BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18–65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUC last , primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUC last was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440–3550] IU h/dL versus 2360 [31.8, 2010–2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998. Electronic supplementary material The online version of this article (10.1007/s00277-019-03747-2) contains supplementary material, which is available to authorized users.
Background Bleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required. Objectives To investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)‐directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers. Patients/Methods In a first‐in‐human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single‐dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated. Results In this study, no hemorrhage, or hypersensitivity or infusion‐/injection‐related reactions were reported. Drug‐related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self‐limited. Dose‐dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio‐to‐baseline: aPTT, range, 1.09–3.11 vs. 1.05 with placebo; FXI, range, 0.70–0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half‐life increased continuously with increasing i.v. dose (range, 28–208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2–73.7). Conclusions BAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose‐dependent prolongation of aPTT and duration of FXI inhibition.
Background Gene therapy for hemophilia A has the potential to reduce the treatment burden for patients and their care providers by eliminating the need for regular factor VIII (FVIII) prophylaxis through long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. Host immunity to the capsid serotype limits patients' eligibility and may impact the balance between vector dose and clinical outcome. BAY 2599023 (AAVhu37FVIII) is the first clinical-stage adeno-associated virus (AAV) gene therapy vector based on the AAVhu37 serotype. BAY 2599023 is a non-replicating AAV vector and contains a single-stranded DNA genome encoding a B-domain-deleted FVIII, under the control of a liver-specific promoter/enhancer combination optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic clade E family, and was selected based on preclinical studies demonstrating efficient liver-directed FVIII gene transfer, favorable biodistribution and durable FVIII expression. However, pre-existing humoral immunity against AAV capsids may limit patient eligibility. Here, we evaluate the seroprevalence and titer levels of pre-existing neutralizing antibodies (Nabs) against AAVhu37, and additional AAV capsids, using cell-based transduction inhibition assays. We also report current, preliminary, long-term safety and FVIII activity following a single intravenous infusion of BAY 2599023, in a phase 1/2 open-label, first-in-human, dose-finding study (NCT03588299). Methods Seroprevalence and titer distribution of Nabs against AAVhu37, AAV5 and AAV8 have been assessed in serum samples derived from 100 US patients with hemophilia A (African American and Caucasian male donors, 19-61 years). For AAVhu37, the clinical trial Nab assay was utilized to determine Nab titer levels according to cellular transduction inhibition. Additionally, we developed and fully validated Nab assays for AAV5 and AAV8. The ongoing BAY 2599023 phase 1/2 dose-finding study included male patients aged ≥18 years with severe hemophilia A, each receiving a single intravenous infusion of BAY 2599023. Patients were enrolled sequentially into three dose cohorts (0.5 × 1013 GC/kg, 1.0 × 1013 GC/kg and 2.0 × 1013 GC/kg), each comprising two patients. Patients had no history of FVIII inhibitors, no detectable neutralizing immunity against the AAVhu37 capsid above a Nab titer of 1:5, and ≥150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). The secondary endpoint was change in FVIII activity from baseline. Informed patient consent and ethics committee approval were obtained. Results In the seroprevalence study, the lowest pre-existing Nab prevalence was found for AAVhu37, with a low maximum observed titer of 1:26. Based on our results, 86% of patients would be eligible for AAVhu37-based treatment (Table 1). To date, patients in the first (0.5 × 1013 GC/kg) and second cohort (1.0 × 1013 GC/kg) have completed ≥52 weeks of observation; patients in cohort 3 (2.0 × 1013 GC/kg) have at least 33 weeks of observation. Regardless of the level achieved and the assay used, 5 out of 6 of patients show sustained FVIII levels (all ≥5%) over time and up to 16 months. Patients in cohorts 2 and 3 have all been off prophylaxis since ~6 weeks after gene transfer. No spontaneous bleeds were reported after achieving protective FVIII levels (>15 IU/dL) and discontinuation of prophylaxis in the third cohort. No SAEs have been reported to date. Mild-to-moderate elevation in alanine aminotransferase/aspartate aminotransferase were recorded for one patient in the second cohort and both patients in the third cohort. All were treated with corticosteroids (one resolved, two in resolution). The latest follow-up data for up to 22 months will be presented. Conclusions BAY 2599023 has a broad patient eligibility due to low seroprevalence and low titers of pre-existing Nabs against AAVhu37 compared with other AAVs. BAY 2599023 has a good safety profile, with the potential to achieve endogenous expression of FVIII at therapeutic levels over an extended period. Successful proof-of-concept has been achieved, with measurable and sustained expression of endogenous FVIII. Disclosures Pipe: Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Ferrante:Bayer: Current Employment. Reis:Bayer: Current Employment. Wiegmann:Bayer: Current Employment. Lange:Bayer: Current Employment, Current equity holder in private company. Braun:Bayer: Current Employment, Current equity holder in private company. Michaels:Bayer: Current Employment.
Background Gene therapy for hemophilia A has the potential to reduce the treatment burden for patients and their care providers by eliminating the need for regular factor VIII (FVIII) prophylaxis through long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. Ongoing phase 3 gene therapy trials for hemophilia A show promise but can result in unpredictable FVIII expression of uncertain durability. Gene therapy must evolve to meet patient expectations of a durable, efficacious and safe treatment. BAY 2599023 (AAVhu37.hFVIIIco) is the first, clinical stage adeno-associated virus (AAV) gene therapy vector, based on the AAVhu37 serotype. BAY 2599023 is a non-replicating AAV vector and contains a single-stranded DNA genome encoding a B-domain-deleted FVIII, under the control of a liver-specific promoter/enhancer combination, optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic clade E family and was selected based on preclinical studies demonstrating efficient, liver-directed FVIII gene transfer, favorable biodistribution and durable FVIII expression. Here, we report safety and FVIII activity levels achieved to date in this first-in-human, dose-finding study of BAY 2599023. Methods The ongoing BAY 2599023 phase 1/2, open-label, dose-finding study (NCT03588299) included male patients aged ≥18 years with severe hemophilia A, no history of FVIII inhibitors, no detectable neutralizing immunity against AAVhu37 (neutralizing antibody titer ≤5), and ≥150 exposure days to FVIII products. Patients received a single intravenous infusion of BAY 2599023 and were enrolled sequentially into three dose cohorts (0.5 × 10 13 GC/kg, 1.0 × 10 13 GC/kg and 2.0 × 10 13 GC/kg), each comprising at least two patients. Patients to be enrolled in a fourth cohort will receive a single infusion of 4 × 10 13 GC/kg (Figure 1). Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). The secondary endpoint was FVIII activity over time. Informed patient consent and ethics committee approval were obtained. Results Three cohorts of ≥2 patients each (N = 9) were enrolled sequentially (Figure 1). At the data cutoff (May 2021), FVIII activity data were available for the first eight patients. BAY 2599023 delivered sustained FVIII expression levels for up to >23 months, with evidence of bleed protection. Patients in Cohorts 2 and 3 have all been off prophylaxis with FVIII products since approximately 6-12 weeks after gene transfer. To date, it has been observed that no spontaneous bleeds requiring treatment have been reported once FVIII levels >11 IU/dL were achieved. Of the 9 patients treated, 5 patients developed an AESI: mild/moderate alanine aminotransferase (ALT) elevations observed in Cohort 2 (n =1) and Cohort 3 (n = 3) were managed with corticosteroid treatment; another ALT elevation was reported as study-drug-related SAE in Cohort 3 (n = 1) but returned to normal a few weeks after interruption of the H2 blocker famotidine. The latest follow-up data for up to 28 months will be presented. Conclusions BAY 2599023 was designed to enhance efficacy and durability of FVIII expression with a favorable safety profile. Sustained FVIII levels allowed suspension of FVIII prophylaxis in the majority of patients, with asymptomatic ALT elevations that responded to corticosteroids, making BAY 2599023 a key candidate in the evolution of gene therapy in hemophilia A. Figure 1 Figure 1. Disclosures Pipe: Genventiv: Consultancy; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Sheehan: BioMarin: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Coppens: Portola/Alexion: Research Funding; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Roche: Research Funding; Daiichi Sankyo: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; Medcon International: Consultancy; MEDtalks: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy. Eichler: Takeda: Consultancy, Honoraria; BioMarin: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Honoraria; Bayer: Consultancy, Research Funding. Linardi: Bayer: Current Employment. Wiegmann: Bayer: Current Employment. Hay: Pfizer: Consultancy, Research Funding; Inspiration: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Spark Therapeutics: Consultancy, Research Funding. Lissitchkov: Bayer: Other: Principal Investigator of Clinical Trials; Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials.
In silver complexes, indirect detection of (109) Ag resonances via (1) H,(109) Ag-HMQC frequently suffers from small or absent JHAg couplings or rapid ligand dissociation. In these cases, it would be favourable to employ H(X)Ag triple resonance spectroscopy that uses the large one-bond JXAg coupling (where the donor atom of the ligand X is the relay nucleus). We have applied an HMQC-based version of the H(C)Ag experiment to a labile silver-NHC complex (NHC=N-heterocyclic carbene) at natural (13) C isotopic abundance and variable temperature. In agreement with simulations, H(C)Ag detection became superior to (1) H,(109) Ag-HMQC detection above -20 °C.
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