Prophylaxis re‐visited: The potential impact of novel factor and non‐factor therapies on prophylaxis

Prophylaxis, defined, as the regular replacement of the missing clotting factor given, in anticipation of, and with the intent to, prevent bleeding in persons with haemophilia (PWH; without inhibitors) was pioneered by a few European haemophilia treatment centres beginning in the late 1950s.1-3 The initial objective of prophylaxis was to convert a person with severe haemophilia (baseline factor [F] VIII/IX level <0.01 IU/mL [1%]) to a bleeding phenotype in keeping with moderate haemophilia by maintaining factor levels >1% at all times. Traditional full dose prophylaxis, begun early in life, has been associated with a >90% reduction in the rate of joint bleeding, an annualized joint bleed rate of <1, and a significant reduction in joint deterioration.4 Longer term benefits include a reduction in musculoskeletal pain, less patient disability and less need for orthopaedic surgery, reduced hospitalization rates and length of hospital stays, improved school and work attendance, and greater participation in professional and leisure activities resulting in improved quality of life (QOL).5 Prophylaxis also protects from other forms of haemorrhage (including intracranial haemorrhage).6 Recognizing its benefits, prophylaxis has become widely adopted, beginning first in more affluent and more recently in less affluent countries, as the ideal way of managing PWH.7, 8 Consensus definitions of prophylaxis have been developed according to when it is commenced (Table 1a) and according to its intensity (Table 1b). In addition, full time (or continuous prophylaxis) has been defined as being on prophylaxis for a minimum of 45 wk/y.9 In general, these definitions of prophylaxis were focused on preventing joint bleeds and maintaining musculoskeletal health. Having prophylaxis regimens that vary in intensity fits with the understanding that patients differ greatly with respect to their propensity to bleed as well as their pharmacokinetic handling of FVIII/IX. Thus tailoring of prophylaxis to individual patients’ needs might allow for more efficient allocation of therapy such that it will not be “wasted” on patients that may not require as much replacement haemostatic products and yet not be denied to patients who require more.11 Tailoring of prophylaxis has consequently become widely practiced over the last 10-20 years. Tailoring of prophylaxis to the ability of a society to pay for it has also led to the development of low dose prophylaxis regimens.12 These regimens have also been shown to achieve considerable, albeit, smaller reductions in rates of joint bleeding. 13 Interventional studies on prophylaxis showing dramatic reductions in bleeding rates probably led to an overinflated view of what could be achieved with the clotting factor concentrates (CFCs) that we have had and led to some in the haemophilia community advocating for a goal of “zero bleeds”. However standard prophylaxis has relied on the frequent intravenous replacement of costly but short-acting (standard half-life; SHL) CFCs and has been burdensome for many patients and families, somewhat tempering the benefits that have been obtained with prophylaxis. The short half-life of SHL-CFC results in: (i) the need for frequent venepunctures - this in young children often leads to the need for central venous access devices (CVADs) and in older children/adults to reduced patient adherence14; and (ii) to prophylaxis being a sinusoidal curve of factor peaks (factor levels of 50%-80%) and troughs (factor levels of 1%-3%) corresponding to times when patients can safely be more active and times when they cannot. There has been an increasing recognition that trough levels of 1%-3% are insufficient to prevent all bleeds in all PWH.15 The development and introduction of new haemostatic therapies in haemophilia are forcing us to revisit the concepts and definitions of prophylaxis. These new therapies (some already in clinical use and others still in development) include extended half-life (EHL) intravenously administered CFCs, subcutaneously administered CFCs,16 FVIII mimetics (Emicizumab) and non-factor drugs that inhibit natural endogenous anticoagulants (antithrombin [AT], tissue factor pathway inhibitor [TFPI] and activated protein C [APC]).17 Many of these agents (particularly non-factor therapies) do not fit with the current concept of prophylaxis as they do not replace the missing coagulation factor, are administered subcutaneously, and in some cases given as infrequently as once or twice monthly. Additionally, many of these agents will eliminate the peak and trough curves of protection that we now see with SHL-CFC prophylactic regimens. Aspirations and expectations of what will be possible with prophylaxis with these new agents are changing. EHL-CFCs allow for less frequent infusions of FVIII/IX, attaining higher trough FVIII/IX levels, or both. This is particularly the case with EHL-FIXs - their half-life extension of 3-5 fold over SHL FIXs permits patients to receive factor once every 7-14 days and still, in the case of some of these EHL-FIXs, maintain FIX trough levels of >10% to 20%.18, 19 More modest reductions in frequency of administration or modest increases in factor trough levels (likely not both) may be accomplished with EHL-FVIIIs. FVIII mimetics and non-factor therapies can similarly be given subcutaneously and very infrequently and yet achieve good/excellent bleed protection. Extended half-life-CFCs, particularly FIX-EHLs, as well as FVIII mimetics may make it easier to start patients at an earlier age on prophylaxis without the need for CVADs. This may cause a reevaluation of what constitutes primary prophylaxis (see Table 1a) as perhaps we will start prophylaxis without waiting for any joint bleeds to occur, and before the age of 1 year of age. EHL-CFCs, as well as FVIII mimetics and non-factor therapies, may allow for more convenient dosing days/times (which might improve adherence) and might lead to increased uptake of prophylaxis among patients not currently on prophylaxis (eg those with moderate haemophilia). Better prophylactic coverage should permit greater level of sports participation (potentially including some sports involving vigorous physical activity that have traditionally been discouraged).20 All of these developments are transforming the concepts of prophylactic intensity. No longer can one refer to full dose prophylaxis as prophylaxis that results in factor trough levels of 1%-3%. With the steady advance of modified clotting factors as well as effective subcutaneous non-factor drugs and promising gene therapies currently in clinical trials,21 it seems that improved clinical outcomes are within reach for our patients: extremely low bleed rates, full or near full prevention of haemophilic arthropathy, fewer restrictions in activities and improved QOL. Whether this will be on the basis of achieving much higher factor trough levels through EHL-CFCs, or through subcutaneously administered CFCs or by means of non-factor therapies or using a combination of both is still to be determined. With these changes, new definitions for prophylaxis are required. Modern prophylaxis definitions will need to be inclusive of a wide variety of haemostatic agents with diverse mechanisms of action, and modes of administration. We propose the following as a new definition of prophylaxis: the regular administration of a haemostatic agent/agents that safely, effectively and conveniently prevent bleeding while allowing PWH to lead active lives. Prophylaxis in the future will create new challenges: The development of new therapies for haemophilia will likely have considerable economic ramifications. Traditionally when new therapies are introduced they tend to be more expensive then available “older therapies”. This may limit the willingness of countries/societies to pay for these newer therapies. However, the price of “older therapies” often tends to drop in such scenarios. This may lead to the increased uptake of traditional prophylaxis with SHL factor concentrates where their reduced price may make traditional prophylaxis much more affordable. Prophylaxis has come a long way from the initial observations of Inga Marie Nilsson and her colleagues beginning in the 1950s. Prophylaxis up until now has been limited by the therapies available (ie CFCs intravenously administered, with short half-lives that create peaks and troughs in factor levels and protection). Excitingly prophylaxis appears to be poised for a dramatic change that will more effectively reduce bleeding risks. As the haemophilia community moves into these new treatment paradigms much work will be needed to optimize this transformation of care. We wish to thank Drs. Victor Blanchette (Chair of the IPSG Executive) and Rolf Ljung (member of the IPSG Executive) for their careful review of our manuscript and for providing helpful suggestions. Manuel Carcao reports having received research support from Bayer, Bioverativ/Sonofi, CSL-Behring, Novo Nordisk, Octapharma, Pfizer and Shire. He has also received honoraria for speaking/participating in advisory boards from Bayer, Bioverativ/Sonofi, Biotest, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche and Shire. Thierry Lambert has served on advisory boards for: Bayer, CSL-Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire and Sobi. Cindy Leissinger reports having served on advisory boards for the following: Bayer, CSL-Behring, Kedrion, Novo Nordisk, Octapharma, Shire and additionally she has received research funding from Roche. Carmen Escuriola-Ettingshausen received honoraria for speaking/participating in advisory boards from Alnylam, Biotest, CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche and Shire. Elena Santagostino has served on advisory boards and/or speaker bureaus for: Bayer, CSL-Behring, Kedrion, Novo Nordisk, Octapharma, Shire, Roche, Pfizer, Grifols, Sobi and Biogen. Louis Aledort has served on advisory boards to Kedrion and Shire; has Chaired a Data Safety Monitoring Board for Octapharma and has received honoraria/speaking fees from Bayer. The International Prophylaxis Study Group (IPSG) is a not for profit Study Group that is supported by grants from Bayer Healthcare, Bioverativ-Sonofi, CSL-Behring, Novo Nordisk, Pfizer and Shire to the Hospital for Sick Children (“SickKids”) Foundation in support of the IPSG. None of the members of the Prophylaxis Expert Working Group receive remuneration for their contributions to the IPSG. All authors are members of the Prophylaxis Expert Working Group of the International Prophylaxis Study Group (the IPSG) and all contributed to writing and editing the manuscript without input from the industry sponsors of the IPSG.

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