Regular, prophylactic intravenous (i.v.) FVIII can be challenging for some patients with haemophilia A. Subcutaneous (s.c.) FVIII administration could provide an alternative treatment option with greater convenience and without the complications associated with venous access. To assess the safety, pharmacokinetics (PK), bioavailability and efficacy of s.c. OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer. This was a single-centre, prospective, open-label, phase I/II study (NCT04046848). Previously treated male patients (≥18 years) with severe haemophilia A were eligible for the study. The primary objective of the study was to assess the safety (including immunogenicity) of OCTA101. Secondary objectives included assessments of PK, bioavailability, and the efficacy of prophylaxis. Thirty patients were treated with OCTA101. FVIII inhibitors developed in five (16.7%) patients during daily prophylaxis with 40-60IU/kg (three cases) and 12.5IU/kg (two cases) OCTA101. The trial was therefore terminated. OCTA101 had a 2.5-fold longer terminal half-life compared with i.v. rFVIII, and bioavailability was 16.6%. Efficacy data at study termination indicated that daily prophylaxis with 40-60IU/kg OCTA101 was efficacious in the absence of FVIII inhibitors. Despite promising PK and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors. The occurrence of inhibitors at two dose levels suggests that their development may be related to the subcutaneous route of administration.

Variable fibrinogen content within cryoprecipitate makes accurate dosing challenging in patients with coagulopathic bleeding, in addition to pathogen transmission risks associated with its administration. Purified and standardized human fibrinogen concentrates (HFCs) represent reliable alternatives. Full cryoprecipitate characterization is required to inform selection of an appropriate fibrinogen source for supplementation therapy. Extended biochemical comparison of pooled cryoprecipitate and HFC (Fibryga, Octapharma) was performed using commercially available assays to determine levels of variability in cryoprecipitate and HFC. In addition to standard procoagulant factors, measurements included activities of platelet-derived microparticles (PMPs) and plasminogen, and levels of fibrin degradation products. Cryoprecipitate contains lower fibrinogen levels than HFC (4.83 vs.19.73 g/L; p<0.001), translating to approximately half the amount of fibrinogen per standard cryoprecipitate dose (two pools, pre-pooled from five donations each) vs. HFC (2.14 vs. 3.95 g; p<0.001). Factor XIII (FXIII) levels were also lower in cryoprecipitate vs. HFC (192.17 vs. 328.33 IU/dL; p = 0.002). Levels of procoagulants in cryoprecipitate, such as von Willebrand Factor (VWF) and factor VIII (FVIII), were highly variable, as was PMP activity. A standard cryoprecipitate dose contains significantly higher levels of measured plasminogen and D-dimer fragments than a standard HFC dose. The tested HFC is a more reliable fibrinogen and FXIII source for accurate dosing compared with cryoprecipitate. Cryoprecipitate appears considerably less predictable for bleeding management due to wide variation in pro- and anticoagulation factors, the presence of PMPs, and the potential to elevate VWF and FVIII to prothrombotic levels.

Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. To report the efficacy and safety results from the NuProtect study. PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

The ProCID study evaluated the efficacy and safety of three doses of a 10% liquid intravenous immunoglobulin (IVIg) preparation (panzyga®) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). This report describes the safety findings. Patients were randomised to receive a 2.0 g/kg induction dose followed by maintenance doses of either 0.5, 1.0 or 2.0 g/kg IVIg every 3 weeks over 24 weeks. All 142 enrolled patients were included in the safety analyses. In total, 286 treatment-emergent adverse events (TEAEs) were reported in 89 patients, of which 173 (60.5%) were considered treatment-related. Most TEAEs were of mild severity. Eleven serious TEAEs were reported in 6 patients. Two serious TEAEs in one patient (headache and vomiting) were considered related to treatment, which resolved without study discontinuation. No treatment-related thrombotic events, haemolytic transfusion reactions or deaths occurred. One patient discontinued the study due to a TEAE (allergic dermatitis) probably related to IVIg. Headache was the only dose-dependent TEAE, with incidences ranging from 2.9 to 23.7%, the incidence of all other TEAEs was similar across treatment groups. Most TEAEs were associated with the induction dose infusion, and the rate of TEAEs decreased thereafter. The median (IQR) daily IVIg dose was 78 (64-90) g, and 94.4% of patients tolerated the maximal infusion rate of 0.12 ml/kg/min without pre-medication. Infusions of 10% IVIg at doses up to 2.0 g/kg with high infusion rates were safe and well tolerated in patients with CIDP. EudraCT 2015-005443-14, NCT02638207.

BackgroundDermatomyositis (DM) is an immune-mediated idiopathic inflammatory myopathy (IIM). Two subsets of autoantibodies have been identified in patients with IIM. The first includes myositis-specific antibodies (MSA) such as anti-Jo-1, anti-TIF-1 and anti-MDA-5. The second includes myositis-associated antibodies (MAA) such as anti-PM-SCL, anti-Ku and anti-Ro, which are also found in patients with other autoimmune diseases. MSA are highly specific for IIMs and represent a unique clinical phenotype and prognosis, and have also been associated with the pathogenesis of various subsets of IIM. The ProDERM study recently demonstrated the efficacy and safety of intravenous immunoglobulin (IVIg) in DM patients (1) but the potential role of MSA and MAA in the treatment responses of these patients has not yet been determined.ObjectivesAutoantibody status at baseline and its relationship to treatment response to IVIg were investigated in a post-hoc analysis of the randomized, placebo-controlled ProDERM study.MethodsIn the ProDERM study, dermatomyositis patients received 2 g/kg IVIg treatment (n=47) or placebo (n=48) every 4 weeks for 16 weeks. From week 16 onwards eligible patients (n=91) received IVIg for a further 24 weeks. The primary endpoint was a Total Improvement Score (TIS) of at least 20 (indicating at least minimum improvement) at week 16 and no confirmed deterioration up to week 16. Serum samples were taken at baseline and analysed for MSA (anti-Jo-1, PL-12, SRP, Mi-2, TIF-1, MDA5, MJ, SUMO) and MAA (anti-PM-SCL, Ku, U1RNP, Ro/SSA) by the Oklahoma Medical Research Foundation. Patients were stratified according to their antibody status as MSA-positive (including patients who were also MAA-positive), MAA-positive only, or antibody negative at baseline. The association of antibody status with treatment response measured by TIS was evaluated.ResultsAt baseline, a total of 49 (52%) patients were MSA-positive, 13 (14%) were MAA-positive, and 33 (35%) were antibody negative. Demographics of patients in each group are shown in Table 1. Of patients who were MSA-positive, 10 were also positive for MAA.The numbers of patients from the ProDERM study with each specific MSA and MAA are shown in Figure 1.In the MSA group, 71% (35/49) of patients had TIS response (score ≥20) at week 16, compared to 55% (18/33) in the autoantibody-negative group. In the MSA group 24 patients were randomized to IVIg and of these 83% (20/24) showed TIS response (score ≥20) at week 16 compared to 60% (15/25) in the group of MSA-positive patients receiving placebo. Additional analyses (including results for specific subgroups in the MSA-positive group) will be presented at the EULAR 2023 congress.ConclusionMyositis-specific antibodies were commonly identified in patients with dermatomyositis in the ProDERM study. Further analyses will determine if specific MSA, such as anti-TIF-1 and others, play a role in treatment response to IVIg.Reference[1]Aggarwal R., Charles-Schoeman C., Schessl J., et al. N Engl J Med 2022;387:1264–1278Table 1.Patient demographics and baseline characteristicsMSA-positive* (N=49)MAA-positive** (N=13)Antibody negative (N=33)Mean (range) age, years51 (22–79)54 (33–70)54 (28–77)Mean (range) time since diagnosis, years3.66 (0.16–15.6)5.04 (0.39–18.4)5.8 (0.09–48.7)Sex, n (% female)39 (79.6)11 (84.6)12 (63.6)Race, n (% White)42 (85.7)13 (100.0)32 (97.0)Mean BMI, kg/m229.827.026.5Disease severity, n (%)MildModerateSevere10 (20.4)31 (63.3)8 (16.3)4 (30.8)8 (61.5)1 (7.7)12 (36.4)17 (51.5)4 (12.1)CDASI score≤14>1419 (38.8)30 (61.2)5 (38.5)8 (61.5)20 (60.6)13 (39.4)Randomised treatmentIVIgPlacebo2425491914BMI, body mass index; CDASI, Cutaneous Disease Area and Severity Index; IVIg, intravenous immunoglobulin; MAA, myositis-associated antibodies; MSA, myositis-specific antibodies.*10 patients positive for MSA were also positive for MAA.**MAA-positive group contains only patients with MAA (no MSA).AcknowledgementsAll investigators and patients.Disclosure of InterestsChristina Charles-Schoeman Consultant of: Abbvie, Bristol Myers Squibb, Octapharma, Pfizer, Priovant, Galapagos, Grant/research support from: AbbVie, Bristol Myers Squibb, Pfizer, and CSL Behring, Jochim Schessl Speakers bureau: Pfizer, Consultant of: Octapharma, Elisabeth Clodi Employee of: Octapharma Pharmzeutika Produktionsges.m.b.H., 1100 Vienna, Austria, Rohit Aggarwal Consultant of: Mallinckrodt, Octapharma, CSL Behring, Bristol Myers-Squibb, EMD Serono, Q32, Kezar, Pfizer, AstraZeneca, Alexion, Argenx, Boehringer Ingelheim (BI), Corbus, Janssen, Kyverna, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, CabalettaBio, Grant/research support from: Mallinckrodt, Pfizer, Bristol Myers-Squibb, Q32, EMD Serono, Jansen, Boehringer Ingelheim (BI), and the ProDERM Investigators: None declared.

PurposeTo achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens.MethodsThree separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient’s weekly dose.ResultsFor Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy.ConclusionsSCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Background The efficacy, safety, and immunogenicity of each of Octapharma's factor VIII (FVIII) products, Nuwiq, octanate, and wilate, have been investigated in previously untreated patients (PUPs) with severe hemophilia A in prospective clinical trials. The aim of the Protect-NOW study is to evaluate the effectiveness, safety, and utilization patterns of Nuwiq, octanate, and wilate in PUPs and minimally treated patients (MTPs; <5 exposure days [EDs] to FVIII concentrates or other blood products containing FVIII) with severe hemophilia A in a real-world setting. Real-world data provide valuable information that complement data obtained from interventional clinical trials. Methods Protect-NOW (ClinicalTrials.gov identifier: NCT03695978; ISRCTN identifier: 11492145) is a real-world study in PUPs and MTPs treated with either the human cell line-derived recombinant FVIII Nuwiq (simoctocog alfa) or a plasma-derived FVIII concentrate containing von Willebrand factor (octanate or wilate). It is a prospective and (partly) retrospective, observational, international, noncontrolled, noninterventional study. A total of 140 PUPs and MTPs with severe hemophilia A will be enrolled across around 50 specialized centers worldwide and followed for either 100 EDs or a maximum period of 3 years from ED1. The primary objectives are to assess effectiveness in the prevention and treatment of bleeding episodes and overall safety, including inhibitor development. The secondary objectives are to assess utilization patterns (including dosage and frequency of administration) and the effectiveness in surgical prophylaxis. Conclusions The Protect-NOW study will provide information on the treatment of PUPs and MTPs in routine clinical practice, which will help guide clinical decision making for treating these patients in the future.

Polymer-borne leachables such as formaldehyde, acetaldehyde, and N-3-(Dimethylamino)propyl)methacrylamide (DMAPMA) may interact with therapeutic proteins. In this study, the leachables were spiked into human derived coagulation factor IX (FIX) at concentrations of 1, 10, 50, 100, and 500 µg/mL, corresponding to a leachable – FIX ratio of 0.5, 5, 25, 50 and 250 %, respectively. The spiked samples were visually inspected, and pH was measured. No visual effects were observed, and pH was within the drug product's specified range. Recovery experiments were performed and no loss of leachables was identified. Protein structure analysis revealed that formaldehyde reacted with lysine contained in two different positions of FIX, in a concentration-dependent manner starting at 10 µg/mL (5 %). The clotting activity of FIX was measured. The activity of the samples spiked with 500 µg/mL (250 %) of formaldehyde dropped by more than half. The activity of the samples spiked with acetaldehyde began to drop at 50 µg/mL (25 %) and continued to decline in concentration-dependent manner. DMAPMA did not impair the activity of FIX. The findings conclude that depending on the concentration, some leachables may react with or modify therapeutic proteins, potentially causing an undesired pharmacological effect however, this is specific to each protein.

Introduction Von Willebrand disease (VWD) is a common congenital haemorrhagic disorder affecting around 1 in every 100 individuals. Prophylactic von Willebrand factor (VWF) replacement therapy in patients with severe VWD, including paediatric patients, is associated with reduced mucosal and joint bleeding rates, decreased median annual bleeding rate (ABR), a reduced incidence of major bleeding events (BEs) and good tolerability. WIL-33 will investigate the efficacy, pharmacokinetics (PK) and safety of a plasma-derived, stable, highly purified, double virus inactivated VWF/factor VIII (FVIII) concentrate (Octapharma) in paediatric patients with severe VWD.