Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment

Summary.  Currently, efficacy of a new factor concentrate is mostly judged by its ability to achieve haemostasis after a bleeding episode. However, in patients on prophylaxis, the effectiveness in preventing bleeds, and thus joint damage, is most important. An albumin-free recombinant factor VIII (FVIII) concentrate was introduced in the Netherlands in 2004. In this study, the efficacy of a new recombinant plasma/albumin-free FVIII concentrate (rAHF-PFM, Advate®) was assessed by comparing bleeding frequency and factor consumption before and after switching to the new product, on both prophylactic and on-demand treatment. Eighty-two previously treated haemophilia A patients with  at least 1-year clinical follow-up were included in this study. Data on 410 patient-years were analysed, including 165 patient-years on other clotting factor products, and 245 patient-years on the new concentrate. In total, 19 628 368 IU of other factor concentrates were administered, to treat 839 bleeds, including 578 joint bleeds and cover 104 years of prophylactic treatment. For rAHF-PFM 33 082 250 IU FVIII, were used to treat 1144 bleeds, including 734 joint bleeds and cover 175 years of prophylactic treatment. No inhibitors, seroconversions or other serious adverse events were observed. Annual FVIII consumption per kg and annual number of joint bleeds before and after switching to the new albumin-free recombinant factor concentrate were similar in all patients. In conclusion, rAHF-PFM is equally effective as other clotting factor concentrates for prophylactic treatment in severe haemophilia.     

Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels

Summary. Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self‐reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero‐inflated Poisson, and zero‐inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77–0.86] of bleeding frequency with every IU dL^‐1 increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01–0.06 IU mL^?1). The best way to analyse low frequency bleeding data is using a negative binomial distribution.     

Retrospective analysis of differences in annual factor VIII utilization among haemophilia A patients

Finding differences in drug utilization patterns within rare patient populations is challenging without access to a large sample. Our objective was to identify patient and treatment-related factors associated with differences in annual recombinant factor VIII (rFVIII) utilization in a large cohort of haemophilia A patients. This retrospective analysis utilized a large, US specialty pharmacy dispensing database from January 2006 to September 2009. Differences in median annual FVIII utilization (IU kg(-1) year(-1)) by age, severity, treatment regimen, rFVIII product type and health insurance plan were tested using non-parametric statistics and regression analysis. A total of 1011 haemophilia A patients were included in the overall analysis. Severe haemophilia patients had higher median annual FVIII utilization than mild/moderate patients (P < 0.0001). Median annual FVIII utilization was also significantly different between treatment regimens (episodic = 1429 IU kg(-1) year(-1) vs. prophylaxis = 3993 IU kg(-1) year(-1) for severe patients, P < 0.0001). Children (0-12 years old), adolescents (13-18 years old) and adults (19+ years old) with severe haemophilia A receiving prophylaxis utilized 4588, 4082 and 3223 IU kg(-1) year(-1) (P < 0.0001). After controlling for age, severity, treatment regimen and insurance type, regression analysis revealed B domain-deleted recombinant FVIII (BDD-rFVIII) was associated with 33% higher FVIII consumption compared with full-length recombinant FVIII (FL-rFVIII) (P = 0.0172). Similar results were also seen when matching BDD-rFVIII and FL-rFVIII patients. Health insurance type was not associated with annual FVIII utilization. As expected, age, severity and treatment regimen were significantly associated with FVIII utilization. After controlling for confounders, patients receiving FL-rFVIII prophylactically were associated with lower annual FVIII utilization compared with patients receiving BDD-rFVIII prophylactically.     

Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials

Summary. Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre‐licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48‐h pharmacokinetic study. The 10–65 year group had ≥75 exposure days on fixed prophylaxis (25–40 IU kg^?1 3–4x per week). Prophylaxis was not fixed but similar for 1–6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg^?1 week^?1 in on average 2.9 infusions (1–6 years), 86 IU kg ^?1week^?1 in 2.7 infusions (10–17 years),and 75 IU kg ^?1week^?1 in 2.6 infusions (18–65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1–6 years, 3.3 for those aged 10–17 years and 2.1 for patients aged 18–65 years. Patients aged 1–6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0–0.4) compared to those who infused later [median 1.8 per year (IQR 0.0–5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10–65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment.     

The impairment in daily life of obese haemophiliacs

Summary. Obesity is a major health concern not only in the general population but also in patients with haemophilia. Little is known about the consequences of obesity for haemophilia patients. As obesity is an important risk factor for osteoarthritis, these effects may be even more pronounced in haemophilia patients who are prone to joint damage. The association between obesity and limitations in daily activities as well as the frequency of bleeds and use of factor VIII (FVIII) concentrate in obese and normal weight haemophilia patients was assessed. Fifteen obese (BMI ≥ 30 kg m^?2) and fifteen normal weight (BMI ≤ 25 kg m^?2) haemophilia A patients matched for severity and age were analysed. The Hemophilia Activities List (HAL) was used to assess the impairment in daily activities. Compared with the normal weight haemophilia patients, obese haemophiliacs had a significantly lower sum score (88/100 and 98/100, respectively, P = 0.02), which was mainly caused by an impaired lower limb function. All other components of the HAL also showed lower scores in the obese patients, but did not reach statistical significance. A higher frequency of bleeds requiring treatment with FVIII concentrate occurred in the obese haemophiliacs (17 bleeds in eight individuals) compared with the controls (three bleeds in three individuals) (P = 0.045). Compared with non‐obese haemophilia patients, obese haemophiliacs had more joint bleeds and a lower overall HAL score, which was driven by a lower limb function score. Prevention of overweight and weight reduction requires special attention from physicians treating haemophilia patients.     

The clinical efficacy and safety of the FVIII/VWF concentrate,BIOSTATE®, in children with von Willebrand disorder: a multi‐centre retrospective review

Summary. Factor replacement with BIOSTATE^®, a factor VIII (FVIII)/von Willebrand factor concentrate, forms the mainstay of treatment for children with von Willebrand disorder (VWD) in Australia and New Zealand. However, published data on the clinical efficacy and safety of BIOSTATE in the VWD paediatric population are limited. We retrospectively assessed the efficacy and safety of BIOSTATE in 43 children with VWD who received treatment for surgery, non‐surgical bleeds or continuous prophylaxis at eight paediatric haemophilia centres in Australia and New Zealand. Data were collected on patient demographics, disease history, treatment history, dosage, administration, adverse reactions, concomitant medications and excessive bleeding events. BIOSTATE provided excellent/good haemostatic efficacy in 90% of surgical procedures (n = 42) with a mean daily FVIII dose of 47 IU FVIII:C kg^?1 and a median treatment duration of 3 days. Excellent/good haemostatic efficacy was achieved in 94% of non‐surgical bleeding events (n = 72) with a mean FVIII dose of 45 IU FVIII:C kg^?1 day^?1 and a median treatment duration of 1 day. There were no bleeding events attributable to lack of efficacy. One case of nausea, possibly related to BIOSTATE administration, was reported. These results suggest that BIOSTATE is safe and effective for the treatment and prophylaxis of bleeding in children with VWD.     

Real‐world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A

Introduction

Prophylaxis with extended half‐life factor VIII (FVIII) is approved for haemophilia A, but data regarding routine clinical use are limited.

Aim

To assess real‐world experience of ADYNOVATE^® (Antihemophilic Factor (Recombinant), PEGylated prophylaxis in children and adults with haemophilia A.

Methods

A retrospective chart review was conducted in three US haemophilia treatment centres. Records of all patients who began Adynovate prophylaxis in routine clinical practice were identified. Demographic, clinical and patient‐reported information beginning 6 months before initiation of Adynovate until the record review was analysed.

Results

Fifteen patients (aged 9 months to 28 years), with median 9 months’ use of Adynovate (range 1‐15 months), were identified. All had switched from another prophylactic regimen, 13 (87%) from standard half‐life recombinant FVIII. Nine (60%) patients had ≥1 bleed within 6 months preswitch. The most frequent reason for switching was to reduce infusion frequency (14 patients). After switching, infusion frequency reduced for 13 patients, and overall weekly factor consumption decreased by 19%. Eight (53%) patients had no bleeds postswitch, three (20%) had spontaneous joint bleeds (vs four pre‐switch), and three (20%) had only mild traumatic bleeds. Patient/parental satisfaction with Adynovate was documented as positive in 13 of 15 (87%) cases; 2 patients were not satisfied and discontinued Adynovate. No adverse events were considered related to Adynovate.

Conclusion

In patients who switched from a standard half‐life FVIII to Adynovate prophylaxis in routine clinical practice, bleeding control was generally improved or maintained, with a lower infusion frequency and factor consumption in most patients.     

Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors

The benefits shown with factor VIII (FVIII) prophylaxis relating to joint health and quality of life (QoL) provide the rationale for FEIBA prophylaxis in haemophilia A patients with persistent FVIII inhibitors. FEIBA has previously shown efficacy in preventing bleeds in inhibitor patients who failed to respond to, or were ineligible for immune tolerance induction (ITI). The study examined the outcome of paediatric patients undergoing long‐term FEIBA prophylaxis. A retrospective chart review included severe haemophilia A patients with persistent inhibitors aged ≤13 years at the start of FEIBA prophylaxis. Baseline characteristics captured dose, frequency of prophylaxis, history of inhibitor development, including baseline titre, historical peak titre and history of ITI. Outcome measurements included annual bleed rate before and during FEIBA prophylaxis, joint status and school days missed. Sixteen cases of FEIBA prophylaxis from two centres are presented. The mean age of subjects at prophylaxis initiation was 7.5 ± 3.6 years and median baseline inhibitor titre was 23 (range 3.1–170) BU. Prior to prophylaxis initiation, median annual joint bleeds among all patients was 4 (0–48), which dropped significantly after the first year of prophylaxis, to a median annual joint bleed rate of 1 (0–7; P = 0.0179). Subsequent years (median = 9) of prophylaxis therapy demonstrated similarly low annual joint bleed rates. There were no life‐threatening bleeds, no viral seroconversions or thrombotic events during FEIBA prophylaxis treatment. FEIBA prophylaxis was effective for preventing joint bleeds and subsequent joint damage, delaying arthropathy and improving outcomes in children with haemophilia A and inhibitors to FVIII, who failed or were ineligible for ITI.     

Secondary prophylaxis treatment versus on‐demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan

Summary. This study compared secondary prophylaxis treatment with on‐demand treatment for severe haemophilia A in Taiwan. Fifty patients from one medical centre were evaluated over a 5‐year period. Differences in annual bleed rates and factor VIII (FVIII) utilization were assessed between patients receiving secondary prophylaxis and patients receiving FVIII concentrates on‐demand. Results were then used as inputs in a pharmacoeconomic model to predict outcomes of future haemophilia therapy strategies in Taiwan. The median annual number of total bleeding episodes was significantly lower in the 13 (26%) patients who received secondary prophylaxis than in the 37 patients who received FVIII on‐demand (7.76 vs. 31.91, P < 0.0001). The between‐group difference in median annual factor VIII utilization was statistically significant (1824.41 IU kg^?1 for the prophylaxis group and 1324.81 IU kg^?1 for the on‐demand group, P < 0.01). It was estimated that approximately $2 million (USD) per year would be added to the cost of treatment by having all severe haemophilia A patients in Taiwan receive secondary prophylaxis instead of on‐demand therapy while 12 566 bleeding will be prevented. It is recommended that National Health Insurance officials utilize these data to evaluate the benefits of enhanced treatment strategies and before making substantial policy changes to haemophilia care in Taiwan.     

Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies

Acquired haemophilia is a rare, but often severe bleeding disorder caused by autoantibodies against a coagulation factor, usually factor VIII (FVIII). Between 1997 and 2004 we observed 14 patients (mean age of 78 years) with acquired haemophilia. The aim of the present study was to investigate the effect of activated prothrombin complex concentrate (aPCC) for bleeds and the response to corticosteroids and cyclophosphamide to eradicate the offending autoantibodies. The most common clinical presentations were severe profuse bruising (12) and haematuria (5). Ten patients were classified as idiopathic. At the time of diagnosis all patients had a very low FVIII level, and one patient also showed factor IX < 1%. High levels of antibodies to FVIII varying from 10 to 1340 Bethesda units (BU) and prolonged activated partial thromboplastin time were disclosed in all patients. Eight severe bleeds were treated with aPCC (FEIBA) at a dosage of 70 IU kg(-1) every 8 h until haemostasis. Ten patients received corticosteroids and cyclophosphamide as immunomodulatory therapy. Effective haemostasis was achieved in all bleeds after aPCC. Ten of 11 patients responded either completely or partially to the immunomodulatory regime within 6 months. Five patients achieved complete response (CR) whereas partial responses were seen in five patients. The anti-CD20 monoclonal antibody rituximab was given to two patients in conventional doses and a CR was seen in one patient. aPCC is effective in treating acute bleeds in patients with acquired haemophilia with high inhibitor levels. The combination of oral corticosteroids and cyclophosphamide seems to be effective to eradicate the inhibitor.     

Clinical assessment of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in the management of patients with haemophilia A

Summary. Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor‐screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high‐purity FVIII product with von Willebrand factor, Optivate^®. Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long‐term studies. Seventy previously treated patients with severe haemophilia A, with ≥20 exposure days, were recruited into two long‐term, multicentre, open‐label studies. The protocols were virtually identical. Patients received Optivate^® either prophylactically or on‐demand. A mean of 159.0 EDs were experienced over 11 320 infusions. Under both conditions, Optivate^® was well tolerated. Only 10% of patients experienced a treatment‐related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on‐demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on‐demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate^® in both prophylactic and on‐demand management of patients with haemophilia A.     

Allergic reaction in a cohort of haemophilia A patients using plasma‐derived factor VIII (FVIII) concentrate is rare and not necessarily triggered by FVIII

In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma‐derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti‐FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti‐pdFVIII IgE and IgG4, but no anti‐recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high‐responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti‐pdFVIII and anti‐rFVIII IgG4 were detected, no anti‐FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti‐FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti‐FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII.     

A survey of factor prophylaxis in the Canadian haemophilia A population

High-dose factor prophylaxis, defined as the infusion of 25-40 factor (F) VIII International Units (IU) kg bodyweight (bw)(-1)> or = x 3 per week, started at age 1-2 years of life in boys with severe haemophilia A prevents the development of significant bleed-related arthropathy. However, programmes of prophylaxis are very expensive and venous access is a challenge. To ascertain patterns of prophylaxis in Canada during the period of a global shortage of recombinant FVIII concentrate a survey was conducted in 2001. The response rate was 83% and the survey identified 247 inhibitor-negative haemophilia A cases receiving prophylaxis, defined as the regular administration of FVIII at least once weekly, from 14 Canadian haemophilia treatment centres. The median age of the group identified was 13 years (range: 1-65) and 95% of cases had severe haemophilia A defined by a circulating factor level of <1%. The median FVIII infusion dose was 26 (range: 16-33) IU kg(-1); infusions were administered > or = x 3 per week in 67% of cases. High-dose factor prophylaxis was used most frequently in boys <5 years of age (23 of 28 cases, 82%) as compared with 56% (56 of 100), 66% (40 of 61) and 62% (36 of 58) of males ages 5-12, 13-18 and >18 years. Prophylaxis accounted for 50% of the annual Canadian FVIII consumption and was a major driving force in the 10% increase (=19.3 million FVIII IU) in the FVIII consumption in Canada in the 4-year period 1999-2003. Given the economic implications of increased use of prophylaxis prospective studies are warranted to better define optimal prophylaxis regimens in the haemophilia A population.     

Low-dose continuous infusion of factor VIII in patients with haemophilia A

BackgroundPatients with haemophilia A (HA) or B (HB) can be given prophylactic or on-demand treatment administered by continuous infusion or bolus injections of factor VIII (FVIII) or IX (FIX). In this study we evaluated the efficacy and safety of low-dose continuous infusion of FVIII or FIX.ResultsA total of 66 continuous infusions (40 in major surgery, 10 in minor surgery and 16 with bleeding episode) in 46 HA patients and 16 (15 in severe and 1 in mild HA) in eight HB patients were included in the study. During the first week of treatment, the median continuous infusion rates in HA patients undergoing major surgery, minor surgery and a bleeding event were 2.18 (0.75–3.68), 1.48 (1.0–2.54) and 2.24 (1.33–3.93) IU/kg/h, respectively. The median FVIII activities were 0.69 (0.37–1.19), 0.47 (0.39–0.84) and 0.52 (0.36–1.06) IU/mL. After the first week of treatment, even lower doses of FVIII were needed. Red blood cell transfusions had to be administered to three patients (2 with severe and 1 with moderate HA) during the continuous infusion and inhibitors developed in five patients. In HB patients, the median continuous infusion rate was 1.85 (1.07–2.94) IU/kg/h and the median FIX activity was 0.62 (0.30–1.04) IU/mL. Red blood cell transfusions were not required, and thrombophlebitis and inhibitors did not appear.DiscussionOverall, low-dose continuous infusion was shown to be an effective and safe way of treating patients with HA. The protocol used also proved efficient and safe in all HB patients.     

The overall effectiveness of prophylaxis in severe haemophilia

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.     

Patient characteristics that influence efficacy of prophylaxis with rFVIII‐FS three times per week: a subgroup analysis of the LIPLONG study

Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose‐formulated recombinant factor VIII [rFVIII‐FS (control)] arm of the LIPLONG study, a randomized, double‐blind, 52‐week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79‐4980 or rFVIII‐FS. The per‐protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg^?1 rFVIII‐FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t‐test. The annualized median (range) number of bleeds was 2.2 (0.0–23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0–17.1) vs. 4.2 (0.0–22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0–19.2) vs. 5.3 (0.0–22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII‐FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.     

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy,emicizumab prophylaxis,and FVIII replacement prophylaxis

Introduction

Head-to-head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly compared.

Aim

To compare bleeding rates in trials evaluating 6 × 10¹³ vg/kg valoctocogene roxaparvovec (GENEr8-1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270–902) in participants with severe haemophilia A (FVIII ≤1 IU/dL).

Methods

Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270–902 versus emicizumab cross-trial comparisons were performed using matching-adjusted indirect comparison (MAIC). Individual participant data from GENEr8-1 and 270–902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds.

Results

After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio [95% CI], .55 [.33–.93]). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio [95% CI], 2.75 [1.20–6.31]) and no treated bleeds (3.25 [1.53–6.90]) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half-life FVIII prophylaxis regimens in 270–902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab.

Conclusion

Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270–902.     

Pharmacokinetic study of minipooled solvent/detergent‐filtered cryoprecipitate factor VIII

Summary. Eighteen cryoprecipitate minipools, each made of 30 units of low volume, concentrated cryoprecipitate, have been treated by solvent‐detergent and filtration (S/D‐F) in a single‐use CE‐marked bag system. The S/D‐F cryoprecipitate contained a mean of 10.5 IU mL⁻¹ factor VIII (FVIII), 17 mg mL⁻¹ clottable fibrinogen, and >10 IU mL⁻¹ von Willebrand factor ristocetin co‐factor, and anti‐A and anti‐B isoagglutinins were undetectable. The products have been infused in 11 severe (FVIII <1%) haemophilia A patients (mean age: 17.4 years; mean weight: 57.6 kg) at a dose close to 40 IU kg⁻¹. Patients were hospitalized for at least 36 h to determine FVIII recovery, half‐life and clearance. They were also closely monitored for possible adverse events. None of the infused patients demonstrated reactions or adverse events even though they did not receive anti‐allergic drugs or corticosteroids prior to infusion. The mean recovery of FVIII 10 min postinfusion was 69.7%. Mean FVIII half‐life was 14.2 h and clearance was 2.6 mL h⁻¹ kg⁻¹. All patients had a bleeding‐free interval of 8–10 days postS/D‐F cryoprecipitate infusion. The data show that S/D‐F cryoprecipitate FVIII presents a normal pharmacokinetics profile, and support that it could be safely used for the control of acute and chronic bleeding episodes in haemophilia A patients.     

Prophylaxis and quality of life in patients with hemophilia A during routine treatment with ADVATE [antihemophilic factor (recombinant), plasma/albumin-free method] in Germany: a subgroup analysis of the ADVATE PASS post-approval, non-interventional study

Antihemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) was evaluated during routine practice in Germany, among consenting subjects of any age with hemophilia A (HA) and no prior exposure to rAHF-PFM. The treating physician chose the dosing and inhibitor testing frequency. Data were captured for 12 months/subject from diaries and clinic records. Of 152 subjects, 69 % had severe HA, and 89 % had >150 exposure 6 days (ED) at baseline. The majority of subjects (63 %) were treated by continuous prophylaxis (CP). Assignment to CP was more likely for subjects ≥2 years of age and for those with FVIII?≤?2 %. Median FVIII consumption was 3,548 IU/kg/year for CP and 999 IU/kg/year for continuous on-demand (OD) therapy. Median annual bleed rate was 0.82 for CP and 4.06 for OD. Of 1,218 bleeds, 97 % were home-treated and 68 % of evaluable bleeds involved joints. Based on evaluable subjects' worst ratings, 83/91 (91 %) on CP had a rating of excellent/good for all prophylactic assessments, 55/59 (93 %) on CP and 41/42 (98 %) on OD had a rating of excellent/good for all bleeding assessments. The de novo high-titer FVIII inhibitor rate in subjects with >50 ED at baseline was 1/144 (0.69 %; 95 % CI, 0.02 % to 3.81 %). No high-titer inhibitor occurred in patients with severe HA and >50 ED at baseline. Reduced HRQOL physical scores were predicted by older age (p?<?0.0001), HIV positivity (p?=?0.02), and presence of ≥1 target joint (p?=?0.003). ADVATE rAHF-PFM is safe and efficacious for routine CP or OD management of patients with HA.     

Prophylaxis for severe haemophilia: clinical and economical issues

Patients with severe haemophilia are treated either in case of bleeds only (on demand), or with regular infusions of clotting factor to prevent bleeds (prophylaxis). The introduction of prophylaxis has been hampered by issues of cost and viral safety. In order to compare results and treatment cost of different treatment strategies in adults, three cohorts of patients with severe haemophilia (born 1970-1980) were compared. 106 French patients were treated on demand, 49 Dutch patients were treated with intermediate dose prophylaxis, and 24 Swedish patients were treated with high dose prophylaxis. The annual number of joint bleeds, and the radiological Pettersson score were used to compare outcome, annual clotting factor consumption was used to compare costs. Prophylaxis reduced bleeds and arthropathy: patients treated on demand had a median of 11.5 joint bleeds/year and a median Pettersson score of 16 points, for intermediate dose prophylaxis median bleeds were 2.8 and Pettersson score was 7 points, and for high dose prophylaxis median bleeds were 0.5 joint bleeds and Pettersson score was 4 points. All differences were statistically significant, except the Pettersson scores in both prophylactic regimens. Treatment cost was only increased for high dose prophylaxis: mean clotting factor consumption was 1612 IU kg-1 yr-1 for on demand treatment, 1488 IU kg-1 yr-1 for intermediate dose prophylaxis, and 4012 IU kg-1 yr-1 for high dose prophylaxis. In young adults, the cost of intermediate dose prophylaxis is similar, but outcome is better than for on demand treatment. The cost of high dose prophylaxis is twofold higher, further improving outcome only slightly.