Elsevier

The Lancet

Volume 397, Issue 10274, 13–19 February 2021, Pages 630-640
The Lancet

Review
The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing

https://doi.org/10.1016/S0140-6736(20)32722-7Get rights and content

Summary

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

Introduction

Haemophilia A and B are rare congenital X-linked coagulation disorders caused by factor VIII (FVIII) deficiency in haemophilia A, and factor IX (FIX) deficiency in haemophilia B.1 In severe haemophilia (FVIII or FIX <1 international units [IU]/dL) there is spontaneous or post-traumatic bleeding, or both, primarily into joints and other tissues, some of which might be life-threatening or organ-threatening. The main observed morbidity is caused by repeated haemarthroses, which lead to a degenerative joint disease (haemophilic arthropathy), resulting in chronic pain and loss of function.1 Prevention of bleeding episodes with replacement therapy has been the cornerstone of management for these disorders for the past decades to reduce mortality and chronic arthropathy.1 Replacement therapy is done with FVIII and FIX concentrates delivered by intravenous injections, either episodically to treat acute bleeds, or according to prophylactic regimens to prevent bleeds.1 Long-term prophylaxis started early in life has been proven to be highly effective in preventing joint damage2, 3 and life-threatening bleeds (ie, intracranial haemorrhage),4 and is the standard of care.5 The frequency of regular intravenous injections needed to attain and maintain adequate haemostatic concentrations of FVIII and FIX might impair adherence to treatment, which might lead to suboptimal treatment effectiveness.6 Moreover, the high cost of treatment restricts access for most patients worldwide.7

Treatment optimisation has been the main objective over the last decade, with progress based on the finding of delayed but not abolished development of joint damage in large cohorts of patients regularly treated with standard prophylaxis.6 Accordingly, prophylactic regimens have shifted from standardised, so-called one-size-fits-all strategies to the individualisation of regimens for the best outcomes both from the clinicians' and the patients' perspective.8, 9

In recent years, with the first of these products licensed in 2014, new bioengineered FVIII and FIX molecules with enhanced pharmacokinetic profiles were developed. Some of these molecules are an improved form of previously used molecules, and some are products with an entirely new origin. Fusion and conjugation technologies (ie, fusion with albumin or the Fc fragment of immunoglobulins; conjugation with polyethylene glycol) have resulted in several extended half-life (EHL) FVIII or FIX products, which have been licensed to treat and prevent bleeding episodes in patients with congenital haemophilia A and B.10, 11, 12, 13, 14, 15, 16, 17 The pharmacokinetic improvement has been more substantial for FIX (3 to 5 times longer half-life) when compared with FVIII (1·5 to 1·8 times longer half-life). This difference is because all FVIII products require stabilisation in plasma from binding to von Willebrand factor (VWF), which creates a ceiling effect by linking the pharmacokinetics of FVIII products to the clearance of VWF.18 These molecules are given less frequently, reduce the treatment burden, and can maintain higher plasma factor concentrations.10

The development of anti-FVIII or anti-FIX neutralising antibodies, known as inhibitors, in patients who are previously untreated is the main complication of replacement therapy,1 even with EHL products;19, 20 with inhibitor incidence in these patients ranging between 25 and 40%. In fact, in the presence of inhibitors, particularly at high titres, haemostasis cannot be restored by factor replacement therapy. Thus, the treatment of acute bleeds requires the use of alternative haemostatic agents that can bypass the inhibitory effect of the antibodies.1 Such bypassing agents (BPA), represented by recombinant activated FVII and activated prothrombin complex concentrate, have many drawbacks: their effectiveness is often suboptimal, inconsistent, and unpredictable; their use is associated with the risk of thrombosis; their haemostatic activity cannot be easily monitored; they are costly treatments; and prophylaxis is challenging and not always effective.21

To close this big therapeutic gap, several new molecules, all delivered subcutaneously, were developed and provide effective prophylaxis despite the presence of inhibitors.22, 23, 24, 25, 26 A humanised bispecific monoclonal antibody (emicizumab) improves haemostatic function by mimicking the co-factorial function of activated FVIII.27 Other novel therapeutics can rebalance haemostasis by targeting the natural inhibitors of the coagulation cascade: antithrombin, tissue factor pathway inhibitor (TFPI), and activated protein C.25, 26, 28, 29, 30

Finally, in this rapidly evolving treatment landscape, a functional cure can be found by gene therapy, with which a protective endogenous steady state production of FVIII and FIX can be established. The safety and efficacy of these approaches are under investigation in several clinical trials, which are still ongoing.31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46

Section snippets

Therapeutic goals in haemophilia: the role of long-term prophylaxis

Over the last decades, the goal of the management of patients with haemophilia has evolved from supportive care, to reducing the risk of spontaneous bleeds, to the elimination of all clinically evident bleeds, including those related to physical activity. These goals can be achieved with prophylactic replacement therapy with FVIII and FIX concentrates. The primary aim of regular long-term prophylaxis is to abolish recurrent joint bleeds and prevent chronic arthropathy. Early insight into

Moving from replacement to non-replacement therapy: a new framework for prophylaxis

Despite the great advantages of prophylaxis over episodic treatment, the restrictions of the route of administration and potential development of neutralising anti-FVIII and anti-FIX antibodies represent the main challenges with replacement therapy. Therefore, the rationale behind the design of new non-replacement therapies is to overcome the difficulties of intravenous delivery and to improve the effectiveness of therapies in all patients, regardless of the presence or absence of inhibitors.

Future innovations for haemophilia prophylaxis

The current therapeutic armamentarium has provided a wide range of options suitable for different patient profiles, thus favouring treatment tailoring to meet specific clinical and personal needs.

More innovations are under investigation for haemophilia care, with the specific aim of providing a high degree of protection against bleeding with low burden treatment regimens that should continue to improve outcomes and quality of life.

Gene therapy: endogenous prophylaxis or cure?

Both haemophilia A and B are ideal candidates for gene therapy because they are monogenic diseases that might be treated effectively by delivering a substitute copy of the FVIII (F8) and FIX (F9) genes. In fact, a successful gene therapy approach would result in a sustained endogenous production of FVIII and FIX proteins at concentrations that could provide effective prophylaxis without the need for exogenous factor replacement therapy. Ideally, sustained concentrations in the normal range in

Gene therapy: current limitations and unknowns

Despite these positive results from gene therapy clinical trials to date, some limitations and potential safety concerns are likely to prevent the widespread use of such an approach.

Future innovations for gene therapy

Beyond the gene addition strategies currently under investigation, there are other technologies that could be used to correct the gene defect of the host genome. One of these techniques, gene editing, relies on the use of clustered regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated protein (Cas) 9. Those molecular scissors induce double-stranded breaks at the target genome site, thus favouring the insertion of template DNA with the wild-type gene.94

Concluding remarks

Haemophilia treatment has seen a rapid revolution in the last several decades. Table 5 summarises the main strengths and weaknesses of the aforementioned therapeutic options.

The availability of safer plasma-derived products and recombinant SHL concentrates favoured the adoption of prophylaxis, thus improving joint outcomes and quality of life. However, these advances came with several drawbacks, including difficult venous access, poor adherence, and scarce affordability on a global scale. The

Search strategy and selection criteria

Data for this Review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms “h(a)emophilia A”, “h(a)emophilia B”, “prophylaxis”, “extended half-life”, “emicizumab”, “concizumab”, AND “gene therapy”. Abstracts and reports from scientific meetings related directly to previously published work were included to give the most updated information. The dates of the articles ranged from January, 2010, to October, 2020, and were in

References (94)

  • M Cardinal et al.

    A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers

    J Thromb Haemost

    (2018)
  • I Hilden et al.

    Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model

    Blood

    (2012)
  • SGI Polderdijk et al.

    Design and characterization of an APC-specific serpin for the treatment of hemophilia

    Blood

    (2017)
  • KA High et al.

    A phase 1/2 trial of investigational SPK-8011 in hemophilia A demonstrates durable expression and prevention of bleeds

    Blood

    (2018)
  • W Miesbach et al.

    Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

    Blood

    (2018)
  • S Pipe et al.

    One-year data from a phase 2b trial of AMT-061 (AAV5-Padua hFIX variant), an enhanced vector for gene transfer in adults with severe or moderate-severe hemophilia B

    Blood

    (2019)
  • AC Nathwani et al.

    Adeno-associated mediated gene transfer for hemophilia B: 8-year follow-up and impact of removing “empty viral particles” on safety and efficacy of gene transfer

    Blood

    (2018)
  • LA George et al.

    Efficacy and safety in 15 hemophilia B patients treated with the AAV gene therapy vector fidanacogene elaparvovec and followed for at least 1 year

    Blood

    (2019)
  • W Miesbach et al.

    Stable FIX expression and durable reductions in bleeding and factor IX consumption for up to 4 years following AMT-060 gene therapy in adults with severe or moderate-severe hemophilia B

    Blood

    (2019)
  • P Chowdary et al.

    A single intravenous infusion of FLT180a results in factor IX activity levels of more than 40% and has the potential to provide a functional cure for patients with haemophilia B

    Blood

    (2018)
  • B Konkle et al.

    Updated follow-up of the Alta Study, a phase 1/2, open label, adaptive, dose-ranging study to assess the safety and tolerability of SB-525 gene therapy in adult patients with severe hemophilia A

    Blood

    (2019)
  • S Pipe et al.

    First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A

    Blood

    (2019)
  • AC Nathwani et al.

    GO-8: preliminary results of a Phase I/II dose escalation trial of gene therapy for haemophilia A using a novel human factor VIII variant

    Blood

    (2018)
  • PW Collins et al.

    Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

    J Thromb Haemost

    (2009)
  • K Fischer et al.

    Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s

    Blood

    (2013)
  • BM Feldman et al.

    Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort

    Lancet Haematol

    (2018)
  • J Mahlangu et al.

    Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

    Blood

    (2016)
  • BA Konkle et al.

    Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors

    J Thromb Haemost

    (2007)
  • G Young et al.

    A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors

    Blood

    (2019)
  • SW Pipe et al.

    Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study

    Lancet Haematol

    (2019)
  • KL Zimowski et al.

    Severe bleeding events in hemophilia A patients receiving emicizumab prophylaxis

    Blood

    (2019)
  • NC Leksa et al.

    Intrinsic differences between FVIIIa mimetic bispecific antibodies and FVIII prevent assignment of FVIII-equivalence

    J Thromb Haemost

    (2019)
  • PJ Lenting et al.

    Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII?

    Blood

    (2017)
  • B Samuelson Bannow et al.

    Factor VIII: long-established role in haemophilia A and emerging evidence beyond haemostasis

    Blood Rev

    (2019)
  • RA Gruppo et al.

    Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia

    J Thromb Haemost

    (2018)
  • S Stanford et al.

    Adenovirus-associated antibodies in UK cohort of hemophilia patients: a seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A

    Res Pract Thromb Haemost

    (2019)
  • K Rajavel et al.

    Co-prevalence of pre-existing immunity to different serotypes of adeno-associated virus (AAV) in adults with hemophilia

    Blood

    (2019)
  • I Zolotukhin et al.

    Potential for cellular stress response to hepatic factor VIII expression from AAV vector

    Mol Ther Methods Clin Dev

    (2016)
  • A Nowrouzi et al.

    Integration frequency and intermolecular recombination of rAAV vectors in non-human primate skeletal muscle and liver

    Mol Ther

    (2012)
  • PM Mannucci et al.

    The hemophilias--from royal genes to gene therapy

    N Engl J Med

    (2001)
  • J Astermark et al.

    Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized

    Br J Haematol

    (1999)
  • MJ Manco-Johnson et al.

    Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia

    N Engl J Med

    (2007)
  • NG Andersson et al.

    Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment

    Br J Haematol

    (2017)
  • A Srivastava et al.

    WFH guidelines for the management of hemophilia, 3rd edition

    Haemophilia

    (2020)
  • MW Skinner

    WFH: closing the global gap--achieving optimal care

    Haemophilia

    (2012)
  • A Iorio et al.

    Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement

    Haemophilia

    (2017)
  • D Nugent et al.

    Haemophilia experiences, results and opportunities (HERO) study: treatment-related characteristics of the population

    Haemophilia

    (2015)
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