Introduction Concizumab, a humanized recombinant monoclonal antibody directed against the tissue factor pathway inhibitor, is under investigation as a subcutaneous prophylactic treatment for patients with hemophilia A or B (HA/HB) with and without inhibitors. In the concizumab phase 2 trials, treatment was well tolerated and a favorable safety profile was shown, with no deaths or thromboembolic events and no adverse events (AEs) leading to withdrawal. We describe the non-fatal thrombotic serious AEs (SAEs) that occurred during the pivotal phase 3 explorer7 (NCT04083781) and explorer8 (NCT04082429) concizumab trials and the risk mitigations incorporated in the explorer clinical trials. Methods The explorer7 and explorer8 trials were initiated in late 2019 to evaluate the efficacy and safety of concizumab prophylaxis in HA/HB patients with/without inhibitors, respectively. Concizumab was administered subcutaneously with a 1.0 mg/kg loading dose (concizumab-naïve patients only) and a maintenance dose of 0.25 mg/kg daily from the second day onwards. Results In March 2020, explorer7 and explorer8 were paused due to the occurrence of two arterial and three venous thrombotic SAEs in three patients with HA or HB with inhibitors. All three patients had thrombotic risk factors present at baseline and had used concomitant hemostatic medication on the day of, and in two cases in the days up to, event onset. Two of the patients were among those with the highest concizumab exposure measured during phase 3. Laboratory parameters in all three patients were as expected. Based on these analyses, risk mitigation plans were developed, including guidelines for the concomitant use of hemostatic agents in the management of bleeding episodes while on concizumab prophylaxis and updates to the concizumab dosing regimen. Conclusion Novo Nordisk has assessed all available data and defined risk mitigation strategies and changes to the explorer trial protocols. Disclosures Seremetis: Novo Nordisk Ins: Current Employment, Current equity holder in private company. Cepo:Novo Nordisk: Current Employment. Skovgaard Rasmussen:Novo Nordisk: Current Employment. Høyer Rose:Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Tamer:Novo Nordisk: Current Employment, Current equity holder in private company, Divested equity in a private or publicly-traded company in the past 24 months. Porstmann:Novo Nordisk Health Care A/G: Current Employment. Haaning:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company.
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.
Introduction Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical development for the subcutaneous prophylactic treatment of hemophilia patients. We present results from the main part (at least 24 weeks) of the concizumab explorer4 phase 2 trial (NCT03196284) in hemophilia A/B with inhibitor (HAwI/HBwI) patients. Methods The primary objective was to assess the efficacy of once-daily subcutaneous concizumab in preventing bleeds in HAwI/HBwI patients. Secondary objectives were the assessment of safety, including concomitant use of recombinant activated factor VII (rFVIIa), and immunogenicity. Patients were randomized 2:1 to concizumab prophylaxis or rFVIIa on-demand treatment via an interactive web-response system. A concizumab loading dose (0.5 mg/kg) was administered, followed by 0.15 mg/kg daily with potential dose escalation to 0.20 and 0.25 mg/kg. Efficacy was evaluated as the number of bleeding episodes (annualized bleeding rate [ABR]) at last dose level. The number of adverse events (AEs) and the occurrence of anti-drug antibodies (ADAs), as well as coagulation-related parameters were evaluated. Concizumab and free TFPI plasma levels were measured by ELISA, and peak thrombin generation (TG) potential using a standardized assay. Results 26 patients were randomized; 9 HAwI and 8 HBwI patients were exposed to concizumab, and 9 patients to rFVIIa (7 with HAwI and 2 with HBwI). All 25 patients who completed the main 24-week part of the trial chose to continue to the extension part. The estimated ABR at the last dose level for concizumab prophylaxis was 4.5 (95% CI: 3.2−6.4) and for rFVIIa on demand, 20.4 [95% CI: 14.4−29.1] (Figure 1). There was a 78, 88 and 79% reduction in all treated bleeds and in spontaneous and joint bleeds, respectively, with concizumab prophylaxis compared with on-demand treatment (Figure 1). Concizumab concentration varied considerably between patients on the same dose level. Increasing concizumab dose was associated with lower free TFPI and normalized TG potential (Figure 2). No deaths, thromboembolic events or AE-related withdrawals occurred. No safety concerns with concomitant use of concizumab and rFVIIa were identified. Three patients had positive (very-low to medium-titer) ADA tests (titer range: 1 to 128), but with no apparent clinical effect. As expected, elevated prothrombin fragment 1+2 and D-dimers were observed across all concizumab dose levels, reflecting the hemostatic effect of concizumab. Conclusions In the phase 2 explorer4 trial, concizumab was efficacious and safe as a subcutaneous prophylactic treatment in HAwI patients, as well as in HBwI patients for whom there is currently no prophylactic regimen available. There was no difference in safety and efficacy across hemophilia subtypes, including with the concomitant use of concizumab and the bypassing agent rFVIIa. The phase 2 trial results, which include the explorer5 trial in HA without inhibitors, support further development of concizumab as a prophylactic treatment for all hemophilia patients and have guided selection of the phase 3 dosing regimen. Disclosures Shapiro: Sangamo Biosciences Inc: Consultancy, Other: Clinical Research Protocol with the company; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Novo Nordisk Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company; OPKO: Other: Clinical Research Protocol with the company; Octapharma: Other: Clinical Research Protocol with the company; Prometic Life Sciences: Consultancy; Shire/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Research Protocol with the company, Research Funding; Bayer: Other: Clinical Research Protocol with the company; Kedrion Biopharma: Other: Clinical Research Protocol with the company; Agios: Other: Clinical Research Protocol with the company; Prometic Bio Therapeutics: Other: Clinical Research Protocol with the company; BioMarin: Other: Clinical Research Protocol with the company; Daiichi Sankyo: Other: Clinical Research Protocol with the company; Glover Blood Therapeutics: Other: Clinical Research Protocol with the company; Novartis: Other: Clinical Research Protocol with the company; Pfizer: Other: Clinical Research Protocol with the company; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cepo:Novo Nordisk A/S: Employment. Hvitfeldt Poulsen:Novo Nordisk: Other: Clinical trials - investigator, Funding meetings and congresses; Bayer Health Care: Other: Clinical trials - investigator, Funding meetings and congresses; Pfizer: Other: Funding meetings and congresses; Sobi: Other: Funding meetings and congresses. Hollensen:Novo Nordisk: Employment. Matsushita:Bioverative: Research Funding; Pfizer: Consultancy, Honoraria; KM biologists: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; CSL: Consultancy, Honoraria; uniQure: Consultancy, Honoraria. Young:Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria. Zupancic-Salek:Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.
Treating hemophilia A or B patients with inhibitors is particularly challenging, as they do not respond to replacement therapy with factor VIII or factor IX concentrates. A room temperature-stable formulation of recombinant activated factor VII (rFVIIa; NovoSeven ® ), which provides improved convenience and treatment access to patients compared with the earlier formulation of rFVIIa, was shown to be safe and effective in a post-authorization, multinational, observational study (Study Monitoring Antibodies against Room Temperature-stable factor 7 [SMART-7™]). In post hoc, subgroup analyses of SMART-7™ data, the hemostatic response following rFVIIa monotherapy in patients with hemophilia A or B with inhibitors by time to first treatment and in different age cohorts was assessed. A total of 482/618 bleeding episodes treated with rFVIIa monotherapy and with (1) valid efficacy assessment, (2) no missing time for bleed start, (3) no missing time for any dose administration, and (4) valid time to first treatment were included in the analyses. Data on the type and location of bleeding episodes treated with rFVIIa monotherapy were also collected. The majority of bleeding episodes treated with rFVIIa monotherapy were treated within 1 hour after bleeding onset (318/482 [66%]) and, among them, 96.5% (307/318) were effectively treated (i.e., bleeding stopped). Hemostatic efficacy remained high for bleeding TH Open 2017;1:e130-e138.
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