Expert opinion paper on the treatment of hemophilia A with emicizumab

ABSTRACT Introduction Prophylaxis with emicizumab, a bispecific monoclonal antibody that mimics FVIII function, has shown encouraging results in clinical trials in terms of efficacy and safety. However, current experience is limited, and many areas of concern to clinicians have yet to be reviewed. Areas covered This paper reviews the experience of hemophilia A patients treated with emicizumab based on the results of clinical trials and real-life studies. The authors place special emphasis on issues such as the management of these patients in situations of hemorrhage and/or surgical interventions, joint health or laboratory monitoring. Expert opinion Treatment with emicizumab has been shown to improve joint health and reduce bleeding, of particular interest to patients with inhibitors and high bleeding rates. However, there are still concerns about its administration in neonates and previously untreated patients due to limited reported experience. Laboratory monitoring is not strictly necessary due to the stable pharmacokinetics emicizumab has been shown to exhibit, however, tests that globally assess hemostasis may be useful especially in cases of bleeding or surgery. The authors are also of the opinion that prophylaxis before minor surgery is not necessary and that major surgeries can be safely performed with additional prophylactic coagulation factor.


Introduction
Hemophilia is a life-threatening inherited bleeding disorder that causes prolonged bleeding that is difficult to control and is most caused by deficiency of clotting factors VIII (FVIII) in hemophilia A (HA) and factor IX (FIX) in hemophilia B (HB) [1].Hemophilia A is much more common, constituting about 80-85% of all hemophilia patients and, although both have similar clinical characteristics, possible differences in hemorrhagic phenotype, factor consumption and degree of arthropathy have been reported [2].
Prophylaxis is still considered the gold standard in the treatment of patients with severe hemophilia or high hemorrhagic phenotype.It is mainly based on substitution therapy, which consists of providing the patient with the deficient clotting factor.However, this approach has major limitations, such as the need for frequent intravenous administration to achieve adequate levels of deficient factor (limited by venous access), the high cost of treatments that compromise their widespread and optimal use, and the development of neutralizing antibodies against FVIII, which drastically reduces the efficacy of replacement therapy [3].The advent of monoclonal antibodies has revolutionized the treatment landscape for many diseases, including HA.In particular, the introduction of emicizumab (Hemlibra®, Hoffman-la Roche, Basel, Switzerland) has been shown to improve the efficacy of prophylaxis in these patients, helping to significantly prevent the number of bleeds in both inhibitor and non-inhibitor patients [4][5][6][7].Emicizumab is a humanized bispecific monoclonal antibody, which can exert the cofactor function of deficient VIII by binding FIX to FX and thus re-establishing the normal course of hemostasis [8].Emicizumab also offers several advantages over conventional therapies, such as a prolonged half-life (4-5 weeks), which allows dosing even every two weeks or monthly; a reduction in total treatment costs; and provides an alternative for patients with inhibitors, as they do not react with emicizumab, due to the lack of similarity that this molecule shares with FVIII [7,9].and without inhibitor) treated with emicizumab were collected, showed very stable drug pharmacokinetics with a reduction in the annual bleeding rate (ABR), mainly from 6 months onwards and maintained over time.Accordingly, the percentage of patients with 0 bleeds increased during the first year, remaining above 80% thereafter.Notably, most patients (95.5%) experienced some adverse events during the trial, but most of them were mild.Only 1.3% (N = 5) of them led to treatment withdrawal and one patient (0.3%) had a fatal outcome.The long-term exposure of emicizumab thus showed a favorable safety profile [10].On the other hand, the HOHOEMI trial, which exclusively collects data from children without inhibitor treated with emicizumab, also showed a reduction in ABR compared to previous treatment, with more than 50% of patients without treated bleeding [11].
The clinical experience with emicizumab in real life was similar to that reported in clinical trials in terms of efficacy and safety.Studies focusing on pediatric hemophilia A population with and without inhibitor showed a reduction in ABR after emicizumab treatment, with a significant increase in the percentage of patients with zero bleeds.The reduction in ABR was more marked in patients with inhibitor.Emicizumab also showed a safe profile, with no treatment withdrawal or thrombotic events during treatment.There was also no loss of efficacy or suspicion of inhibitor development against the drug [12,13].Studies involving adult patients, with and without inhibitor, also reported an improvement in ABR and a significant increase in the percentage of patients with zero bleeds when compared to previous treatment.Most of the bleeds observed in these patients were traumatic in origin and often coincided with low emicizumab levels, assuming they could be due to nonadherence to treatment [14][15][16].The study by Wall C et al. also reported several adverse events, although in a low percentage of patients (2.4%) and most of them occurred during loading doses [16].Table 1 shows the ABR before and after emicizumab treatment, as well as the main adverse events reported in the most relevant studies based on real-life experience.
Regarding treatment adherence, the group of Buckner TW et al. observed a considerable increase compared to factor-treated patients (82% vs. 44%).Proportion of days covered also increased after switching to emicizumab (92% vs. 71% for FVIII) [17].

Bleeding and perioperative management in patients treated with emicizumab
Perioperative and bleeding management in emicizumab-treated patients remains an issue of concern among clinicians due to the lack of consensus on how to treat patients in these situations.The study by Santagostino E et al. recorded the surgical procedures that occurred during phase III of the HAVEN  The age of the population is expressed as the median age at initiation of emicizumab therapy.a 5-month-oldinfant with high responding (20 BU/ml) inhibitor.Death associated with major bleeding after additional treatment with low molecular weight heparin and additional dose of rFVIIa following detection of thrombosis by echocardiogram.b Traumatic intracranial hemorrhage.c Thrombophlebitis in patient with history of multiple deep venous thromboses.d Serious adverse events only.e Severe headaches.f Anti-drug antibody.g Recurrence of inhibitors.h These studies only take into account treated bleedings for the ABR calculation.Thrombosis (thromb.).Thrombotic microangiopathy (TMA).Years (yrs).
1-4 study in HA patients treated with emicizumab, observing a total of 233 surgeries (18 minor and 215 major surgeries).31.6% of patients underwent at least one surgery during the trial.Interestingly, 90.8% of the minor surgeries did not result in postoperative bleeding requiring treatment, even in the absence of prophylaxis.Only one patient suffered a postoperative bleed after major surgery, despite having received prophylaxis [18].Therefore, FVIII prophylaxis is not considered strictly necessary before minor surgery.In the case of dental interventions, the administration of local tranexamic acid (mouthwash) has proven to be sufficient.However, in major surgeries or invasive procedures with a high risk of bleeding, it is recommended to maintain FVIII levels above 50% by administering additional prophylactic coagulation factor before and after surgery.Table 2 shows the recommended first doses of FVIII for the treatment of bleeding and prophylaxis before surgery in patients with hemophilia without inhibitors [19].
In patients with inhibitor, current guidelines recommend administration of rFVIIa as first line and aPCC as second line.Minor surgeries can also be performed without prophylaxis and major surgeries depending on inhibitor response: FVIII for low-responder inhibitors and rFVIIa (or aPCC) for high-responder inhibitors.The UK Haemophilia Doctors Organisation (UKHCDO) guidelines recommend two doses of 90 µg/kg/4 h of rFVIIa, while the German guidelines recommend reducing the dose to 45 µg/kg after 4-6 h.Both guidelines recommend the administration of an aPCC only if strictly necessary and, if so, close monitoring for thrombosis and/or thrombotic microangiopathy.The German guidelines recommend administration of 15-25 IU/kg of aPCC, although the UKHCDO guidelines consider that it may be ineffective in some bleedings, so the dose could be increased but not exceeding 50 IU/kg [20,21].Due to concerns about the thrombotic risk of aPCC use, a recent study evaluated the concomitant effect of aPCC with emicizumab by thrombin generation test (TGT), suggesting that patients could safely receive higher doses than recommended.Although this study reports the experience of only a few patients, these results are very encouraging and should be explored further.In addition, these authors suggest that TGT could be very useful tool for the individualization of aPCC dose for the treatment of bleeding [22].
Nevertheless, most of the procedures collected in these studies were minor procedures, so more studies need to be collected to help assess the actual efficacy of emicizumab treatment in this setting.Indeed, the UK Hemophilia Center Physicians' Organization has opted for the time being to delay major nonurgent surgery in emicizumab-treated patients until more information on its efficacy is available [12,13,23].
The group of Lewandowska M, et al. recently published actual center-based experience of surgical procedures performed in HA patients treated with emicizumab, considering that these patients could be treated as if they had mild hemophilia.However, they observed a higher-than-desired rate of bleeding, so they also consider that there is a need to optimize emicizumab prophylaxis and establish protocols to help determine optimal doses and duration of treatment with additional hemostatic agents when necessary [24].In children, most of the surgical interventions reported in the studies are minor and virtually no cases of major bleeding were observed [12,13].
Regarding breakthrough bleeding in patients treated with emicizumab, current WFH guidelines recommend treatment with FVIII using the same doses as the patient was receiving when on FVIII substitution prophylaxis.For minor bleeding, strict clinical monitoring before treatment is recommended, with special care for patients with established arthropathy and FVIII treatment for severe bleeding with doses adjusted to the type, site and severity of bleeding [19,25].

Emicizumab and joint health
Recurrent episodes of joint bleeding in hemophilia patients lead in most cases to chronic synovitis and the development of hemophilic arthropathy, a disabling condition characterized by chronic pain, joint deformities with loss of function and reduced quality of life.These bleedings mainly affect 6 joints: elbows, knees and ankles.Often, arthropathy is developed in some of these joints, which becomes target joints if three or more spontaneous bleeds occur within a consecutive 6-month period [26].Although prophylactic treatment has been shown to significantly reduce the development of this condition, approximately 50% of patients continue to develop hemophilic arthropathy from childhood [27].A study in patients with severe hemophilia A showed that patients developed joint damage regardless of the presence or absence of FVIII inhibitors, revealing the need to optimize current treatments and/or explore new ones [26,28].
Results from the HAVEN 1-4 trials revealed that in the 121-144 weeks period, 95.1% of emicizumabtreated patients achieved resolution of target joints and 94.1% had zero bleeds.Regarding spontaneous bleeds, 98.9% of patients showed resolution of target joints [10].Compared to prophylactic FVIII treatment, emicizumab-treated patients had a 68% reduction in ABR and a significant reduction in the percentage of patients with target joints was also observed [6].Although these authors did not evaluate the degree of arthropathy, the high percentage of patients with resolution of target joints gives evidence of the benefits of emicizumab use on patients' joint health.In fact, recently published results obtained from the HAVEN3 and HAVEN4 studies reported clinically relevant improvements in joint health assessed by the Hemophilia Joint Health Scores (HJHS) in young patients and those with target joints after 48 weeks of emicizumab as well as an improvement of quality of life in adult patients [29,30].

Emicizumab in neonates and previously untreated patients (PUPs)
Some 52% of the most severe forms of hemophilia A are usually diagnosed in the neonatal stage [31,32].These patients, along with previously untreated patients (PUPs), are considered a vulnerable population due to the high risk of severe bleeding [33].To date, the World Federation of Haemophilia (WFH) recommends early initiation of prophylaxis before the onset of joint disease and ideally before the age of 3 years, in order to prevent spontaneous and generalized bleeding, including hemarthrosis, which can lead to joint disease.However, the WFH recognizes that subcutaneous administration of emicizumab would facilitate the initiation of prophylaxis at an even earlier age, allowing children to be protected even from birth.Early initiation of prophylaxis would help to reduce the risk and incidence of intracranial hemorrhage, which is one of the main complication clinicians must deal with in this type of patient.In fact, the study by Stieltjed et al. reported an incidence of intracranial hemorrhages of 26% in patients aged 0-24 months, with more than 90% of these occurring in patients with severe hemophilia [34].These hemorrhages usually occur around month 6-9 of age coinciding, in most cases, with the start of prophylactic treatment [35].In agreement with the WFH, some authors and entities such as the Medical and Scientific Advisory Council (MASAC) of the national hemophilia foundation also recommend that prophylaxis with emicizumab of infants should be considered at any time after birth [36] (https://www.hemophilia.org/sites/default/files/document/files/258_emicizumab.pdf).
Nevertheless, experience with emicizumab in neonates and PUPs is very limited.To date, published studies globally assess all children under 12 years of age, and most of them started treatment at 5 years of age [11,12].Of note is the single-center study that evaluated the experience of forty children who started treatment with emicizumab, nine of whom started when they were less than 1 year old.Consistent with the results of the HAVEN trials, the experience with emicizumab in these patients was very favorable.There were no serious adverse events, except for major bleeding after circumcision in a child under 1 year of age who was treated exclusively with tranexamic acid [13].Thus, although the results are very promising, further studies are needed to evaluate the use of emicizumab treatment in these patients.A Phase 3b study of emicizumab is currently evaluating efficacy, safety, pharmacokinetics, and pharmacodynamics in participants from birth to 12 months of age (clinicaltrials.govNCT04431726).

Laboratory monitoring of patients treated with emicizumab
Although some experts agree that laboratory monitoring of emicizumab-treated patients could be useful in special cases such as bleeding or surgery, current protocols do not yet provide for this practice (https:// www.ema.europa.eu/en/documents/overview/hemlibra-epar-medicine-overview_en.pdf).Perhaps one of the main reasons is that routine tests such as activated partial thromboplastin time (aPTT), FVIII activity and FVIII inhibitor titer have proven to be unreliable for monitoring these patients.This is because emicizumab acts by activating the intrinsic pathway, which distorts aPTT results, generates false-positive inhibitor results and increases FVIII levels [37,38].A modified aPTT assay has been developed in which plasma samples are diluted, allowing a linear relationship between emicizumab concentrations and clotting times [39,40].The use of bovine chromogenic assays are an option to evaluate endogenous FVIII, as FVIII chromogenic assays are only sensitive to emicizumab with factors of human origin [41].A nearly linear relationship between emicizumab concentration and activated factor X generation can be obtained with this assay [37].In fact, the study by A. McCormick et al suggests that the most effective method for monitoring emicizumab therapy combines the use of the bovine chromogenic assay and the modified aPTT [42].However, these assays are sensitive to the presence of other procoagulant molecules (e.g.FVIII or aPCC) and results may differ between tests from different manufacturers and even if different batches are used [37,43].
On the other hand, the use of techniques that globally assess hemostasis such as TGT, thromboelastogram (TEG) or thromboelastometry could facilitate patient monitoring [38].In fact, the group of Kizilocak et al. proposes the use of TGT for perioperative bleeding control to minimize the potential risk of thrombotic events and thrombotic microangiopathy [44].On the other hand, the group of Yada et al. has already evaluated the use of ROTEM, observing a shortening of the NATEM-based CT + CFT values in the presence of emicizumab, although the other parameters such as clot firmness and alpha angle proved to be unsuitable for quantitative assessment [45].

Conclusions
Although experience is limited, especially in neonates, PUPs and patients undergoing major surgery, emicizumab has been shown to be a promising therapeutic option for HA.Clinical trial and real-life studies have shown that emicizumab is successful in reducing ABR, suggests improved joint health with resolution of target joints and thus an improvement in patients' quality of life.Clinical trial results have also revealed a safe drug profile, with no serious adverse events or development of FVIII inhibitors in most patients.In addition, emicizumab-treated patients were able to undergo minor and major surgeries safely, without the need for prior prophylaxis in the case of minor interventions.The stability of emicizumab's pharmacokinetics also generates confidence among clinicians, as there is no need for laboratory monitoring of drug levels.Still, more studies are needed to help confirm these findings and address some of the concerns that continue to plague clinicians and are outlined in this article.

Expert opinion
According to the authors' opinion based on their own experience, emicizumab treatment is changing the clinical landscape of HA patients by significantly reducing the number of bleeds.In particular, the authors believe that emicizumab could be a valid option for patients with a bleeding phenotype, with inhibitors and/or who have difficulty with intravenous administration, as the initiation of emicizumab treatment is faster and more effective, as there are no problems with the route of administration.Emicizumab could also be a possible option for neonates and PUPs, although there is currently not much published evidence on the treatment experience in these patients, so there is still some concern, especially about the possible development of inhibitors against the drug.
Regarding laboratory monitoring of emicizumab, the authors are of the opinion that it is not strictly necessary, as the pharmacokinetic properties of the drug allow for stable long-term therapeutic levels, regardless of age, weight, or the presence of inhibitors.However, aPTT monitoring, although not specific to emicizumab activity, may be particularly interesting because an elongation could indicate the presence of anti-drug antibodies.Furthermore, tests that globally assess hemostasis, such as ROTEM®, could be a plausible option in case of treatment of bleeding or in the follow-up of patients undergoing surgery.
In relation to surgery, the authors consider that patients can undergo minor surgery without prior administration of prophylaxis, although they should be monitored for factor levels and bleeding in order to administer treatment promptly if necessary.However, surgeries should be scheduled considering that emicizumab levels take time to reach the steady state concentration when treatment is initiated (after 4 weekly loading doses).For major interventions, the administration of an additional prophylactic coagulation factor should be considered.The authors recommend the use of global tests before surgery (after factor infusion) to check the normalization of hemostasis, during the surgical procedure to ensure its maintenance and/or after surgery to avoid possible post-surgical complications.
The experts also say that emicizumab treatment has substantially improved the joint health of their patients in the short term by reducing the annual rate of bleeds, with the most notable improvement in inhibitor patients, who had the most bleeds overall.Although it remains to be seen whether these results are sustained in the long term.They also believe that, although the 'Hemophilia Joint Health Score (HJHS)' is tedious and time-consuming, it is very useful for monitoring the joint health of their patients.
Despite the demonstrated benefits, experts are concerned about the attitude of their patients to change treatment, as they are sometimes reluctant, especially if it is the clinicians who propose it.In addition, patients do not seem to be very aware of joint health, unless they have major complications, which makes it even more difficult for less severe patients to accept a change of treatment.This situation has been further aggravated during the COVID-19 pandemic, as switching regimens involves strict monitoring of patients.Therefore, the authors agree that it is necessary to intensify health education of patients, who generally assume that bleeding is normal, without understanding that the aim of prophylaxis is not to treat, but to prevent it.

Disclosure statement
Francisco J.López Jaime has participated as consultant or speaker for CSL Behring, Novo Nordisk, Roche, Sobi and Takeda.Olga Benítez has participated as consultant, speaker or has received medical grants from Bayer, CSL Behring, Pfizer, Sobi, Roche and Takeda.Bolívar Luis Díaz Jordán has participated as speaker, in advisory boards and sponsored symposia with, CSL Behring, Novo Nordisk, Roche, Daiichi-Sankyo, Takeda, Sobi, Fresenius, Zambon and Bial.Julia Coll Vallier has participated as speaker, in advisory boards and sponsored symposia with, Bayer, Takeda, Roche, LEO Pharma, Daiichi Sankyo, Novartis, Sanofi, Pfizer and Sobi.María del Carmen Gómez del Castillo Solano has participated as speaker, in advisory boards and sponsored symposia with Novo Nordisk, Bayer, Takeda, Roche, Pfizer, Amgen and Sobi.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Table 1 .
Annual rate of bleeding and adverse events during emicizumab treatment.

Table 2 .
Recommended first FVIII dosing for the treatment of bleeding episodes and for prophylaxis before invasive procedures/surgery in hemophilia A patient without inhibitors.
a Either for standard or extended half-life FVIII concentrates.b Bleeding causing possible airway compression.c Dose to administer prior to surgery.d Including polypectomy, treatment of varices, biliary or pancreatic sphincterotomy, PEG placement and other operative endoscopies.Adapted from Coppola A, et al. [19].