Octapharma (Austria)

The mudminnow ( Umbra krameri ) has its westernmost distribution area in Austria near Vienna (Wanzenböck 1995, for historical and current distribution maps see the Power Point presentation in the Suppl. material 1). The species is considered the most threatened fish species in Austria and was believed to be extinct in the second half of the 20th century (Böhm 1978, Hacker 1983, Herzig-Straschil 1994). In 1992 it was rediscovered in the Fadenbach, a backwater system within the Danube Floodplain National Park and shortly thereafter in a wetland south of Vienna (Jesuitenbach) (Wanzenböck and Spindler 1995, Spindler and Wanzenböck 1995). Over the past four decades, several conservation measures have been implemented in the National Park in order to protect the mudminnow, including studies on habitat preferences (Sehr and Keckeis 2017), monitoring programs (Jung et al. 2018, Jung et al. 2024), habitat restoration projects (Spindler 2006) and captive breeding efforts. Furthermore, a reintroduction attempt was carried out in the Hanság wetland, a drainage-ditch system on the Austrian-Hungarian border. Captive bred mudminnows, whose parental generation originated from the Fadenbach population, were stocked there (Benesch 2004, Benesch 2008). The Fadenbach-population was the only one that had been regularly monitored over the past decades starting immediately after its discovery. During the 1990s, mudminnow densities were relatively high, but showed large fluctuations most likely due to high winter mortality (Fig. 1). In 2013 even higher densities were recorded and the population appeared to have extended its range within the Fadenbach system (Keckeis and Sehr 2014), most likely due to the creation of so called “survival ponds” – deeper sections within the backwater system. Between 2018 and 2023 severe droughts led to a dramatic decline. Currently, the population remains at a very low level and the species has disappeared from the upper reaches of the Fadenbach system. The recent droughts and persistently low water levels are part of a long-term trend: in the area, mean groundwater levels have dropped by approximately 1.5 metres since 1940 (Fig. 2) mainly due to river regulation (diking), agricultural irrigation, incision of the Danube river bed and a decline in precipitation. Therefore, a new conservation initiative was launched by the Danube Floodplain National Park with the project “PonDiversity” which focuses on the European pond turtle ( Emys orbicularis ), water pineapple ( Stratiotes aloides ) and mudminnow. The project includes comprehensive surveys of the mudminnow habitats within the National Park using electrofishing, an assessment of existing captive stocks established in the 1990s and genetic analysis of both, wild and captive populations. In a second phase, habitat restoration measures and improved captive breeding programmes will be implemented based on the outcome of population genetic studies. The reintroduced population in the Hanság area survived for around 15 years - at least until 2018 - but was no longer detected in 2023 (Jung et al. 2024). Its current status must be regarded as uncertain, as no extensive surveys have been carried out so far. In contrast to the Fadenbach- and Hanság-populations, the Jesuitenbach-population has recently shown a significant increase with highest densities recorded in 2024 (Jung et al. 2025). A possible explanation for this development is the decline of roach and pike populations during the recent dry periods, which may have led to reduced competition and predation pressure without deteriorating habitat conditions for the mudminnow. The population increase provided an opportunity to establish an ex situ population of Jesuitenbach mudminnows at Zoo Schönbrunn.

Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4F-PCC beyond its approved indications.

Introduction: Octaplex®/Balfaxar® (Octapharma AG, Switzerland) is an intravenously administered four-factor freeze-dried human prothrombin complex concentrate (4F-PCC) available since 2003 and approved in 87 countries, including the USA. 4F-PCC is used for the treatment and perioperative prophylaxis of bleeding in congenital or acquired vitamin K-dependent coagulation factor deficiency, and is being investigated for direct oral anticoagulant (DOAC)-associated bleeds and coagulation factor deficiency during cardiac surgery. We review the efficacy and safety of Octapharma’s 4F-PCC and recent advances in clinical research. Methods: We reviewed all studies of Octaplex®/Balfaxar®, including literature searches of “octaplex” using PubMed, Google Scholar and Clinicaltrials.gov to capture studies reporting clinical safety and efficacy. Results: The Octapharma clinical trial program for Octaplex®/Balfaxar® included 7 studies: 5 completed (n=444) and 2 ongoing in DOAC reversal and cardiac surgery. Five published studies of urgent reversal of vitamin K antagonists (VKA) for bleeding or perioperative prophylaxis are reported. In a head-to-head Phase III randomized double-blind study (n=208), Octaplex®/Balfaxar® was non-inferior to control 4F-PCC (Kcentra®, CSL Behring) in achieving hemostatic efficacy with similar INR correction and safety profiles. Additionally, other studies of 4F-PCC in patients treated for urgent reversal of VKA, showed effective hemostasis and rapid correction of INR. Proportions of TEEs were low and not significantly different between groups. In a study of 20 patients, excellent hemostatic efficacy was achieved for 85% after a single infusion and in another study (n=56), the timely correction of INR to target levels was achieved for 91% of patients. A randomized, phase II investigator-led study (FARES) evaluated Octaplex® and FFP in patients undergoing cardiac surgery with cardiopulmonary bypass. The Octaplex® group (n=54) required significantly reduced additional hemostatic therapy compared with the FFP group (n=47) and used fewer allogeneic blood products. Conclusions: Multiple clinical studies have shown that Octaplex®/Balfaxar® is an effective hemostatic agent for various indications including VKA reversal, with a favorable safety profile. Ongoing studies are expanding the role of 4F-PCC.

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.

Background and AimsThe 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.MethodsPatients 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.ResultsAll 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.InterpretationInfusions of 10% IVIg at doses up to 2.0 g/kg with high infusion rates were safe and well tolerated in patients with CIDP.Clinical trial numbersEudraCT 2015-005443-14, NCT02638207.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-023-01326-z.