Annualized Bleeding Rate Research Articles

Long-Term Real-World Safety and Efficacy of Liver-Directed AAV Gene Therapy for Severe Hemophilia with and without Inbibitors in Privately Owned Dogs

Background Hemophilia A (HA) and hemophilia B (HB) are inherited bleeding disorders resulting from deficiency of coagulation factors VIII (FVIII) or factor IX (FIX) activity, respectively. HA and HB both occur naturally in dogs. The bleeding phenotype of severe canine HA and HB is analogous to the human patient experience with frequent spontaneous and trauma-induced bleeding. Previous studies of dogs from HA and HB colonies at research institutes have been highly informative about the safety and efficacy of adeno-associated virus (AAV) liver-directed gene therapy for HA and HB. However, these animals are housed in highly controlled environments; in contrast, pet dogs with HA or HB are exposed to real-world challenges that likely affect their bleeding phenotype and the efficacy of novel therapeutics. In this regard, privately owned dogs may better recapitulate the human patient experience. Aims To determine the real-world efficacy of liver-directed AAV gene therapy for HA/HB in privately owned canines with and without inhibitors. Methods Eleven dogs with severe HA and one dog with severe HB were treated with liver-directed AAV gene therapy with canine (c) FVIII or cFIX, as detailed in Table 1. Pre-existing neutralizing antibodies to AAV8 were detected using a luciferase-based transduction inhibition assay. Pre- and post-gene therapy annualized bleeding rates were calculated by cumulative bleeding events divided by the age at gene therapy (pre) or duration of follow-up (post). FVIII activity was determined using a chromogenic assay and FIX activity using a one-stage assay. Results All dogs had AAV8 neutralizing antibody titers ≤ 1:5 at enrollment. The HA dogs (10 males and 1 female) were treated with either dual chain vectors of cFVIII-SQ (n = 2, total dose of 5 x 1013 vg/kg) or single-chain vectors encapsidating high-expression cFVIII variants: cFVIII-ΔF (n = 2, 6x1012 vg/kg) or cFVIII-ΔF/V3 (n = 7, 5.4-9 x 1012 vg/kg). F8 genetic testing revealed intron 22 inversions (n=7), small deletion (n=2), missense (n=1) and complex mutation (n=1) all compatible with severe HA. Of note, one HA dog (PC3) had a pre-existing FVIII inhibitor which was eradicated following gene therapy. In all dogs with available data (n=10), FVIII activity is > 1% with 5 in the moderate hemophilia range and 4 in the mild range with a median FVIII activity of 3.2% (range 1.1-13.8%) after a median duration of 4.1 years (range 2.6-8.9 years). In HA dogs, the ABR post-gene therapy declined by an average of 93%. The sole HB dog carried two missense F9 mutations and was treated with wildtype cFIX at 3 x 1012 vg/kg and has been followed for 4.5 years with FIX activity of 5.7% and has had no bleeding episodes since gene therapy. Three animals have died during follow up. The previously inhibitor positive dog (PC3) died approximately 2 years after gene therapy from an unrelated cause. An HA dog (PC1) treated with dual chain vector with expression in the ~2% normal range died from a bleeding episode at 8.8 years after gene therapy. Notably, many of his bleeds were associated with real-world activities including having his legs being pulled by a toddler. A third HA dog (PC9) was euthanized 3.5 years post-gene therapy after being diagnosed with widely disseminated cancer; the details of the vector integration analysis of his tumor will be reported elsewhere. Conclusion AAV gene therapy was successful at substantially ameliorating the bleeding phenotype in both male and females dogs with > 1 year of follow-up. However, some dogs continued to have bleeding, especially animals with <5% normal cFVIII activity. One animal developed cancer after gene therapy; there were no other safety concerns. As we have described previously, liver-directed AAV gene therapy also induced immune tolerance in an HA dog with a pre-existing inhibitors. We show that AAV liver-directed gene therapy is safe and efficacious in a real-world experience of privately owned dogs with severe HA and HB. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Burden and Patient Preference in Patients with Hemophilia A or B with Inhibitors on Concizumab Prophylaxis: Results from the Phase 3 explorer7 Study

Introduction: Concizumab is a humanized, recombinant monoclonal antibody that acts to inhibit tissue factor pathway inhibitor to enhance coagulation. Patients with hemophilia A or B with inhibitors (HAwI/HBwI) received concizumab as a once-daily subcutaneous prophylactic treatment in the phase 3 explorer7 study (NCT04083781). In the explorer7 primary analysis, concizumab prophylaxis was shown to reduce the annualized bleeding rate for patients with either HAwI or HBwI when compared with no prophylaxis. Concizumab was also considered to be safe and well tolerated for HAwI/HBwI, with the latter patient population having the greatest unmet medical need. Subcutaneous administration of concizumab using a pen device may contribute to a lower treatment burden when compared with intravenous factor replacement therapy. Here, we present data on patient-reported treatment burden and patient preference from patients with HAwI/HBwI treated with concizumab in explorer7. Methods: A total of 133 patients aged ≥12 years were either randomized 2:1 to concizumab prophylaxis (arm 2; n=33) or no prophylaxis (arm 1; n=19) or assigned to non-randomized concizumab prophylaxis treatment (arms 3 or 4; n=81) based on the treatment they were receiving before entering the study. Patients were prompted to complete the Hemophilia Treatment Experience Measure (Hemo-TEM; Brod et al. abstract presented at ISTH 2022 [PB0654]) questionnaire at baseline (Week 0) and Week 24. In addition, patients were asked to complete the hemophilia patient preference questionnaire (H-PPQ) at Week 24. Results from both questionnaires were reported as exploratory endpoints in the study. Due to technical reasons, a number of patient-reported outcomes records could not be collected for statistical analysis. Analysis of covariance was applied to estimate mean change in Hemo-TEM domain and total scores from baseline to Week 24 in arms 1 and 2, with treatment, type of haemophilia and bleeding frequency prior to screening as factors, and the baseline value as a covariate. Descriptive statistics were used to describe the results of the H-PPQ questionnaire. Results: The Hemo-TEM total score improved in patients on concizumab prophylaxis (n=19) from baseline to Week 24 (mean estimate -17.0 points [95% CI: -23.7; -10.3]), while patients on no prophylaxis (n=6) did not experience an improvement (mean estimate 3.0 points [95% CI: -9.4; 15.3]). The estimated treatment difference in Hemo-TEM total score between the two arms was statistically significant (-19.9 points [95% CI: -34.3; -5.6]; P=0.009; Figure 1). Improvements were observed across all Hemo-TEM domains for patients on concizumab prophylaxis, with significant improvements in the domains "injection difficulties", "interference", and "emotional impact" (Figure 1). A total of 99 patients received the H-PPQ questionnaire; 77 (78%) indicated that they preferred concizumab over their previous treatment, while only one patient (1%) preferred their previous treatment (16 patients did not respond, and 5 patients had no preference). Out of the 83 patients who responded, 93% preferred concizumab over their previous treatment. The three main reasons for their treatment preference were "fewer bleeds" (75%), "require less time" (43%), and "less painful to inject" (33%). Conclusion: A lower treatment burden was observed for daily concizumab prophylaxis as patients generally reported better Hemo-TEM domain and total scores. For the Hemo-TEM total score, the estimated treatment difference between concizumab and no-prophylaxis arms was statistically significant. Most patients who responded to the H-PPQ questionnaire preferred concizumab prophylaxis over their previous treatment. Intravenous injection of replacement factor products poses a major burden to hemophilia patients. The observed improvements in treatment burden with subcutaneous administration of concizumab may have the potential to also improve treatment adherence and thereby achieve better clinical outcomes for patients with hemophilia. The combination of effective prophylaxis and reduced bleeding (especially in HBwI) together with lower treatment burden of subcutaneous delivery resulted in a clear patient preference in favor of concizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Viral Vector Based Gene Therapy in Patients with Hemophilia a: A Systematic Review

Background: Hemophilia A results from a mutation in the gene for coagulation factor VII and serious disease can cause bleeding in soft tissues and joints. These patients rely on exogenous factor VIII. However, frequent infusions are needed due to the short half-life of factor VIII which can lead to non-compliance to therapy and poor quality of life. Gene therapy aims to safely impart the expression of stable factor VIII. In this review, we will assess the efficacy and safety of gene therapy in hemophilia A. Methods: We searched PubMed, Web of Science, and clinicaltrials.gov with mesh terms, "hemophilia A" and "genetic therapy" from the inception of data till May 30, 2022. Out of 6,699 articles, 4 clinical trials (N=173) were included based on inclusion criteria measuring the efficacy and safety of gene therapy in hemophilia A. Case reports, review articles, systematic reviews, meta-analyses, pre-clinical studies, and clinical trials with irrelevant treatment or population were excluded. Results: In 4 clinical trials, 173 adult patients (<18 years old) were treated with vector-based gene therapy. Adeno-associated virus serotype 5 (AAV5) vector was used in 155 patients while SPK-8011 was used in 18 patients. 146 patients were treated at a high dose of 6x1013 vg/kg. All patients had a factor VIII activity of <1 IU/dl before therapy. In 2 clinical trials (N=139), mean factor VIII activity significantly increased to 45.42 IU/dl on treatment with 6x1013 vg/kg of AAV5-hFVIII-SQ. However, the activity level was ≤2 IU/dl after treatment at lower doses. On three years follow-up by Pasi et al. (N=7), the mean factor VIII activity level was 31 IU/dl. The mean annual bleeding rate decreased from 5.95 (N=139) to 0.95 after therapy. Mean consumption of factor VIII decreased from 4130.8 (N=139) to 21.84 IU/kg after treatment with 6x1013 vg/kg of AAV5-hFVIII-SQ. In one clinical trial by George et al., 18 patients were treated with SPK-8011-FVIII-SQ and the median annual bleeding rate decreased from 8.5 to 0.3. Mean factor VIII activity was 8 at a dose of 2x1012. ALT elevations, adrenal insufficiency, pyrexia, diarrhea, rectal hemorrhage, and progression of arthropathy were among the serious side effects reported in patients with gene therapy. Table 1. Conclusion: Gene therapy was well tolerated by most of the patients and ALT elevation was the most common adverse effect reported. AAV5-hFVIII-SQ and SPK-8011-FVIII-SQ significantly improved the endogenous production of factor VIII, bleeding rate, and factor VIII concentrate consumption, especially at doses of 6x1013 and 2x1012 vg/kg, respectively. AAV5-hFVIII-SQ was safe and effective in patients with hemophilia A on long-term follow-up. More randomized double-blind clinical trials are needed to confirm these results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of factor expression levels with annual bleeding rate in people with haemophilia B.

Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. We evaluated the association between FEL and ABR in PwHB. This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p<.001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p<.05). This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.

Safety and efficacy of long‐term emicizumab prophylaxis in hemophilia A with factor VIII inhibitors: A phase 3b, multicenter, single‐arm study (STASEY)

BackgroundThe bispecific monoclonal antibody emicizumab bridges activated factor IX and factor X, mimicking the cofactor function of activated factor VIII (FVIII), restoring hemostasis. ObjectivesThe Phase 3b STASEY study was designed to assess the safety of emicizumab prophylaxis in people with hemophilia A (HA) with FVIII inhibitors. MethodsPeople with HA received 3 mg/kg emicizumab once weekly (QW) for 4 weeks followed by 1.5 mg/kg QW for 2 years. The primary objective was the safety of emicizumab prophylaxis, including incidence and severity of adverse events (AEs) and AEs of special interest (thrombotic events [TEs] and thrombotic microangiopathies). Secondary objectives included efficacy (annualized bleed rates [ABRs]). ResultsOverall, 195 participants were enrolled; 193 received emicizumab. The median (range) duration of exposure was 103.1 (1.1–108.3) weeks. Seven (3.6%) participants discontinued emicizumab. The most common AEs were arthralgia (n = 33, 17.1%) and nasopharyngitis (n = 30, 15.5%). The most common treatment‐related AE was injection‐site reaction (n = 19, 9.8%). Two fatalities were reported (polytrauma with fatal head injuries and abdominal compartment syndrome); both were deemed unrelated to emicizumab by study investigators. Two TEs occurred (myocardial infarction and localized clot following tooth extraction), also deemed unrelated to emicizumab. The negative binomial regression model–based ABR (95% confidence interval) for treated bleeds was 0.5 (0.27–0.89). Overall, 161 participants (82.6%) had zero treated bleeds. ConclusionsThe safety profile of emicizumab prophylaxis was confirmed in a large population of people with HA with FVIII inhibitors and no new safety signals occurred. The majority of participants had zero treated bleeds.

Gamma Knife® stereotactic radiosurgery for intracranial cavernous malformations

IntroductionGamma Knife® stereotactic radiosurgery (GKSRS) is a non-invasive alternative to surgical resection for cerebral cavernous malformations (CCMs), especially in eloquent locations. MethodologyA retrospective review was performed on an Australian cohort of patients receiving GKSRS for CCMs at a single institution. All patients exhibited symptoms and/or radiological evidence of haemorrhage before therapy. The minimum follow-up was 1-year post-GKSRS. McNemar’s test was used for differences in matched-pair outcomes pre- and post-GKSRS with an α = 0.05. A systematic review and meta-analysis was additionally performed to synthesise the current published evidence on the clinical efficacy of stereotactic radiosurgery in reducing haemorrhage risk in CCMs using a DerSimonian and Laird random effects model. ResultsThirty-five patients (39 cavernomas) underwent GKSRS. 87.2 % of patients had evidence of at least one haemorrhage before GKSRS and the remainder exhibited seizures. The median dose was 12.5 Gy in a single fraction (IQR 12–13). The median follow-up duration from GKSRS was 809 days (IQR 536–960). There was a significant reduction in matched annual bleed rate from pre-GKSRS (52.1 %) compared to after SRS (12.3 %) (p < 0.001) [OR = 0.07, 95 % 0.008–0.283] There was no statistically significant difference in seizure incidence pre- (30.7 %) versus post-GKSRS (17.9 %) (p = 0.13) [OR = 0.167, 95 %CI 0.004–1.37]. One patient (3 %) with a brainstem lesion experienced long-term treatment-related oedema with persistent ipsilateral weakness and tremors. On meta-analysis of 25 pooled studies, radiosurgery for the treatment of CCMs was associated with a statistically significantly relative risk (RR) reduction in haemorrhage events [random effects RR 0.12 (95 % CI 0.074–0.198), p < 0.001)], with most of the proportionate risk reduction occurring in the initial 2 years following SRS. ConclusionGKSRS significantly reduces the annual rate of haemorrhage for intracranial cavernomas in this cohort and on meta-analysis, particularly in the first 2 years following treatment. The overall risk of treatment-related morbidity is low.

Real-world experience of emicizumab prophylaxis in young children with hemophilia A: retrospective data from China.

As a new non-factor therapy for hemophilia A (HA), real-world study of emicizumab is still scarce. This study aimed to investigate the real-world use of emicizumab in Chinese boys with HA. Patients with moderate or severe HA were enrolled at Beijing Children's Hospital. They take emicizumab weekly (3 mg/kg) for a month and then went into a maintenance period with a different dosing regimen. After obtaining platelet-poor plasma at end of the loading period and during the maintenance period, coagulation ability and FVIII inhibitor were determined using human and bovine chromogenic Bethesda assay. Patients' bleeding rates were calculated through patients' records from 24 weeks before to at least 6 months after the switch (to emicizumab). In total, 13 pediatric patients with HA (severe: moderate = 11:2) were enrolled in this study. The patients' age was 3.51 (0.73-6.65) years. Eight had FVIII inhibitors at enrollment and one of them developed FVIII inhibitors again during the switch. The coagulation level of the maintenance period was 19.6 (13.5-32.8) IU/dL (N = 10). The median dose of each emicizumab injection was 2.7 (1.3-3.8) mg/kg and the monthly consumption of emicizumab was 5.2 (3.2-6.8) mg/kg/month. After switching to emicizumab, reduced annualized bleeding rate (ABR) [0.5 (0-4) vs. 4 (0-18), P < 0.01], annualized joint bleeding rate (AJBR) [0 (0-1.1) vs. 1.0 (0-12), P < 0.01], and annualized spontaneous bleeding rate (ASBR) [0 (0-1) vs. 2.0 (0-18), P < 0.01] were observed. In patients with or without FVIII inhibitor, similar ABR [0.33 (0-4) vs. 0.5 (0-3), P = 0.78], AJBR [0 (0-1.1) vs. 0 (0-0.5), P = 0.63], and ASBR [0 (0-1) vs. 0 (0-1.5), P = 0.73] were also noticed. Five inhibitor-positive patients (at enrollment) all had their inhibitor titer reduced. In addition, all target joints vanished after switching to emicizumab. Emicizumab could reduce bleeds in pediatric patients with/without FVIII inhibitors and eliminate target joints.

Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: A review of the literature.

People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life. To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making. A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life. Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n=609) and 29% (n=668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n=599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health. There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype.

Reversal agents for severe bleeding associated with direct oral anticoagulants

Direct oral anticoagulants (DOACs) have demonstrated a positive benefit-risk balance compared with vitamin K antagonists in both clinical trials and real-world studies. However, with increased DOAC use, the risk of bleeding should not be underestimated. In clinical practice, the annual rate of DOAC-related major bleeding is between approximately 1.5% and 3.5%. The outcome of major bleeds was similar or better in patients receiving DOACs than in those taking vitamin K antagonists. Due to their short half-lives, supportive measures are sufficient to manage most bleeds in patients receiving DOACs. Anticoagulant reversal should only be considered with life-threatening bleeds or with serious bleeds that fail to respond to usual measures. Effective strategies to reverse the anticoagulant effects of DOACs are now available. Idarucizumab has been approved for dabigatran reversal and andexanet alfa was recently granted approval for the reversal of apixaban or rivaroxaban in patients with life-threatening or uncontrolled bleeding events. Other reversal agents (e.g. ciraparantag for heparins and DOACs) are under development. Non-specific prohemostatic agents (e.g. prothrombin complex concentrate) can counteract the anticoagulant action of DOACs in emergency situations, when specific reversal agents are unavailable. However, specific reversal agents are efficacious and safe and should be preferred when available.

A newly designed disk-lobe occluder with isogenous barbs for left atrial appendage closure: Initial multicenter experience.

BackgroundAlthough the implant success rate of left atrial appendage closure (LAAC) has increased and complications have decreased over time, there are still anatomically and technically complicated cases where novel LAA occluders may simplify the procedure and thus might potentially improve the clinical outcome.ObjectivesThis study aimed to assess the safety and efficacy of the newly designed device with isogenous barbs in LAAC.MethodsEight centers in China participated in this prospective study from July 2016 to April 2018. Peri- and post-procedural safety and efficacy were evaluated through scheduled follow-ups and transesophageal echocardiography (TEE).ResultsA total of 175 patients with a mean age of 68.4 ± 9.2 years old, a mean CHA2DS2-VASc score of 4.7 ± 1.8, and a mean HAS-BLED score of 3.2 ± 1.3, were included. The device was successfully implanted in 173 patients (98.9%). The device size ranged from 18 to 34 mm. Clinically relevant pericardial effusion (PEF) in the perioperative period, occurred in 3 patients (1.7%). TEE follow-up was available in 167 (96.5%) patients at 12-month. During follow-up, 9 patients suffered serious adverse event: 4 death (2.3%), 1 ischemic stroke (0.6%), and 2 gastro-intestinal bleeding (1.2%) and 2 device-related thrombus (DRT) (1.2%). Estimated annual thromboembolism rate reduced by 90% and estimated annual major bleeding rate reduced by 81% after LAAC with the newly designed device.ConclusionThe newly designed device with isogenous barbs for LAAC could be performed effectively with a low incidence of adverse events and a high incidence of anatomic closure.

The Impact of Pharmacokinetic-Guided Prophylaxis on Clinical Outcomes and Healthcare Resource Utilization in Hemophilia A Patients: Real-World Evidence from the CHESS II Study.

BackgroundUsing a pharmacokinetic (PK)-guided approach to personalize the dose and frequency of prophylactic treatment can help achieve and maintain targeted factor VIII (FVIII) trough levels in patients with hemophilia A.ObjectiveInvestigate clinical and healthcare resource use outcomes in patients with hemophilia A treated with or without PK-guided prophylaxis using data from the Cost of Haemophilia in Europe: A Socioeconomic Survey (CHESS) II database.MethodsCHESS II was a cross-sectional, retrospective, burden-of-illness study incorporating data from eight European countries. Patients were eligible for this analysis if they were male, ≥18 years of age, and diagnosed with congenital hemophilia A of any severity. The clinical endpoints included annualized bleeding rate (ABR), presence and number of problem/target joints, and occurrence of joint surgeries. Healthcare resource utilization endpoints included the number of hematologist consultations and bleed-related hospitalizations or emergency department admissions. Data from November 2018 to October 2020 were included and were stratified according to treatment regimen and use of PK-guided dosing.ResultsAltogether, 281 patients on prophylaxis had available FVIII trough level data. Mean (SD) age was 35.7 (13.8) years. A specific FVIII trough level was targeted in 120 (42.7%) patients and 47 (39.2%) received PK-guided dosing. Patients receiving PK-guided dosing had a mean (SD) ABR of 2.8 (2.1) and target joint number of 0.5 (0.7), compared with 3.9 (2.7) and 0.9 (1.4), respectively, for patients receiving non–PK-guided treatment. The mean (SD) number of hematologist consultations was 7.1 (5.3) for patients receiving PK-guided dosing versus 10.7 (5.7) for those who were not. A higher proportion of patients in the non–PK-guided group required hospitalization during their lifetime compared with the PK-guided group.ConclusionThis analysis of real-world data suggests that PK-guided dosing for prophylaxis has a beneficial impact on clinical and healthcare resource utilization outcomes in patients with hemophilia A.

Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab

PurposeReal-world data and study data regarding therapy with Emicizumab in pediatric cohorts with haemophilia A is scarce. Especially, data on previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) are missing.MethodsThirteen pediatric patients with haemophilia A and treatment with Emicizumab were retrospectively evaluated for Annual Bleeding Rates (ABR) pre-and post-Emicizumab treatment. Safety data and data on management of minor surgery as well as laboratory results were collected. Additionally, we describe the clinical features of two PUPs and one MTP that are included in our cohort.ResultsMedian age at initiation of Emicizumab was 5.3 (range: 0.26–17.5) years, three patients were younger than one year at initiation of treatment with Emicizumab. Median follow-up time on Emicizumab was 23.8 (range: 0.7–40) months. Total ABR (p = 0.009) as well as spontaneous (p = 0.018), traumatic (p = 0.018), and joint (p = 0.027) ABR reduced significantly post-Emicizumab transition. Safety profile was favourable as only one local site reaction occurred; no cessation of treatment was necessary. Surgery was successfully performed in three patients receiving rFVlla pre- and post-surgery. Emicizumab trough levels showed a median of 43.2 μg/ml (range: 23.9–56.8) after three doses of 3 mg/kg and 51.9 μg/ml (range: 30.4–75) at first follow-up with 1.5 mg/kg.ConclusionEmicizumab is safe and efficient in pediatric patients with and without inhibitors. More data on larger multicenter cohorts and especially on PUPs/MTPs are still needed.

Adding a Clinical Hemophilia Pharmacist to the Hemophilia Comprehensive Care Model Improves Health Care–Related Outcomes and Drug-Related Costs in an Integrated Health Care System

IntroductionThe National Hemophilia Foundation has advocated for a comprehensive care model in caring for patients with hemophilia. Currently pharmacists are not included as part of the team, and the impact of specific team members on patient outcomes is unknown. The authors designed an intervention to add a clinical pharmacist to this care model. The authors evaluated the impact of this intervention on bleeding outcomes, medication access and adherence, and cost within an integrated health care system. MethodsThe authors performed a multicenter, retrospective analysis of all hemophilia A and B patients enrolled in the hemophilia pharmacy service between March 2017 and February 2019. The authors analyzed data prior to and after this quality improvement project, encompassing the period between March 2016 and February 2020. Primary outcomes included an evaluation of the annualized bleed rates, emergency department visits, and hospitalizations. ResultsIn the cohort of patients with hemophilia A and B, the overall bleed rate was reduced from 40 per 100 patient-years to 37.6 per 100 patient-years. Similarly, emergency department visits were reduced from 22.7 to 18.3 per 100 patient-years, and hospitalizations reduced from 6.4 to 3.0 per 100 patient-years (p values >.05). This was augmented by the use of a unique factor recycling program that saved $900,000 in medication costs over a 12-month period. DiscussionThis study shows that the addition of a clinical pharmacist to the core hemophilia team leads to positive trends toward improved bleeding outcomes for patients, improved medication access and adherence, and substantial cost savings to the health system.

Individualised prophylaxis based on personalised target trough FVIII level optimised clinical outcomes in paediatric patients with severe haemophilia A.

As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol. Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS-Hemo. Fifty-eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were:<1IU/dl, 17.2% (10/58); 1-3IU/dl, 53.5% (31/58); 3-5IU/dl, 15.5% (9/58);>5IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p<.0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p<.0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%-69.0%) and zero joint bleeding proportion (46.5%-81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p=.04) and HJHS (p=.02) were also reported at study exit. Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis.

Efficacy of Replacement and Anti-Platelet Therapies in a Patient with Severe Haemophilia A Undergoing Percutaneous Coronary Stent Implantation.

IntroductionSevere haemophilia A is characterized by serious factor VIII deficiency (biological activity <1%) resulting in frequent spontaneous haemorrhage and abnormal bleeding after minor injury, surgery or tooth extraction.Patient and MethodsWe report the case of a 58-year-old patient with severe haemophilia A without inhibitors but with other comorbidities (HCV and HIV seroconversion), who underwent coronary angioplasty and stent implantation after acute myocardial infarction.ResultsCompared with previous therapy, Nuwiq® led to a reduction of about 20% in drug consumption (360,000 IU vs 540,000 IU per year) and in the annualized bleeding rate (ABR) (5 vs 15).DiscussionPharmacokinetic-guided personalized prophylaxis with Nuwiq® provided bleeding protection with good tolerability and a satisfactory pharmacokinetic profile in a patient with severe haemophilia A and comorbidities whose replacement therapy had to be adjusted because of other contraindicated treatment.LEARNING POINTSHaemophilia A is characterized by frequent haemorrhage.Pharmacokinetic-guided personalized prophylaxis with Nuwiq® provided bleeding protection with good tolerability.Nuwiq® leads to a reduction of about 20% in both drug consumption and the annualized bleeding rate.

A prospective, multicenter, clinical Study to evaluate the Safety, Pharmacokinetics, and Efficacy of Bleed Outcomes, with HemoRel-A® in severe Hemophilia A Patients.

To evaluate efficacy for an on-demand treatment of acute bleeding events, pharmacokinetics, safety, and tolerability of HemoRel-A® in severe hemophilia A. A total of 44 male subjects with severe hemophilia A with an annualized bleed rate of 12 while on-demand treatment with factor VIII (FVIII) were enrolled in the study and received HemoRel-A® for bleed treatment. The efficacy of HemoRel-A® was evaluated based on a four-point scale (excellent, good, moderate, or none). Six-point pharmacokinetic (PK) assessment was performed following a single dose of 50 IU/kg in 12 subjects after a 7-day wash-out period. Safety evaluations were performed at each visit and inhibitor testing was performed in all patients at screening and end of study. Forty-four male subjects received at least a single dose of the study medication and were included in the intent-to-treat (ITT) analysis and safety outcome. In 23 (7.52%) out of the 306 bleeding events, HemoRel-A® efficacy was rated as excellent, in 272 (88.89 %) bleeds it was rated as good, and in 11 (3.68%) bleeding events it was rated as moderate. No failure of efficacy was noted in any of the bleeding events. Thus overall out of 306 bleeding events, 295 (96.41%) showed excellent or good efficacy. Pharmacokinetic assessment based on plasma FVIII activity measured by the chromogenic assay in 12 patients showed comparative results similar to FVIII preparations. A total of 12 adverse events (AEs) were reported in this study. There was no inhibitor development in this previously treated patients (PTP) cohort. HemoRel-A® was established to be efficacious and safe in the treatment of acute bleeding events in subjects with severe hemophilia A. CTRI/2018/05/013790. Registration date: 9th May 2018.

RFVIII-Fc in severe haemophilia A: The incentive switch in case of high risk of joint bleedings.

Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life? MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number. A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis. The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.

S297: ASSESSING THE COST-EFFECTIVENESS OF LONG-TERM PROPHYLAXIS STRATEGIES IN VON WILLEBRAND DISEASE

Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder. Patients with vWD may experience excessive bleeding events resulting in morbidity, reduced quality of life, and a substantial economic burden. Management strategies include von Willebrand factor concentrates either as on-demand treatment (ODT) of bleeds or long-term prophylaxis (LTP) to prevent bleeds. According to recent treatment guidelines, long-term prophylaxis is recommended in individuals with severe and frequent bleeds. Aims: To assess the cost effectiveness of ODT and LTP treatment strategies in vWD patients with low, medium and high annual bleed rate (ABR), using pdVWF/FVIII 2,4:1 products (2,4:1 product A in the United Kingdom (UK) and 2,4:1 product B in Sweden). Methods: A Markov structure considering risk of joint surgery and bleed rate was used to estimate the life years (LYs), quality-adjusted life years (QALYs), and costs of vWD treatment over a lifetime horizon. Treatment options included ODT or LTP with pdVWF/FVIII 2,4:1 or pdVWF/FVIII 1:1 in the UK and in Sweden. Product dosing for LTP and for ODT were obtained from each product’s summary of product characteristics or assumed equal to similar products where data are not available. Bleed risks (major and minor bleed) were estimated for each product in ODT and LTP using published prophylaxis studies and were used to estimate costs of product needed and to determine the probability of requiring joint surgery over time based on the progression of Pettersson Score. Resource use (inpatient and outpatient) costs for bleeds and joint surgery were obtained from standard country-specific costing sources. All costs are shown in 2021 GBP or Swedish Kr for the UK and Swedish analyses, respectively. Health-state utility weights and disutilities of bleeds were obtained from published literature. Annual discount rates for costs and outcomes were 3.5% for the UK and 3% for Sweden. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty. Each analysis considered a low, medium, and high ABR patient population. Results: In the base case analyses (medium ABR) over a lifetime horizon, pdVWF/FVIII 2,4:1 LTP regimens were cost-effective compared with ODT. For pdVWF/FVIII 2,4:1 in the UK, LTP was both cost-saving (-£831,206 incremental cost) and more effective (6.14 incremental QALY) than ODT. Costs of bleed events more than offset the costs of prophylaxis. In Sweden with pdVWF/FVIII 2,4:1, LTP was also dominant (-8,841,901 kr; 6.52 QALY) compared with ODT. In comparisons of LTP regimens, pdVWF/FVIII 2,4:1 was dominant versus pdVWF/FVIII 1:1 in both the UK (-£2,307,370; 1.56 QALY) and in Sweden (-21,939,947 kr; 1.42 QALY). In comparison of ODT regimens, pdVWF/FVIII 2,4:1 was less expensive than pdVWF/FVIII 1:1 in the UK (-£1,250,369; equal QALY) and in Sweden (-7,923,741 kr; equal QALY) due to differences in product costs. Results were similar for comparisons in the high ABR populations. In probabilistic sensitivity analyses, pdVWF/FVIII 2,4:1 was dominant in over 95% of simulations in the UK and in over 85% of simulations in Sweden, and was cost-effective in 95% or more of simulations in both countries. Summary/Conclusion: These results suggest that LTP with pdVWF/FVIII 2,4:1 is a cost-effective strategy compared with ODT, in both the UK and Sweden, for medium and high ABR vWD patients. pdVWF/FVIII 2,4:1 was shown to be cost-effective compared with pdVWF/FVIII 1:1 in the LTP setting, as well as less costly for patients treated ODT for both the UK and Swedish settings, respectively.

Real-World Clinical Outcomes and Replacement Factor VIII Consumption in Patients with Haemophilia A in Italy: A Comparison between Prophylaxis Pre and Post Octocog Alfa (BAY 81-8973).

(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry®, Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% (p = 0.003), and the overall FVIII consumption decreased by 25,542 (−7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products.

Pharmacokinetic and clinical improvements after PK-guided switch from standard half-life to extended half-life factor VIII products

IntroductionExtended half-life (EHL) factor VIII (FVIII) products have been designed to allow less frequent infusions and higher bleeding protection than standard half-life (SHL) products. Only few reports analyzed this switch in clinical practice.AimTo analyze the differences observed in pharmacokinetics (PK) and clinical outcomes after the switch from SHL to EHL products in severe/moderate haemophilia A (HA) prophylaxis. Materials and methodsObservational, cross-sectional, multicenter, prospective study comparing PK parameters and clinical variables between SHL FVIII replacement therapy followed by EHL along two consecutive one-year periods. PK estimations were performed through WAPPS-Hemo. FVIII consumption, annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) of each period were compared between both periods. ResultsSeventy-five patients were included (median age 26.0 years). After the switch median reductions of 33.3 % in weekly infusion frequency and 20.4 % in dose/kg/week were observed, avoiding 39.1 infusions/patient/year. Significant improvements were achieved in all PK parameters with EHL, showing mean ratios in half-life and area under the curve (AUC) of 1.5 and 1.9. Significant decreases in median ABR (2.0 vs. 0.0), AJBR (1.0 vs. 0.0) and target joints, and zero total bleeds (27.4 % vs. 54.8 %) and zero joint bleeds (42.5 % vs. 72.6 %) were increased after the switch to EHL. Similar improvements were reported in patients <12 and ≥12 years. No differences were observed in PK parameters between EHL products, but lower AJBR were associated to PEGylated products. ConclusionsPK-guided switch to EHL FVIII provided significant improvements in PK and lower bleeding rates, treatment burden and consumption compared to SHL products.