BAY 94‐9027, a PEGylated recombinant factor VIII,exhibits a prolonged half‐life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies

Introduction

Recombinant factor VIII (rFVIII) products with extended half‐lives, such as BAY 94‐9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard‐acting FVIII products.

Aim

To characterize the pharmacokinetic (PK) profile of BAY 94‐9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A

Methods

Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18–65 years, ≥150 EDs), PROTECT VIII (12–65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25‐IU/kg or 60‐IU/kg BAY 94‐9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60‐IU/kg infusion and in PROTECT VIII Kids after a single 60‐IU/kg infusion. The chromogenic assay was used to assess FVIII activity.

Results

Compared with sucrose‐formulated rFVIII, BAY 94‐9027 had reduced clearance that resulted in a ~1.4‐fold increase in half‐life and dose‐normalized area under the curve (AUC). The BAY 94‐9027 PK profile was comparable after single‐ and repeated‐dose administrations. Dose‐proportional increases were observed between 25‐ and 60‐IU/kg administrations. BAY 94‐9027 PK characteristics were age dependent, consistent with other FVIII products.

Conclusions

BAY 94‐9027 shows an extended half‐life and increased AUC vs standard‐acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.     

Multicentre pharmacokinetic evaluation of rFVIII‐Fc (efmoroctocog alfa) in a real life and comparison with non‐extended half‐life FVIII concentrates

The use of enhanced half‐life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII‐Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non‐EHL FVIII. The in vivo recovery (IVR) of rFVIII‐Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half‐life (T_1/2) of rFVIII‐Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T_1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII‐Fc vs non‐EHL FVIII showed a T_1/2 ratio of 1.4 in favour of rFVIII‐Fc, regardless of the patient's age. However the relative increase in T_1/2 with rFVIII‐Fc was lower than 30% in one‐third of patients evaluated, particularly when the previous FVIII administered was a BHK‐derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.     

Impact of timing of prophylaxis commencement,F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A

Introduction

The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA).

Aim

To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL).

Methods

Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively.

Results

The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p < .001), EQ-5D-5L index (0.9647 vs. 0.904, p = .022), EQ VAS (87 vs. 75, p = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS.

Conclusion

Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.     

Clinical experience with moroctocog alfa (AF‐CC) in younger paediatric patients with severe haemophilia A: Two open‐label studies

Introduction

The pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF‐CC) have been demonstrated in haemophilia A patients aged ≥6 years.

Aim

These studies aimed to further describe moroctocog alfa (AF‐CC) experience in paediatric patients (<12 years) with severe haemophilia A (FVIII:C < 1%).

Methods

Two prospective, open‐label studies enrolled patients aged <12 years: one study with 37 previously treated patients (PTPs) and another with 23 previously untreated patients (PUPs). All patients initially received 50 IU/kg of moroctocog alfa (AF‐CC) to evaluate either recovery alone, or with other PK parameters (6 to <12 years) before continuing treatment for 100 exposure days (EDs) or 24 months.

Results

At baseline, mean (±SD) recovery ranged between 1.32 ± 0.65 (PUPs aged <2 years) and 2.13 ± 0.82 (PTPs aged 6 to <12 years). The mean (±SD) half‐life was 9.12 ± 1.94 hours in PTPs aged 6 to <12 years. No new safety signals were detected in either study, 2 transient lower titre inhibitors occurred in PTPs while 8 inhibitors (3 low and 5 high titre) were detected in PUPs. Most bleeding episodes resolved with one infusion (94% [893/954]). The annualised bleeding rate (ABR) in the PTP study was 27.5 and 4.2 for patients reporting an on‐demand and routine prophylaxis regimen at baseline, respectively. In the PUP study, the overall ABR was 5.9.

Conclusion

Moroctocog alfa (AF‐CC) had expected PK findings (lower recovery in young children compared with older children) along with being safe and efficacious in a population of young severe haemophilia A patients.     

Similarity in joint function limitation in Type 3 von Willebrand's disease and moderate haemophilia A

Type 3 von Willebrand's disease (VWD) is a rare bleeding diathesis with complete or near complete deficiency of von Willebrand factor (VWF) and low factor VIII (FVIII) levels. In contrast, only FVIII is decreased in haemophilia A (HA). Both disorders are complicated by arthropathy. The purpose of this study was to further clarify the roles of FVIII and VWF: Antigen (VWF:Ag) in joint range of motion (ROM) loss over time. We compared joint ROM loss and other bleeding manifestations in 100 Type 3 VWD subjects (FVIII< 5%) and 1814 moderate HA subjects (FVIII 1–5%) within the U.S. Universal Data Collection (UDC) database. High rates of bleeding were reported at baseline. During follow‐up, moderate HA patients reported a joint (46% vs. 34%, P < 0.0001) or muscle bleed (27% vs. 16%, P < 0.0001) in a higher proportion of visits than VWD patients. Other bleeds, including mucosal, were reported in a greater proportion of visits among patients with Type 3 VWD than among those with HA (49% vs. 32%, P < 0.0001). Multivariate analysis revealed no difference in joint ROM loss over time in the Type 3 VWD vs. moderate HA populations. A higher FVIII level was protective in both VWD and HA (P < 0.001). Our findings support the hypothesis of primacy of the FVIII level in determining risk of joint haemorrhage, and may help target therapy in Type 3 VWD and moderate HA to prevent joint disability.     

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.     

Bioequivalence between two serum‐free recombinant factor VIII preparations (N8 and ADVATE®) – an open‐label,sequential dosing pharmacokinetic study in patients with severe haemophilia A

Summary. Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum‐free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate^®, a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open‐label, first human dose (FHD), multicentre trial. Twenty‐three patients first received a single dose of 50 IU kg^?1 body weight Advate^® followed by 50 IU kg^?1 body weight N8 at the next visit. A 4‐day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate^® and N8 were comparable. The 90% CI for the treatment ratio (Advate^®/N8) for all primary endpoints (incremental recovery, t_1/2, AUC and Cl), and the secondary endpoints (AUC_last and C_max) were within the bioequivalence interval of 0.8–1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72‐h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate^®. Furthermore, N8 is well tolerated in the FHD trial.     

Pharmacokinetics of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in patients with severe haemophilia A

Summary. Optivate^® is a high purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate, which is manufactured using two antiviral processes: solvent/detergent and terminal dry heating (80°C for 72 h). A multicentre, non‐randomized open‐label study in 15 patients was conducted to test the pharmacokinetics (PK) of Optivate^®. PK variables were analysed for the patients’ prior FVIII product (PK1), their first dose of Optivate^® (PK2) and at 3 months therapy (PK3). Mean non‐compartmental half‐lives (h) were 14.1, 12.4 and 12.1, respectively (P = 0.45), mean clearances (mL h^?1 kg^?1) were 3.6, 3.2 and 3.1, respectively (P = 0.051), MRTs (h) were 19.0, 17.3 and 17.4, respectively (P = 0.39) and mean AUC_0–48h (h IU mL^?1) were 14.3, 15.4 and 16.6, respectively (P = 0.051) and mean AUC_0–∞ (h IU mL^?1) were 15.9, 16.4 and 17.9, respectively (P = 0.18). The recovery data from this PK study was aggregated with recovery data collected from another study, with similar design but devoid of the other PK measurements. A total of 309 recoveries were conducted in 70 patients. The overall mean recovery per subject across 27 Optivate^® batches was 2.7 IU dL^?1 per IU kg^?1. There were no clinical differences between Optivate^® and other FVIII products, and except for volume of distribution (Vd), no statistically significant differences were seen with respect to any of the other PK variables, or in recovery between weeks 0 and 12. Therefore, the PK of FVIII is not affected by the processes used to manufacture Optivate^®, which can be expected to be effective in the management of patients with haemophilia A.     

Correlation between von Willebrand factor antigen,von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma

Background The laboratory diagnosis of von Willebrand Factor (VWF) deficiencies includes qualitative and quantitative measurements of VWF and clotting factor VIII (FVIII). Since the FVIII activity is frequently normal in patients with mild type 1 or 2 von Willebrand disease (VWD), there is controversy whether FVIII testing should accompany VWF Antigen (VWF:Ag) assay. Methods The aim of this study was to explore the correlation between VWF:Ag, VWF ristocetin cofactor activity (VWF:RCo) and FVIII in 213 consecutive patients undergoing screening for VWD. Results Forty-six patients were identified with VWF:Ag levels lower than the diagnostic threshold (54 IU/dl). A significant correlation was observed between VWF:Ag and VWF:RCo (r = 0.892; p < 0.001), VWF:Ag and FVIII (r = 0.834; p < 0.001), VWF:RCo and FVIII (r = 0.758; p < 0.001). Receiver operating characteristic curve analysis of the VWF:Ag assay revealed an area under the curve of 0.978 and 0.957 for detecting life-threatening values of FVIII (<30 IU/dl) and VWF:RCo (<40 IU/dl), respectively. The negative and positive predictive values at the VWF:Ag threshold value of 54 IU/dl were 100% and 33% for detecting life-threatening FVIII deficiencies, 94% and 80% for identifying abnormal values of VWF:RCo. Conclusions Due to the excellent correlation between VWF:Ag and FVIII and to the diagnostic efficiency of VWF:Ag for identifying abnormal FVIII levels in patients with VWF deficiency, routine measurement of FVIII may not be necessary in the initial screening of patients with suspected VWD. However, the limited negative predictive value of VWF:Ag for identifying type 2 VWD does not allow to eliminate VWF:RCo or VWF:FVIIIB assays from the diagnostic workout.     

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.     

A cross-sectional follow-up study of physical activity in adults with moderate and severe haemophilia

Aim

To conduct a cross-sectional follow-up assessment of physical activity (PA) in people with moderate and severe haemophilia (PwMSH) from the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study.

Methods

Between June–December 2021, participants’ PA was measured over one week using accelerometery, and was compared with their previously measured data from the original iPATH assessment. Self-awareness of PA and the impact of the Covid-19 pandemic on PA, pain, mobility and function were retrospectively examined using a survey.

Results

Of 30 participants who returned surveys [n = 19, severe (FVIII, <.01 IU/mL); n = 4, moderate (FVIII, .01–.05 IU/mL); n = 7, severe (FIX, <.01 IU/mL); age: 47 (36, 55) years], 28 completed accelerometery (follow-up time: 3 years). There were no significant differences in accelerometer PA (all p > .05), but achievement of World Health Organisation guidelines increased (67.9%–75.0%; p = .646). Increased self-awareness of PA was reported by 76.7%, and 66.7% reported desires to become more physically active. Compared to normal, most reported either no differences or lower levels of PA during lockdown restrictions. Self-reported PA increased for most when restrictions eased from April 2021 onwards. Beyond the pandemic, concerns included pain and access to exercise resources.

Conclusion

Self-reported PA throughout the pandemic was variable, whilst there were no significant differences in objectively measured PA between assessment periods, despite reports of increased self-awareness and desires to be physically active at follow-up. Further qualitative research is needed to design personalised PA and health interventions, capturing perspectives of patients, their families, and multi-disciplinary haemophilia healthcare providers.     

First analysis of 10‐year trends in national factor concentrates usage in haemophilia: data from CHARMS,the Canadian Hemophilia Assessment and Resource Management System

The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema‐Quebec (HQ), to hospitals and to patients’ homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1 009 097 765 IU) and FIX (272 406 859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC‐based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.     

Comparing bleed frequency and factor concentrate use between haemophilia A and B patients

Summary. Haemorrhagic manifestations in patients with haemophilia A and B are considered quite similar for comparable level of factor deficiency. We investigated the bleeding frequency and factor usage between HA and HB patients with comparable disease severities. We collected data on frequency of bleeds and factor concentrate utilization over 3 years, from January 2001 to December 2003. Information was gathered from home infusion logs recorded by patients or their parents, and treatment records from the Hemophilia Clinic or the Hospital Emergency Department. Data were available on 58 patients with severe HA (FVIII < 0.01 U mL^?1), 10 with moderate HA (FVIII < 0.05 U mL^?1), 15 with severe HB, and five with moderate HB who required treatment for episodic bleeds, postoperative haemostasis and for primary or secondary prophylaxis. The HA patients bled more frequently than HB patients (14.4 vs. 8.63 bleeds/patient/year), but used similar amounts of concentrate per year. HA patients underwent surgical procedures 3.2 times more frequently than HB patients to correct musculoskeletal complications. A total of 21 363 409 IU of recombinant FVIII was used by patients with HA (104 722 IU/patient/year) and 6 430 960 IU of recombinant factor IX, by patients with HB (107 182 IU/patient/year). The difference in factor concentrate usage is not statistically significant (P > 0.05). The decrease in bleed frequency in haemophilia B indicates that the conclusions from randomized trials of prophylaxis in HA may not be accurately applied to HB.     

Comparison between preprandial vs. postprandial insulin aspart in patients with type 1 diabetes on insulin pump and real‐time continuous glucose monitoring

Background

The objective was to compare glycemic control between preprandial and postprandial bolus administration (15 min before [PRE] or immediately after the meal [POST]) in patients with type 1 diabetes using insulin pump and real‐time continuous glucose monitoring.

Methods

Between September 2015 and February 2016, a single‐centre, open randomized, 2‐way crossover study of patients on bolus insulin aspart administration was conducted during two 14‐day periods and according to 2 administration regimen schedules (PRE/POST or POST/PRE). Inclusion criteria were as follows: patients with type 1 diabetes, ≥18 and ≤ 65 years old, treated with insulin aspart using a Medtronic® insulin pump and trained on functional insulin therapy. Patients were randomly assigned to either regimen schedule. At the beginning of each period, each patient was provided with a standardized high fat meal. Primary outcome was the area under the curve for interstitial glucose above 140 mg/dL per minute (AUC > 140 mg/dL/min) during each period. Secondary outcomes were time spent in hypo/eu/hyperglycemia, glycemic variability indices, and AUC during 4 hours after high fat meal calculated with continuous glucose monitoring data.

Results

Twenty‐two patients were included. Mean AUC > 140 mg/dL/min was statistically higher in patients on POST (43.70 mg/dL/min; 95%CI: 34.08 to 53.31) versus PRE insulin aspart regimen (37.24 mg/dL/min 95%CI: 27.63 to 46.85) (P = 0.03). Mean interstitial glycemia and glycemic variability indices were also increased (P < 0.05) on POST regimen. The mean AUC 4 hours after the high fat meal was higher on POST regimen but not statistically different (P = 0.06).

Conclusions

In our study, postprandial administration of insulin aspart appears to mildly increase glycemic excursion and glycemic variability.     

Safety and pharmacokinetics of Alpha-1 MP (Prolastin®-C) in Japanese patients with alpha1-antitrypsin (AAT) deficiency

Background

Alpha₁-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60?mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60?mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD.

Nocturnal hypoglycemia is underdiagnosed in older people with insulin-treated type 2 diabetes: The HYPOAGE observational study

Background

There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D.

Methods

This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am).

Results

The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA_1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00–1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05–1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59–33.4]), heart failure (OR: 4.81 [1;48–15.6]), and depressive disorder (OR: 0.19 [0.06–0.53]) were associated with nocturnal time in hypoglycemia.

Conclusion

Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.     

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment

Introduction

Patients with Von Willebrand disease (VWD) are regularly treated with VWF‐containing concentrates in case of acute bleeding, trauma and dental or surgical procedures.

Aim

In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate^® P) in patients with VWD was evaluated.

Patients/Methods

Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate^® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII‐based treatment regimens were compared to predefined target levels in national guidelines.

Results

In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act.

Conclusion

High VWF:Act and accumulation of FVIII were observed after perioperative FVIII‐based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.     

Cases of less-than-expected FVIII activity in previously treated patients during post-marketing surveillance of N8-GP

Introduction

Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide.

Aim

To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP.

Methods

The post-marketing safety database was searched using keywords such as ‘coagulation FVIII level decreased’. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded.

Results

Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product.

Conclusion

In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.     

A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome

Objective

To evaluate the outcome of preoperative therapy with ketoconazole (KTZ) and/or metyrapone (MTP) in previously untreated patients with Cushing's syndrome (CS).

Design and patients

Sixty‐two patients with CS (85% ACTH dependent), treated with steroidogenesis inhibitors prior to surgery between 1983 and 2010, were retrospectively studied. T₀ and t₁ defined baseline and end of preoperative medical treatment.

Results

Outcomes were based upon clinical and biochemical (normal UFC) control of hypercortisolism at t₁: group CO (controlled) included 20 patients (32%) with eucortisolism and significant clinical improvement; group NC (not controlled) 30 (48%) with persistent hypercortisolism and no control of symptoms; and group PC (partially controlled) 12 patients (19%) who despite eucortisolism had no real clinical improvement. Median duration of treatment was 4 months (range: 1–30·7), and median cumulative dose of KTZ and MTP was 57 g (range: 3·6–240) and 120 g (range: 7·5–1215). CO patients were treated more with KTZ alone than the other groups (P < 0·05). MTP alone was administered more in PC than in CO patients (P < 0·01). No clinical differences were observed between groups at baseline. Systolic blood pressure at t₁ was higher in PC than in NC patients (P < 0·05). Hypertension persisted more in PC patients than in the other groups (P < 0·05) after a median postsurgery follow‐up of 108 months (range: 4–276).

Conclusions

Preoperative administration of KTZ, MTP or both normalized UFC in 52% of patients with CS, but concomitant clinical improvement did not always follow. Larger, multicentre studies are needed to individualize preoperative medical treatment and improve outcome in patients with CS.     

von Willebrand factor contributes to longer half‐life of PEGylated factor VIII in vivo

PEGylation of B‐domain deleted factor VIII (PEG‐FVIII‐BDD) prolongs the half‐life of the molecule by approximately twofold in animals (Mei et al., Blood 2010; 116 : 270). To investigate the role of von Willebrand factor (vWF) in the catabolism of PEG‐FVIII‐BDD in vivo, a FVIII‐BDD mutant (F8V), which is incapable of binding vWF, was generated by deleting the vWF‐binding region in the a3 domain of FVIIII‐BDD. F8V was expressed, purified and PEGylated by site‐specific conjugation. The biochemical and biological properties of F8V and PEGylated F8V (PEG‐F8V) were evaluated in vitro and in vivo. The specific activity of purified F8V by a chromogenic assay was similar to FVIII‐BDD and PEGylation had minimal impact on the specific activity of F8V in this assay. Analysis by Biacore indicated that both F8V and PEG‐F8V display greatly reduced vWF binding in vitro. Pharmacokinetic studies in FVIII knockout (HaemA) mice showed that the terminal half‐life (T_1/2) of F8V was dramatically reduced relative to FVIII‐BDD (0.6 h vs. 6.03 h). PEGylation of F8V promoted a significant increase in T_1/2, although PEGylation did not fully compensate for the loss in vWF binding. PEG‐F8V showed a shorter T_1/2 than PEG‐FVIII‐BDD both in HaemA mice (7.7 h vs. 14.3 h) and in Sprague‐Dawley male rats (2.0 ± 0.3 h vs. 6.0 ± 0.5 h). These data demonstrated that vWF contributes to the longer T_1/2 of PEG‐FVIII‐BDD. Furthermore, this suggests that the clearance of the FVIII:vWF complex, through vWF receptors, is not the sole factor which places an upper limit on the duration of PEG‐FVIII circulation in plasma.