hemophilia B, suffered from frequent bleeds and died of a brain hemorrhage at the age of 31. Two of her daughters, Alice and Beatrice, were carriers of hemophilia B and transmitted the disease to the Spanish, German and Russian royal families.

In the 1950s and early 1960s, people with hemophilia could only be treated with whole blood or fresh plasma. Unfortunately, there is insufficient FVIII or FIX in these blood products to arrest severe bleeding. Thus, most people with severe hemophilia died in childhood or early adulthood of bleeding after surgery or trauma or hemorrhages in vital organs (particularly the brain).[9] [10] The patients who survived developed severe damage to the musculoskeletal system, which resulted in them being bedridden or confined to a wheelchair. In 1964, Judith Graham Pool discovered that the precipitate left from thawing and spinning plasma contained large amounts of FVIII. This was a huge step forward in hemophilia care since it enabled blood banks to produce and store cryoprecipitate and, for the first time, enough FVIII could be infused in relatively small volumes to control severe bleeding and to make emergency and elective surgery possible.[11]

The most significant advance in hemophilia therapy occurred in the 1970s, due to the industrial manufacturing and large-scale commercial availability of freeze-dried plasma concentrates containing FVIII and FIX. This innovation revolutionized hemophilia care because factor concentrates could be stored easily, which made it possible to infuse these products at home. The widespread adoption of home therapy enabled early control of bleeds with a related decrease in musculoskeletal damage and a drastic reduction in the requirement of hospital visits, resulting in dramatic improvements of quality of life and life expectancy.[10] Sweden was a pioneer in using such products to implement the prophylactic treatment of hemorrhages (primary prophylaxis), instead of only treating bleeding, episodically, when it occurred.[12] [13] In 1977, the demonstration that desmopressin (DDVP), a synthetic drug, was efficacious clinically as a non-transfusional method of FVIII replacement in mild hemophilia A and von Willebrand disease (VWD) was another important step forward.[14] A major advantage of DDAVP was that of reducing patients' exposure to large-pool, plasma-derived products which, unfortunately, had been responsible for the transmission of blood-borne viruses (the human immunodeficiency virus and the hepatitis B and C viruses) during 1980s.[15] However, this gloomy decade was accompanied by progresses in virucidal or viral removal techniques, which greatly increased the safety of plasma-derived coagulation products, and molecular medicine, which led to the first production of recombinant coagulation FVIII and IX in the 1990s.[16] The narration of this review begins with this period, which is conventionally considered the beginning of modern hemophilia therapy. This review is an update of a previous one on the history of hemophilia published to celebrate the 40^th anniversary of this Journal.[6] [Fig. 1] summarizes the most important progresses, decade by decade, of hemophilia therapy.

Fig. 1 The most important progresses of hemophilia therapy. APCC, activated prothrombin complex concentrates.

Search Strategy

For this narrative review we analyzed the medical literature for published articles on the recent history of hemophilia therapy. The Medline and PubMed electronic database was searched for publications without temporal limits using English language as a restriction. The Medical Subject Heading and keywords used were: “hemophilia A,” “hemophilia B,” “therapy,” “history,” “prophylaxis,” “recombinant coagulation products,” “plasma-derived concentrates,” “standard,” “extended half-life,” “bleeding,” “inhibitor,” “replacement therapy,” “non-replacement therapy,” “emicizumab,” “gene therapy,” and “quality of life.” We also screened the reference lists of the studies identified and of the most relevant review articles for additional studies not captured in our initial literature search.

Replacement Therapy: from Standard to Extended Half-Life Recombinant Products

As mentioned, the prevention of bleeding through prophylaxis has become the evidence-based standard of care over the last 20 years after it was demonstrated to be superior to on-demand management of bleeds in preserving the articular integrity of hemophilia patients.[17] [18] In addition, the availability of large amounts of increasingly safe recombinant clotting factor concentrates (i.e., manufactured with ultrafiltration and nanofiltration viral inactivation techniques and with no proteins other than FVIII and FIX in the culture medium or final formulation) allowed a widespread implementation of prophylaxis regimens, at least in high-income countries.[19] However, while primary prophylaxis has important advantages, with a dramatic improvement of patients' quality of life, it also has have some drawbacks, such as the need of frequent intravenous injections owing to the short plasma half-life of the replaced coagulation factors (range 10–12 hours for FVIII, 18–20 hours for FIX). This problem can lead to suboptimal adherence to prophylaxis, particularly by younger patients in whom the issue of vein access is particularly cogent, such that it is sometimes necessary to use ports or other central venous access devices for the delivery of replacement therapy.

Starting in 2010s, attempts were made to overcome this problem by engineering clotting factors using recombinant technology, the goal being to obtain therapeutic products that, through higher factor peaks and trough levels, remained longer in the circulation and therefore managed to reduce the frequency of intravenous injections and the burden of prophylaxis.[20] The two techniques mainly adopted were coagulation factor fusion to proteins such as the fragment crystallizable (Fc) component of IgG1 or albumin; and conjugation with chemicals such as polyethylene glycol (PEG).[21] [22] [23] While albumin and Fc fusion prolong coagulation factor plasma half-life through avoidance of clearance by endolysosomal degradation, PEG, which is attached site-specifically or randomly to coagulation factors, acts by reducing clotting factor susceptibility to proteolysis and renal elimination.[24] [25] [26] A number of extended half-life (EHL) recombinant FVIII and FIX coagulation factors have been licensed and marketed over the last 8 years ([Table 1]). The strategies to improve pharmacokinetic parameters resulted in significant extensions of the half-life of FIX concentrates, usually three to five times longer than the standard half-life (SHL) of standard FIX products.[27] [28] [29] [30] [31] [32] However, EHL recombinant FVIII products achieved half-lives only 1.5 to 1.7 times longer than those of SHL FVIII concentrates.[33] [34] [35] [36] [37] [38] [39] [40] [41] [42] This lesser improvement in pharmacokinetic parameters is due to the binding of FVIII to von Willebrand factor (VWF), which stabilizes this moiety in plasma. Consequently, the maximum half-life that can be achieved by EHL FVIII products is the same as that of VWF.[43] A novel EHL recombinant FVIII product (BIVV001), created by the fusion of the B-domain deleted FVIII protein with the D′D3 domain of VWF, is under clinical development with the goal to overcome this limitation.[44]

Table 1 Licensed extended half-life recombinant factor VIII and factor IX products

Protein	Brand name, manufacturer	Plasma half-life (hours)	Half-life prolongation vs. SHL products
Efmoroctocog alfa, rFVIII	Elocta/Eloctate Biogen/Sobi	19	1.5–1.7
Rurioctocog alfa pegol, rFVIII	Adynovi/Adynovate Baxalta/Takeda	14.3	1.3–1.5
Damoctocog alfa pegol, rFVIII	Jivi Bayer	19	1.6
Turoctocog alfa pegol, rFVIII	Esperoct Novo Nordisk	19.9	1.6
Eftrenonacog alfa, rFIX	Alprolix Biogen/Sobi	82	4.3
Albutrepenonacog alfa, rFIX	Idelvion CSL Behring	101	5.3
Nonacog beta pegol, rFIX	Refixia Novo Nordisk	111	5.8

Abbreviations: rFIX, recombinant factor IX; rFVIII, recombinant factor VIII; SHL, standard half-life.

Source: Adapted from Mannucci, 2020[20] and Ozelo and Yamaguti-Hayakawa, 2022.[48]

Finally, improved VWF affinity and prolongation of the FVIII half-life were also recently attempted by using the single chain technology, in which the heavy and light chains of FVIII are covalently bound together to form a novel, more stable, recombinant protein.[45]

Pivotal clinical studies on adults and children with hemophilia identified EHL products as effective and safe in managing surgical interventions as well as in stopping or preventing bleeding in the context of episodic and prophylactic treatment regimens, with median annualized bleeding rates being markedly lower in patients receiving prophylaxis than in those receiving episodic treatment.[26] [46] [47] [48] Thanks to their better pharmacokinetic profile, EHL FVIII products can be administered effectively prophylactically twice a week instead of three times a week as done for SHL FVIII products. EHL FIX products are, however, much more satisfactory, because they can be administered every 10 or even 15 days. From a clinical point of view, the higher trough levels of both FVIII (2–3%) and FIX (5–10%) that can be achieved with EHL than with SHL products have lowered the annual burden of intravenous injections (average reduction of approximately 60% with EHL FIX and 30% with EHL FVIII) and hence decreased the annual consumption in units of EHL products, while maintaining a favorable median annualized bleeding rate. All these factors result in an improvement of adherence to prophylaxis and, ultimately, a better quality of life for patients.[24]

Management of Inhibitor Patients and Non-replacement Therapy

The development of inhibitory alloantibodies against FVIII or FIX is one of the most challenging complications of replacement therapy. Inhibitors, which develop in approximately 30% of patients with severe hemophilia A and in 10% of those with severe hemophilia B, make replacement therapy ineffective, limit patients' access to a safe and effective prophylaxis and increase their risks of morbidity and mortality.[49] [50] [51] [52] The rate of inhibitor formation varies depending on various factors, including the degree of deficiency, ethnicity (hemophiliacs belonging to African or Hispanic races have higher risks of inhibitor formation), type of genetic mutations (complete deletion of F8 or F9 and other null gene mutations predispose to inhibitor development) and environmental factors, the last including the class of replacement product, with plasma-derived products being associated with a reduced risk of inhibitors compared with recombinant products.[53] Although the introduction of bypassing agents, including recombinant activated factor VII (rFVIIa, NovoSeven) and activated prothrombin complex concentrates (Factor Eight Inhibitor Bypassing Activity or FEIBA), in the 1990s was a major improvement in the management of acute bleeding in inhibitor patients, several unmet needs still remained, first of all to reduce the frequency of the intravenous injections and render the prophylactic regimens more practical.[54] [55] [56] [57] Considering these unmet needs, innovative therapeutic strategies were developed not based on replacing or bypassing the deficient factor.[58] [59] Such non-factor-based therapies act by amplifying the coagulation cascade to generate thrombin (emicizumab) or by inhibiting naturally occurring anticoagulant pathways (fitusiran and concizumab).[59] So far, however, only the bispecific monoclonal antibody emicizumab has been licensed and marketed.[52] Emicizumab, by aligning activated FIX and factor X, facilitates their spatial interaction and thus promotes thrombin formation by mimicking the cofactor activity of activated FVIII independently of the degree of factor deficiency and the presence of inhibitors. Administered subcutaneously, emicizumab concentrations reach a steady state with a long plasma half-life, enabling long dosing intervals (at least every week or even every 2 weeks).[60] [61] [62] A series of pivotal trials (HAVEN 1-4) confirmed the efficacy and safety of emicizumab for prophylaxis of bleeding in children and adults with hemophilia A, with and without inhibitors, and this drug is currently licensed with these indications.[63] [64] [65] [66] The high rate of zero bleeding observed in the HAVEN trials of prophylaxis makes emicizumab the first-choice therapy for regular prophylaxis in hemophilia A patients with inhibitors. The fact that it has also been licensed for hemophilia A patients without inhibitors makes it an important alternative to current available options of SHL and EHL clotting factors, and it also has the advantage of a subcutaneous rather than intravenous route of administration, although no head-to-head comparative studies between replacement and non-replacement products have been conducted. Various randomized trials are, however, assessing the use of emicizumab prophylaxis in previously untreated children with severe hemophilia A at high risk of developing inhibitors.[48] Apart from the evident advantages of emicizumab, first and foremost the user-friendly subcutaneous route of administration which is particularly attractive for infants and children, a number of its potential disadvantages must be considered, including the difficulty in laboratory monitoring as proxy of its hemostatic efficacy and the still unproven long-term impact on the preservation of joint and bone heath.[24] [67] In addition, the management of breakthrough bleeds or surgery in severe hemophilia A patients under emicizumab prophylaxis may be challenging.[68] [69] In this context, the concomitant use of activated prothrombin complex concentrates should be avoided and rFVIIa preferred in inhibitor patients due to the lower thrombotic risk of the latter.[69] Similarly, the risk of de novo inhibitor development arising from the use of FVIII replacement in previously untreated patients in dangerous, high-risk circumstances (i.e., trauma, surgery) warrants more data.[48] Finally, although it has been hypothesized that the use of emicizumab prophylaxis during immune tolerance induction (ITI) in order to reduce bleeding and inflammation during tolerization could potentially ease the treatment burden of ITI, data regarding outcomes, annualized bleeding rates, and best dosing regimens of concomitant ITI regimens with emicizumab have yet to be assessed and are currently the object of research.[70] [71]

Gene Therapy

Gene therapy has been increasingly investigated during the last two decades, considering that it is the only treatment aimed at definitively curing hemophilia A and B.[72] The adeno-associated virus (AAV) represented the first vector associated with gene transfer in hemophilia animal models and, so far, AAV vectors (mainly AAV5 and AAV8) are the only vectors demonstrated to be able to achieve therapeutic levels of FVIII and FIX in hemophilia patients.[73] [74] A number of AAV vector-mediated gene therapy trials for hemophilia A and B have been conducted in humans so far or are currently ongoing.[48] In the beginning, gene transfer was performed preferentially in hemophilia B because the F9 gene is smaller than the F8 gene, which made it easier to pack the F9 cDNA in AAV vectors. This problem of the larger size of the F8 gene in hemophilia A was solved by using B-domain deleted human FVIII cDNA with a liver-specific promoter.[75] In addition, use of the gain-of-function F9 Padua gene mutation has improved FIX expression levels from these vectors, thus enabling lower vector doses to be used.[76] One hemophilia B trial found that F9 expression was sustained for 8 years after transgene delivery,[77] whereas F9 transgene expression in an earlier AAV-based trial had been relatively short-lived, with decreases being documented after 4 to 6 weeks.[78] Regarding gene therapy in hemophilia A, F8 expression in the longest trial has shown a decline over 4 years although still providing clinical benefit.[79] A more recent hemophilia A trial has demonstrated sustained F8 expression for more than 2 years, which suggests that it may be possible to achieve durable F8 transgene expression.[80] Finally, a phase 3 trial of sustained endogenous production of FVIII using the AAV5-hFVIII-SQ (Valoctocogene roxaparvovec) vector recently provided striking clinical results.[81] All in all, although the interim results of such trials are quite promising, several important issues regarding hemophilia gene therapy remain unsolved. First, there is the problem of achieving persistent expression of a non-integrating vector, such as AAV. The cellular immune response against transduced hepatocytes that present AAV capsid peptides may contribute to the observed lack of persistent transgene expression. The optimal immunosuppressive therapy does, however, still need to be determined. Other problems are the variability in the levels of FVIII and FIX expression among subjects participating in clinical trials and the unpredictability of the responses seen in both hemophilia A and B gene therapy trials. Finally, safety concerns regarding integration and a potential risk of malignancy can only be put to rest by long-term follow-up.[20]

Conclusion

Although the treatment of hemophilia has been in continuous evolution over the last 30 years, there have been amazing therapeutic advances in the last decade. The introduction of EHL recombinant FVIII and FIX has been a major advance in the management of hemophilia patients, enabling greater personalization of dosing regimens, with the ideal goal of completely avoiding, through higher trough plasma levels of the clotting factor, all spontaneous bleeds (zero bleeding). Although the newer products have been commercially available for less than 10 years, preliminary real-world data on their use suggest that they have a good safety profile, with no particular concerns regarding the risk of more inhibitor development.

Moreover, innovative products are available (e.g., emicizumab) or are in an advanced stage of development. These products are no longer based simply on replacement of the deficient clotting factor, but have new mechanisms of action. Emicizumab, thanks to its long half-life and the more acceptable subcutaneous route of administration has revolutionized hemophilia therapy, particularly in patients with inhibitors.

Finally, gene therapy is the only way to cure hemophilia definitively through the correction of the cause of this inherited bleeding disorder, although a number of critical issues must be resolved before it can become a first-line therapy for severe hemophilia. Nevertheless, the potential of gene therapy to maintain appropriate clotting factor levels and sustained expression over many years, releasing patients from the burden of injections, makes it clearly the most attractive potential therapeutic weapon and certainly the main field of clinical research in hemophilia in the coming decade.

Conflict of Interest

P.M.M. reports other from Bayer, personal fees from Kedrion, personal fees from Roche, during the conduct of the study.

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Publication History

Article published online:
15 September 2022