Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).

Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study.

ABSTRACT: Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single IV dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in 1 participant within 6 hours of infusion and resolved within 24 hours after infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%), and at week 104 it was 25.4% (range, 0.9%-71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or confirmed inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest dose cohort. This trial was registered at www.clinicaltrials.gov as #NCT03061201.

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Extent to which array genotyping and imputation with large reference panels approximate deep whole-genome sequencing.

Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array genotyping followed by genotype imputation can approximate WGS in studies of individuals of African, Hispanic/Latino, and European ancestry in the US and of Finnish ancestry in Finland (a population isolate). For each study, we performed genotype imputation by using the genetic variants present on the Illumina Core, OmniExpress, MEGA, and Omni 2.5M arrays with the 1000G, HRC, and TOPMed imputation reference panels. Using the Omni 2.5M array and the TOPMed panel, ≥90% of bi-allelic single-nucleotide variants (SNVs) are well imputed (r2 > 0.8) down to minor-allele frequencies (MAFs) of 0.14% in African, 0.11% in Hispanic/Latino, 0.35% in European, and 0.85% in Finnish ancestries. There was little difference in TOPMed-based imputation quality among the arrays with >700k variants. Individual-level imputation quality varied widely between and within the three US studies. Imputation quality also varied across genomic regions, producing regions where even common (MAF > 5%) variants were consistently not well imputed across ancestries. The extent to which array genotyping and imputation can approximate WGS therefore depends on reference panel, genotype array, sample ancestry, and genomic location. Imputation quality by variant or genomic region can be queried with our new tool, RsqBrowser, now deployed on the Michigan Imputation Server.

How I approach bleeding in hospitalized patients.

Excessive bleeding is relatively common in adult inpatients, whether as the primary reason for admission or as a development during the hospital stay. Common causes include structural issues, medication effects, and systemic illnesses; occasionally, unexpected bleeding can develop as a result of an undiagnosed or newly acquired bleeding disorder. The first step in caring for the inpatient who is bleeding is to determine whether the bleeding symptom is truly new or whether the patient has a history of abnormal bleeding. Patients with a history of abnormal bleeding may warrant evaluation for inherited bleeding disorders, such as platelet function disorders, von Willebrand disease, hemophilia, or rare factor deficiencies. Patients with no history of bleeding, for whom other causes, such as liver dysfunction, medication effect, disseminated intravascular coagulation, or certain vitamin deficiencies have been ruled out may require evaluation for acquired coagulopathies, such as acquired hemophilia or acquired von Willebrand disease. Here, we present 3 cases to discuss the diagnosis and management of the 2 most common acquired bleeding disorders as well as a patient with a congenital bleeding disorder with a historical diagnosis.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

The importance and evolution of bleeding disorder registries.

Registries are excellent sources of data to address questions that are typically not evaluated in randomized clinical trials, including natural history, disease prevalence, treatment approaches and adverse events, and models of care. Global and regional registries can provide data to identify differences in outcomes and in haemophilia care between countries, economic settings, and regions, while facilitating research and data sharing. In this manuscript, we highlight five bleeding disorder registries: Country registries from Australia and China, Paediatric Network on Haemophilia Management (PedNet) data on children who have received emicizumab, data from the European Haemophilia Safety Surveillance (EUHASS) system, and data on women and girls with haemophilia from the World Federation of Haemophilia (WFH) registries. Data from these and other bleeding disorder registries have been and will continue to be used to advance patient care, understand treatment patterns and adverse reactions, and identify areas of increased need and focus.

A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories.

INTRODUCTION: Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half-life. AIM: Evaluate the accuracy of measuring efanesoctocog alfa FVIII activity in one-stage clotting assays (OSAs) and chromogenic substrate assays (CSAs). METHODS: Human plasma with no detectable FVIII activity was spiked with efanesoctocog alfa or a full-length recombinant FVIII product comparator, octocog alfa, at nominal concentrations of 0.80 IU/mL, 0.20 IU/mL, or 0.05 IU/mL, based on labelled potency. Clinical haemostasis laboratories (N = 35) tested blinded samples using in-house assays. Data from 51 OSAs (14 activated partial thromboplastin time [aPTT] reagents) and 42 CSAs (eight kits) were analyzed. RESULTS: Efanesoctocog alfa activity was reliably (±25% of nominal activity) measured across all concentrations using OSAs with Actin FSL and multiple other aPTT reagents. Under- and overestimation of FVIII activity occurred with some reagents. No specific trend was observed for any class of aPTT activators. A two- to three-fold overestimation was consistently observed using CSAs and the OSA with Actin FS as the aPTT reagent across evaluated concentrations. CONCLUSION: Under- or overestimation occurred with some specific OSAs and most CSAs, which has been previously observed with other modified FVIII replacement products. Efanesoctocog alfa FVIII activity was measured with acceptable accuracy and reliability using several OSA methods and commercial plasma standards.

BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.

BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).

Cryptic resolution sites in the vector plasmid lead to the heterogeneities in the rAAV vectors.

Recombinant adeno-associated virus (rAAV) vectors carry a cassette of interest retaining only the inverted terminal repeats (ITRs) from the wild-type virus. Conventional rAAV production primarily uses a vector plasmid as well as helper genes essential for AAV replication and packaging. Nevertheless, plasmid backbone related contaminants have been a major source of vector heterogeneity. The mechanism driving the contamination phenomenon has yet to be elucidated. Here we identified cryptic resolution sites in the plasmid backbone as a key source for producing snapback genomes, which leads to the increase of vector genome heterogeneity in encapsidated virions. By using a single ITR plasmid as a model molecule and mapping subgenomic particles, we found that there exist a few typical DNA break hotspots in the vector DNA plasmid backbone, for example, on the ampicillin DNA element, called aberrant rescue sites. DNA around these specific breakage sites may assume some typical secondary structures. Similar to normal AAV vectors, plasmid DNA with a single ITR was able to rescue and replicate efficiently. These subgenomic DNA species significantly compete for trans factors required for rAAV rescue, replication, and packaging. The replication of single ITR contaminants during AAV production is independent of size. Packaging of these species is greatly affected by its size. A single ITR and a cryptic resolution site in the plasmid work synergistically, likely causing a source of plasmid backbone contamination.

BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression.

Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.

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

INTRODUCTION: 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. AIM: We evaluated the association between FEL and ABR in PwHB. METHODS: 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. RESULTS: 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 9.95 IU/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). CONCLUSION: 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.

Depression and anxiety in persons with Von Willebrand disease.

OBJECTIVE: We assessed sociodemographic and clinical characteristics associated with depression and anxiety in individuals with Von Willebrand disease (VWD) aged ≥12 years. METHODS: The study collected data on patients' sociodemographic, joint problems and health-related quality of life (HRQoL) using EQ-5D-3L, 8-item patient health questionnaire for depression and 7-item Generalized Anxiety Disorder Questionnaire from participants in seven geographically diverse US haemophilia treatment centres. RESULTS: Analyses included 77 participants. The rates of depression and anxiety were 63.6% and 58.3%, respectively. Persons with low VWF displayed higher rates of depression (86.7%) or anxiety (69.2%) compared to those with VWD (58.1%, p = .04 for depression, and 55.9%, p = .38 for anxiety). Logistic regression analyses demonstrated that having joint problems (odds ratio [OR] = 6.3, confidence interval [CI] = 2.0-20.1) was the most important variable associated with depression, followed by being single, divorced, widowed, or separated in adult participants or parents of participants age < 18 years (OR = 7.0, CI = 1.7-29.0. The most important variable associated with anxiety was being single or lacking a partner (OR = 10.8, CI = 2.5-47.5), followed by age 12-17 years old (OR = 6.7, CI = 1.6-26.9), or having worse health compared to 3-months ago (OR = 12.3, CI = 1.3-116.2). Mean covariates adjusted EQ visual analogue scale score was significantly lower among persons with depression (68.77 ± 3.15 vs. 77.58 ± 4.24, p = .03) than those without depression. CONCLUSIONS: Our study revealed concerning levels of depression and anxiety in this VWD sample. Lack of social support was determined an important factor associated with depression and anxiety in this sample. Mental health screening is critical in VWD clinical evaluation and care.

Phenotypic analysis of erythrocytes in sickle cell disease using imaging flow cytometry.

The morphology and other phenotypic characteristics of erythrocytes in sickle cell disease (SCD) have been analyzed for decades in patient evaluation. This involves a variety of techniques, including microscopic analysis of stained blood films, flow cytometry, and cell counting. Here, we analyzed SCD blood using imaging flow cytometry (IFC), a technology that combines flow cytometry and microscopy to enable simultaneous rapid-throughput analysis of cellular morphology and cell-surface markers. With IFC, we were able to automate quantification of poikilocytes from SCD blood. An important subpopulation of poikilocytes represented dense cells, although these could not be distinguished from other poikilocytes without first centrifuging the blood through density gradients. In addition, CD71-positive RBCs from SCD patients had two subpopulations: one with high CD71 expression and a puckered morphology and another with lower CD71 expression and biconcave morphology and presumably representing a later stage of differentiation. Some RBCs with puckered morphologies that were strongly positive for DAPI and CD49d were in fact nucleated RBCs. IFC identified more phosphatidylserine-expressing red cells in SCD than did conventional flow cytometry and these could also be divided into two subpopulations. One population had diffuse PS expression and appeared to be composed primarily of RBC ghosts; the other had lower overall PS expression present in intense, punctate dots overlying Howell-Jolly bodies. This study demonstrates that IFC can rapidly reveal and quantify RBC features in SCD that require numerous tedious methods to identify conventionally. Thus, IFC is likely to be a useful technique for evaluating and monitoring SCD.

How do I facilitate a rapid response to a public health emergency requiring plasma collection with a public-private partnership?

In March 2020, there were no treatment options for COVID-19. Passive immune therapy including anti-SARS-CoV-2 hyperimmune globulin (hIVIG) was a logical candidate for COVID-19 therapeutic trials, given past success treating emerging pathogens with endogenous neutralizing antibodies. We established a plasma collection protocol for persons recovered from COVID-19. To speed recruitment in the first U.S. hotspot, Seattle, Washington, federal and state public health agencies collaborated with Bloodworks Northwest to collect convalescent plasma (CP) for manufacturing hIVIG. During March-December 2020, we identified and recruited prospective CP donors via letters to persons recovered from COVID-19 with laboratory-confirmed SARS-CoV-2 infection. Prospective donors were pre-screened and administered a medical history survey. Anti-SARS-CoV-2 neutralizing antibody (NAb) titers were classified as qualifying (≥1:80) or non-qualifying (<1:80) for enrollment based on a live virus neutralization assay. Generalized estimating equations were used to identify characteristics of donors associated with qualifying versus nonqualifying NAb titers. Overall, 21,359 letters resulted in 3207 inquiries, 2159 prescreenings with laboratory-confirmed SARS-CoV-2 infection, and 573 donors (27% of all pre-screenings with confirmed infection) who provided a screening plasma donation. Of 573 donors screened, 254 (44%) provided plasma with qualifying NAb titers, resulting in 1284 units for hIVIG manufacture. In a multivariable model, after adjusting for other factors, time (60 days) from COVID-19 symptom onset to screening was associated with lower odds of qualifying NAb (adjusted odds ratio = 0.67, 95% CI: 0.48-0.94). The collaboration facilitated a rapid response to develop and provide hIVIG for clinical trials and CP for transfusion. Only 1 in 12 donor inquiries resulted in a qualifying plasma donation. Challenges included recruitment and the relatively low percentage of persons with high NAb titers and limited screening capacity. This resource-intensive collaboration may not be scalable but informs preparedness and response strategies for plasma collection in future epidemics. Operational readiness plans with templates for screening, consent, and data collection forms are recommended.

The critical need for postmarketing surveillance in gene therapy for haemophilia.

INTRODUCTION: The goal of gene therapy for haemophilia is to alter the clinical phenotype to a milder form or even cure, by increasing endogenous coagulation factor levels through transfer of a functional gene encoding the respective deficient coagulation factor and subsequent transgene expression. Over the past decade, there has been tremendous progress in gene therapy, particularly in use of liver-directed adeno-associated viral vectors, such that several programmes for both haemophilia A and B are in phase 3 trials. With regulatory approval of the first gene therapy product expected as early as mid-2020, there is an urgent need for a mechanism to collect long-term data on safety and variability and durability of efficacy. There will be elements required by regulators for postmarketing surveillance and additional data needed to enhance our understanding of gene therapy outcomes and their impact on the lives of people with haemophilia. AIM: The aim of this manuscript was to describe efforts underway by the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to collect long-term harmonized data and considerations of the European and US regulatory agencies, which will inform ongoing data collection. METHODS: The status of data collection around gene therapy in haemophilia and important outcome measures were obtained by literature review. Each author described elements relevant to the activities of their organization. CONCLUSION: Support of all stakeholders in gene therapy, providers, patients, industry and regulators, augers successful capture of uniform long-term safety and efficacy data to ensure optimal treatment of people with haemophilia.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 µg/mmol during vaso-occlusive crises to 2.62 µg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Long-term safety and efficacy results from the phase 3b, open-label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A.

INTRODUCTION: Previous studies reported the efficacy and safety profile of extended half-life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients. AIM: This study evaluated long-term safety and efficacy of rurioctocog alfa pegol for prophylaxis and treatment of bleeding in previously treated children and adults. METHODS: In this phase 3b, prospective, open-label, multicentre study (NCT01945593), eligible patients ≤ 75 years with severe haemophilia A (FVIII < 1%) received prophylactic rurioctocog alfa pegol in a fixed dose (FD, twice-weekly or less frequent) or pharmacokinetic (PK)-tailored dose regimen. Co-primary endpoints were incidence of confirmed FVIII inhibitory antibody development and spontaneous annualized bleed rate (ABR), analysed using a generalised linear model. Secondary endpoints included overall haemostatic efficacy, occurrence of adverse events and health-related quality of life (HRQoL). RESULTS: Overall, 216 patients were included; mean (SD) age at enrolment was 22.8 (15.7) years. No patients developed confirmed FVIII inhibitors. The point estimate (95% CI) of mean spontaneous ABR was 1.20 (0.92-1.56) among 186 patients receiving twice-weekly FD prophylaxis and 0.96 (0.54-1.71) among 25 patients receiving PK-tailored prophylaxis. Overall haemostatic efficacy was rated good or excellent in 88.6% of all bleeds. No new safety signals were observed. Patients reported improvements in HRQoL measures of pain, and physical and mental well-being. CONCLUSION: These results highlight the long-term safety and efficacy of rurioctocog alfa pegol prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR reduction.

Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: Final results from the ASPIRE extension study.

INTRODUCTION: The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study. AIM: To report the long-term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. METHODS: Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. RESULTS: A total of 150 subjects from A-LONG and 61 subjects from Kids A-LONG enrolled in ASPIRE. Most subjects received the IP regimen (A-LONG: n = 110; Kids A-LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A-LONG and Kids A-LONG was 3.9 (0.1-5.3) years and 3.2 (0.3-3.9) years, respectively. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was <1.0) and extended-dosing intervals were maintained (median of 3.5 days) for the majority of subjects in ASPIRE. CONCLUSION: ASPIRE results, which include up to 5 years of follow-up data, confirm earlier reports on the consistent and well-characterized safety and efficacy of rFVIIIFc treatment for severe haemophilia A.