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Evolving protection in haemophilia

Support for the preparation of this report was provided by Swedish Orphan Biovitrum

Long gone are the days when patients with haemophilia had to inevitably suffer the devastating consequences of this disease, which included life-threatening bleeding, pain, and disability. With the increasing adoption of coagulation factor replacement therapies, prophylaxis outcomes have substantially improved for patients, not only clinically but also in terms of quality of life (QoL). 
However, limitations to the long-term effectiveness and ability to prevent complications still persist with conventional anti-haemophilic coagulation factors. New coagulation factor replacement therapies with extended half lives that aim to provide individualised approaches and that are, at the same time, reducing treatment burden for patients, as well as being cost-effective, are now available. Indeed, the cornerstone of treatment remains preventing and controlling bleeding, and the current treatment paradigm is evolving, broadening its scope to include a more ‘holistic’ perspective of the disease, where joint care, pain control and QoL play a significant role.
In the past, the most common treatment regimens for haemophilia A involve the administration of factor VIII coagulation factor 3–4-times a week,1 but a 12-month retrospective study in Europe showed that many patients still presented moderate-to-severe bleeding episodes, with median annualised bleeding rates (ARBs) ranging from 1.0 to 8.0 for patients on prophylaxis, and from 4.5 to 18.0 for those treated on demand.2
Similar findings can be observed in patients with haemophilia A and B (Figure 1).2 The data demonstrate that there is still an unmet need with regards to offering protection against bleeding.Extended half-life factors can help support prolonged haemostatic protection. Recombinant human coagulation factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life FVIII molecule (Elocta®; approved in 2015 for the treatment of haemophilia A). rFVIIIFc has a lower clearance, compared with conventional rFVIII therapies, of approximately 33%, as well as 1.5-fold longer half-life and a greater mean elimination half-life (19.0 versus 12.4 hours) in adults and adolescents with haemophilia A.3
Figure 1: Annualised bleeding rates in patients with haemophilia A and B in several European countriesa
There is also potential to individualise dosing with rFVIIIFc according to according to clinical and patient objectives, either by reducing the number of injections per week and/or weekly consumption while at least maintaining the desired trough level, based on modelling of pharmacokinetic profiles of patients receiving FVIII replacement in the Phase I/IIa and Phase III studies.2,4,5 Recombinant factor IX Fc fusion protein (rFIXFc; Alprolix®, approved in 2016 for the treatment of haemophilia B) also demonstrates a reduced clearance and prolonged half life when compared with conventional rFIX.6

Clinical experience with recombinant Factors VIIIFc and FIXFc

rFVIIIFc and rFIXFc were evaluated in the pivotal Phase III A-LONG (NCT01181128) and B-LONG (NCT01027364) studies3,6 and paediatric studies7,8 (NCT01458106 and NCT01440946). Extension studies (NCT0145473 and NCT01425723) have also been conducted9,10 in haemophilia A and B. Overall, rFVIIIFc and rFIXFc count with >3.5 and ~4.0 years of real-world evidence, respectively (Figure 2).11–14 
Figure 2: Clinical experience with rFVIIIFc in haemophilia A and rFIXFc in haemophilia B
Data from the Phase III A-LONG trial showed a median ABR for rFVIIIFc of 1.6 for patients on individualised prophylactic treatment and 3.6 for those receiving a weekly prophylactic regimen vs. 33.6 for patients receiving on-demand treatment. The median rates for annualised spontaneous bleeding and joint bleeding were zero, and 45.3% of patients experienced no bleeding episodes. Moreover, the majority of the bleeding episodes was controlled with 1–2 injections of clotting factor.3 A post hoc analysis of A-LONG data showed reduced ABRs with individualised rFVIIIFc prophylaxis in the last three months of the study, compared to before the study, with a median dosing interval of 3.5 days and 98.8% of the patients decreasing injection frequency.3,15
A post-hoc analysis of data showed prophylaxis with rFVIIIFc also resulted in continuous improvements in the Modified Haemophilia Joint Health scores (mHJHs) during the extension study (ASPIRE), which was approximately 4 years in adults and adolescents, and 3 years in children. The components of the mHJHs showing the greatest improvements were swelling, range of motion, and strength, with a mean change in total score from the A-LONG baseline of –4.1 after 2 years.16,17 In addition, health-related QoL scores in the sports and leisure, physical health, and feeling subdomains in the Haem-A-QoL questionnaire also improved over time.18
Compared with conventional rFIX therapies, rFIXFc presented a 4.8 longer half-life, with reduced ABRs in adults and adolescents in the Phase III B-LONG study (reduction by 83% and 87% for weekly and interval-adjusted prophylaxis compared with episodic treatment); the median prophylactic dosing interval in this study was 14 days, achieved by 53.8% of the patients in the last three months of treatment.6,19 Subsequent analysis showed that more than three-quarters of patients receiving prophylaxis continued or increased their physical activity, and physical health and sports and leisure scores also improved in the B-LONG study.20,21
Additionally, rFIXFc shows efficacy when used for perioperative management, with haemostasis rated as ‘excellent’ by investigators in the majority of major and minor surgeries from the pre-operative dose until the end of the procedure with a single infusion, and no serious adverse events deemed to be related to the blood coagulation factor or the development of neutralising inhibitor antibodies.10,22,23 rFVIIIFc also showed efficacy in the perioperative management of major and minor surgeries.3,7,9,24
Finally, interim data from the ASPIRE and B-YOND extension studies confirmed the long-term safety of both products, with no inhibitor development during the parent studies,9,10 and real-world surveillance data confirms the unchanged benefit–risk profiles.11–14
rFVIIIFc and rFIXFc are currently being tested in previously untreated patients in the PUPs A-LONG (NCT02234323) and PUPs B-LONG (NCT02234310) studies. rFVIIIFC is not approved for immune tolerance induction (ITI) in haemophilia patients with inhibitors; however, two prospective studies are ongoing to assess rFVIIIFc for ITI in patients with severe haemophilia A who are undergoing the first treatment for ITI (NCT03093480) or who have failed prior ITI therapy (NCT03103542). 

Does intense prophylaxis always lead to the desired outcomes?

Despite the plethora of data showing the advantages of standard rFVIII and rFIX therapies, prophylaxis with these products may delay versus prevent the onset of joint disease. A German study followed up 49 patients with haemophilia A for 28 years and revealed that they developed joint disease despite intensive prophylactic treatment, most prominently located in the ankles. Moreover, this linear pathological process only became apparent approximately ten years after treatment initiation.25
A cross-sectional study using magnetic resonance imaging to evaluate joint status in patients with severe haemophilia A, according to time of initiation of primary prophylaxis, confirmed that the ankle was the most frequently affected joint. Interestingly, it was observed that only patients who started their prophylactic regimens before reaching two years of age did not develop arthropathy during the 28-year follow-up period; by contrast, patients who started treatment when they were aged 2–6 years developed joint disease as young adults.26
The Joint Outcome Study further pointed to a reduction of 83% in the risk of developing joint damage in patients on prophylaxis over 4–5 years versus those receiving on-demand treatment, but 7% of the patients still showed worsening of their articular status. The number of total and joint bleeds was 3.27 and 0.63 per patient per year, respectively, for patients on prophylactic regimens compared with 17.69 and 4.89 for those following an enhanced episodic infusion schedule.27 Another study conducted in Sweden evaluated the effects of lifelong prophylaxis in adults with severe haemophilia A or B, confirming that early prophylaxis (starting at or before three years of age) was effective in controlling joint bleeding and preserving joint status.28
Altogether, these data indicate that although prophylactic treatment with conventional / standard half-life therapies has substantial benefits versus on-demand treatment, these may not be sufficient from a lifetime perspective to prevent the onset of joint disease. In fact, breakthrough bleeds may still occur throughout prophylactic treatment, and there may be joint damage without overt bleeding. In addition, most patients develop joint damage over time, and it progresses once arthropathy is present, even in the absence of bleeding. 
These observations of the limitations with current prophylaxis raise the issue of how intense treatment should be to improve outcomes related to joint health. A 3%–5% threshold of FVIII activity levels has been shown to protect against spontaneous joint bleeds,29 but the ultimate aim is to eliminate spontaneous bleeding, in particular in the joints, and to reduce the risk of clinically silent bleeds and chronic synovitis. Therefore, personalised and more intensive regimens are needed to control arthropathy in haemophilia.

Protecting people with haemophilia A: From practicalities to treatment outcomes

Despite its achievements in preventing bleeding, prophylaxis in haemophilia ultimately aims to increase function by reducing joint bleeds, prolong survival by reducing severe life-threatening bleeds, and improve QoL by reducing pain and improving mobility. Prophylaxis is most effective when started early after the diagnosis,25,30,31 but the frequency of injections is dependent on the half-life of the clotting factors being administered,30 which may in turn have an impact on treatment adherence. In fact, it has been shown that there is an increased risk of bleeds when factor levels fall below 1IU/dl in severe haemophilia A patients.32
Prophylaxis can be personalised with the use of clotting factors with extended half-lives (EHL), and some aspects related to the entire ecosystem around the patients must be taken into consideration when switching to such agents. A schedule of 2–3 weekly injections is common for children and adolescents, but not so much for adults, who might prefer a less demanding dosing schedule with more time between injections. 
Also, practicalities are important. It is important to identify the patients who will benefit the most from the switch, for example, those who prefer a more flexible and convenient dosing schedule, those who need more intensive treatment but do not wish to initiate or escalate prophylaxis with conventional FVIII, those who are at risk of residual or subclinical haemarthroses, and hence at risk of subsequent arthropathy, due to insufficient trough FVIII levels, and those who request it after having learned about the benefits of these new products.
A monocentre case study in France showed that, out of 48 patients who switched to rFVIIIFc, 32 changed their dosing schedules, reducing the injection frequency or introducing prophylaxis. Of those 48 patients, 40 received long-term prophylaxis, without any obvious preference for a particular treatment pre-switch, and 8 were treated on demand. After switching to rFVFc, prophylaxis was continued or initiated in 47 patients, with a good/excellent qualitative assessment of efficacy in 44 out of 45 patients evaluated. 
As of now, FVIII trough levels (1–4%) were shown to be consistent with the clinical outcomes, and no inhibitor development was observed. Although larger and longer surveys need to be conducted to determine QoL and health economic outcomes, rFVIIIFc may optimise outcomes in some patients by increasing the level of protection in patients at risk of residual bleedings, and by making prophylaxis acceptable and feasible among patients reluctant to changes in their treatment plans.

Reconsider treatment goals in haemophilia B: Clinical experience with rFIXFc

One of the major achievements of prophylaxis regimens for haemophilia patients is sustained protection from bleeds; however, among the treatment goals reported by patients to be important to them is decreased injection frequency to reduce the treatment burden and improve QoL. In addition, having weekly injections allows patients and/or their carers to remember to take their medication, which contributes to improved adherence. However, these patient-related benefits are related to clinical outcomes. 
The anticipated desired outcomes with rFIXFc are to achieve and maintain low ABRs, as well as attain adequate FIX levels (individualised for the patient’s bleeding phenotype, joint status, and activity levels), prevent bleeding when undergoing surgical or invasive medical procedures, and enhance patient experience.
A study was conducted in the Republic of Ireland to assess FIX usage among patients with haemophilia B on conventional or EHL FIX after switching to rFIXFc  At baseline, 22 and 6 patients were receiving prophylaxis and on-demand treatment with FIX, respectively, compared with 26 and 0 patients on rFIXFc. The mean prophylactic doses were higher for the conventional agents, and some of the patients were on quite high weekly doses.
After three months on rFIXFc prophylaxis, FIX trough levels increased compared with rFIX trough levels before switching, and the median ABR after six months of follow-up was 3 for the standard agents versus 1 for rFIXFc, with approximately half of the patients on rFIXFc experiencing zero bleeds. Moreover, weekly consumption in patients on doses >98 IU/kg/week of rFIX decreased significantly.
A total of eight patients underwent minor surgical procedures, and only one experienced bleeding and required local homeostasis and more than one injection in this study. With regard to patient experience, ease of use, efficacy and confidence were reported by individual patients, although these were not formally quantified.
It is important to identify patients who are more likely to benefit from treatment with rFIXFc: those with poor venous access or needle phobia, or those who show poor adherence to prior therapy, those who are not receiving adequate treatment because of fast clearance, those with breakthrough bleeds and/or synovitis with conventional replacement treatment, or those with a very active life. It is also important to agree in advance on the individual treatment goals, taking into consideration what constitutes a good measure of success (for example, increased protection, fewer bleeding episodes, or improved convenience) and re-evaluating goals and outcomes at three and six months post-switch.

Key insights

Current prophylaxis regimens provide significant benefits to patients, but may not be optimal if other aspects beyond bleeds prevention are considered, such as joints protection, patients’ adherence and QoL. The new EHL-Fc clotting factors could facilitate at least maintaining adequate protection, even in cases of fast drug clearance, and improve adherence, as well as patient confidence and experience. The question that remains is if the available clinical trial data will translate into the clinical practice. 
Based on the data and the experience presented, the audience felt that the priority when setting treatment goals for patients was the reduction of breakthrough and joint bleeds, but the importance of trough levels as an indicator of a favourable direction of treatment must be emphasised, and noted that relief of patient treatment burden can lead to better protection. Therefore, although bleeding remains at the cornerstone of expected treatment outcomes, ABRs alone should not be considered as the only treatment objective. Joint health, QoL and increased/maintained physical activity are also important goals, although QoL is not usually assessed in clinical practice. 
Finally, the audience in this symposium presentation voted real-world evidence to be most useful when evaluating new treatments for haemophilia. Pivotal clinical trials undoubtedly provide fundamental data for a specific patient population, whereas real-world studies can contribute valuable information reflecting use in real-world conditions, outside of a clinical trial setting. Both rFVIIIFc and rFIXFc have the longest real-world experience among EHL products, and the many ongoing real-world experiences may complement these data and help shed light on the best strategies to improve outcomes for patients with haemophilia.

The satellite symposium Evolving Protection in Haemophilia and Helping to Advance the Standard of Care was held on 7 February 2018 at the 11th Annual Congress of the European Association for Haemophilia and Allied Disorders, Madrid, Spain



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