IntroductionTuroctocog alfa pegol (N8‐GP) is a site‐specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half‐life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8‐GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A.Aim and methodsWe investigated the safety and efficacy of N8‐GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8‐GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively.ResultsFifty‐five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections.ConclusionsWeekly N8‐GP was well tolerated and efficacious and may benefit selected “low bleeder” patients with haemophilia A.
Introduction: Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in phase 3 clinical development as a once-daily, subcutaneous prophylaxis across all hemophilia subtypes. The phase 2 trials explorer4 (NCT03196284) and explorer5 (NCT03196297) investigated the efficacy and safety of daily subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors and in patients with severe hemophilia A without inhibitors, respectively. Minor surgeries and diagnostic procedures were permitted during both trials, allowing for the assessment of conducting such procedures during concizumab prophylaxis. Objective: The aim of this analysis was to describe surgeries and diagnostic procedures performed while on concizumab prophylaxis during the main and extension parts of the concizumab phase 2 trials. Methods: Both the explorer4 and explorer5 trials consisted of a main and an extension part, with patients receiving concizumab at an initial maintenance dose of 0.15 mg/kg (with an additional loading dose of 0.5 mg/kg as a first dose in explorer4) in both trials, with the option to dose escalate to 0.20 and 0.25 mg/kg in case of ≥3 spontaneous treated bleeds within the previous 12 weeks. Concomitant treatment with systemic anti-fibrinolytics was not allowed in either trial, while local/topical use was permitted. Minor surgery, defined as an invasive operative procedure in which the skin, mucous membranes, or superficial connective tissue are manipulated, such as skin biopsies, implanting of central venous access devices, or simple dental procedures, were allowed at the investigator's discretion during both trials. Major surgery was not permitted and thus constituted a protocol deviation. Only patients who had been receiving concizumab as part of explorer4 or explorer5 up until, during and immediately after surgery were included in this analysis. Results: Seven of the 25 patients treated with concizumab in explorer4 had a total of 17 surgeries while treated with concizumab during the trial. The patients who underwent surgery were aged between 24 and 45 years old. Five of these patients underwent a single procedure, 1 patient 2 procedures, and 1 patient underwent a total of 10 procedures while in the trial. At the time of surgery, with the exception of 1 patient who was receiving concizumab at 0.20 mg/kg, all patients were on 0.15 mg/kg. Additional perioperative hemostatic treatment was permitted and was given at the investigator's discretion. The majority of procedures involved dental surgery, although a venous catheter removal, hordeolum removal, and laser eye surgery were also performed (Table 1). Out of a total of 6 recorded surgery-related bleeding episodes in patients receiving concizumab in explorer4, 1 was classified as severe, while the remaining 5 as mild or moderate. In explorer5, 13 of the 36 patients treated with concizumab (26-65 years old) underwent a total of 33 surgeries while receiving concizumab prophylaxis. Seven of these patients had more than 1 surgery, ranging between 2 and 8 per person. The majority of patients (8/13) were receiving concizumab at 0.15 mg/kg, 1 patient at 0.20 mg/kg and 2 patients at 0.25 mg/kg at the time of surgery, and 2 patients were on 0.15 mg/kg concizumab for their first surgeries and switched to 0.20 mg/kg for later surgeries. Additional hemostatic treatment was given at the investigator's discretion. Dental procedures constituted most surgeries, and other procedures included vaccinations and cataract surgery, diagnostic procedures such as biopsy, endoscopy and gastroscopy, as well as a hair graft (Table 1). A total of 9 surgery-related bleeds were recorded during explorer5, all of which were classified as mild or moderate. Conclusion: Across both concizumab phase 2 trials, between 28-36% of all patients (7/25 in explorer4 and 13/36 in explorer5) receiving daily concizumab prophylaxis underwent 1 or more surgeries during the overall trial periods of 18 and 22 months, respectively. A wide range of surgeries, including invasive diagnostic procedures, were conducted while the number of surgery-related bleeds was low and classified as mild or moderate, with 1 exception. Prophylactic treatment with concizumab in patients with hemophilia is currently being investigated further in ongoing phase 3 trials. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Benson: Novo Nordisk A/S: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Sobi: Speakers Bureau. Eichler: Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Biotest: Consultancy, Honoraria. Marie Tønder: Novo Nordisk Health Care AG: Current Employment. Cepo: Novo Nordisk A/S: Current Employment. Jimenez Yuste: Novo Nordisk A/S: Consultancy, Research Funding; Bayer: Consultancy; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy. Kavakli: Novo Nordisk A/S: Consultancy, Other: Clinical Trial Support; Takeda: Consultancy, Other: Clinical Trial Support; Roche: Consultancy, Other: Clinical Trial Support. Wong: Astellas Pharma, INc.: Research Funding. Matsushita: Baxalta/Shire/Takeda: Consultancy, Honoraria; Bayer: Consultancy; Novo Nordisk A/S: Consultancy, Honoraria, Other: educational and investigational support ; Chugai: Consultancy, Honoraria, Other: educational and investigational support ; Pfizer: Consultancy; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria; Octapharm: Honoraria; Sysmex: Honoraria.
Relative to the general population, health-related quality of life (HRQoL) is impaired in patients with hemophilia, who report increased pain and reduced physical activity. It is therefore of interest to assess the change in HRQoL after long-term prophylactic treatment. Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in clinical development for a subcutaneous, prophylactic treatment of patients with hemophilia. Here, we present results from exploratory analyses assessing changes in HRQoL after long-term concizumab treatment (≤126 treatment weeks), which includes data from the main and extension parts of explorer4 (NCT03196284) and explorer5 (NCT03196297) phase 2 trials. Both trials comprised a main part (≤24 weeks), and an extension part (explorer4: ≤94 weeks; explorer5: ≤102 weeks). In explorer4, patients with hemophilia A and B with inhibitors (HAwI/HBwI) were recruited and randomized 2:1 to concizumab prophylaxis (n=17) or recombinant activated factor VII on-demand treatment (n=9). Patients in the on-demand arm switched to concizumab prophylaxis in the extension part. Twenty-six patients were recruited for explorer4, 25 patients were exposed to concizumab in the extension part, and 22 patients completed the trial. In explorer5, 36 patients with severe hemophilia A (HA) were recruited, 32 patients entered the extension part, and 30 patients completed the trial. Patients were asked to complete the 36-item Short Form Health Survey (SF-36v2) at baseline (for this analysis, baseline was defined as the last assessment before first treatment with concizumab), and throughout the main and extension parts. Scoring was conducted according to the SF-36v2 scoring software (version 5.0). Only patients who completed the entire trial were included for analysis. T score points of SF-36v2 domains were used to determine clinically meaningful differences at group level from baseline to the end of the extension part, based on minimally important difference criteria (MID; SF-36v2 manual 3rd edition, 2013). At an individual level, a responder analysis was conducted to identify the proportion of patients who had improved scores in the physical component summary (PCS), physical function (PF) and bodily pain (BP) domains, based on the recommended individual-level response threshold of 3.4, 4.3 and 6.2, respectively (based on 2009 United States general population norms; SF-36v2 manual). The results presented here demonstrate the change in HRQoL before and after long-term concizumab use in the main and extension parts of explorer4 and explorer5. For explorer4, 22 patients (14 HAwI; 8 HBwI) were included in the current exploratory analysis, which showed that the difference in improvement from baseline to end of extension part exceeded the MID thresholds for PCS score (Table 1), at group level. Additionally, the MID thresholds were also met for PF, BP, role-physical, general health, vitality, social functioning, and mental health domains in explorer4 (Table 1). At an individual level, the responder analysis revealed that 63.6%, 54.5% and 50.0% of 22 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. In the 30 patients with severe HA included in the explorer5 analysis, PCS score met the MID threshold for difference in improvement from baseline to end of extension, although large standard deviations were observed (Table 1). At an individual level, the responder analysis revealed that 43.3%, 33.3% and 33.3% of 30 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. While these analyses are exploratory and should be interpreted with caution, they illustrated that patients with HAwI/HBwI reported improved HRQoL after long-term, subcutaneous concizumab prophylaxis, particularly in clinically relevant domains such as PF and BP, suggesting a potential positive effect of concizumab prophylaxis on physical functioning and reduced pain. Interestingly, PCS improvement was observed across all hemophilia subgroups, suggesting better functional health, albeit the large standard deviation reported. The potential beneficial effect of concizumab prophylaxis on HRQoL in hemophilia patients is being investigated further in the ongoing phase 3 trials. Figure 1 Figure 1. Disclosures Faller: Novo Nordisk Health Care AG: Current Employment. Marie Tønder: Novo Nordisk Health Care AG: Current Employment. Porstmann: Novo Nordisk Health Care AG: Current Employment.
Introduction Concizumab is a high-affinity, anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody currently in clinical investigation for the once-daily subcutaneous prophylactic treatment of patients with hemophilia. We present results from the combined main and extension parts (at least 76 weeks) of the phase 2 explorer4 trial (NCT03196284), which aimed to assess the safety and longer-term efficacy of concizumab in patients with hemophilia A with inhibitors (HAwI) and hemophilia B with inhibitors (HBwI). Methods explorer4 comprised a main part, which lasted at least 24 weeks for all patients, and an extension part, which lasted at least 52 weeks. The primary objective of the main part of explorer4 was to assess the efficacy of concizumab in preventing bleeds in patients with HAwI/HBwI, evaluated as annualized bleeding rate (ABR) at the last dose level after at least 24 weeks. This objective has been addressed in previous reporting of the main part of the trial (Shapiro A, et al. Blood 2019; 134[22]:1973-1982). During the main part of the trial, patients were randomized 2:1 to receive either concizumab prophylaxis or on-demand treatment with recombinant activated factor VII (rFVIIa). At the end of the main part, patients in the rFVIIa on-demand arm were switched to 0.15 mg/kg concizumab for the extension part. Concizumab dose was escalated to 0.20 and 0.25 mg/kg in both the main and extension parts if a patient experienced ≥3 treated spontaneous bleeding episodes within 12 weeks and if deemed safe by the investigator. The objective of the extension part of the trial was to assess safety and longer-term efficacy of concizumab. Endpoints included ABR after at least 76 weeks of treatment, concizumab and free TFPI concentrations prior to last dose administration at 76 weeks, number of adverse events (AEs) and occurrence of anti-drug antibodies (ADAs) during 76 weeks of treatment. ABR was estimated using LS-means estimates, based on a negative binomial regression with log of exposure time to concizumab in main and extension part as offset. Results Twenty-five patients with inhibitors were exposed to concizumab during the explorer4 trial; 15 with HAwI and 10 with HBwI. Eight of these patients received on-demand treatment with rFVIIa during the main part of the trial before receiving their first concizumab dose in the extension phase. The estimated ABR at the last dose level for all patients treated with concizumab during the main and extension parts was 4.8 (95% CI: 3.2-7.2), while during the trial this was 5.7 (95% CI: 4.2−7.8) (Table 1). During the main and extension parts, 4 (16%) patients had zero treated bleeding episodes on their last dose level. Plasma concentrations of concizumab were variable during the extension part of the trial (Table 2). Increased concizumab concentration was observed in patients who received concizumab 0.20 mg/kg; these patients also had lower concentrations of free TFPI (Table 2). There were no AEs leading to withdrawal, no thromboembolic events and no deaths during the main and extension parts of the trial. ADAs developed in 6 patients. Elevated prothrombin fragment 1+2 and D-dimer levels were observed in some patients treated with concizumab. Conclusions Results from the combined main and extension parts of the phase 2 explorer4 trial were in line with the clinical proof of concept established in the main part of the trial and provided further details of the safety and longer-term efficacy of subcutaneous prophylactic treatment with concizumab for at least 76 weeks in patients with HAwI and HBwI. Disclosures Shapiro: BioMarin: Research Funding; Agios: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Glover Blood Therapeutics: Research Funding; Octapharma: Research Funding; Pfizer: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding. Castaman:Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; Baxalta/Shire: Honoraria; Sobi: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Werfen: Speakers Bureau; Kedrion: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cepo:Novo Nordisk: Current Employment. Marie Tønder:Novo Nordisk: Current Employment. Matsushita:Sysmex: Honoraria; Octapharm: Honoraria; Bayer: Consultancy, Honoraria; Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire/Takeda: Honoraria; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Genentech/Roche, Grifols, and Takeda: Research Funding. Zupancic-Šalek:NovoNordisk Health Care AG: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Octapharma: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.
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