Non-Joint Bleeds in Hemophilia A or B Patients with Inhibitors: Concizumab Explorer7 Study

PB0851 Non-joint bleeds in patients with hemophilia A or B with inhibitors: Concizumab explorer7 study Amy Shapiro1*, Ana Boban2, Ren e Brown Frandsen3, Giancarlo Castaman4, Kingsley Hampton5, Keiji Nogami6, Jameela Sathar7, Senthil Vel3, Jerzy Windyga8, Victor Jimenez Yuste9 1Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; 2Hemophilia Centre, Department of Hematology, University Hospital Centre Zagreb, Zagreb, Croatia and School of Medicine, University of Zagreb, Zagreb, Croatia; 3Novo Nordisk, S borg, Denmark; 4Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy; 5Department of Cardiovascular Science, University of Sheffield, Sheffield, UK; 6Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan; 7Department of Hematology, Ampang Hospital, Kuala Lumpur, Malaysia; 8Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 9Department of Hematology, La Paz University Hospital; Coagulopathies and Disorders of Hemostasis Group IdiPaz, Aut noma University, Madrid, Spain. *Presenting author Presented at the 33rd Congress of the International Society on Thrombosis and Haemostasis (ISTH) 2025, 21 25 June, Washington, D.C., U.S.

Background & aims Concizumab is an anti-TFPI (tissue factor pathway inhibitor) monoclonal antibody intended for prophylaxis in people with hemophilia A/B with (HAwI/HBwI) and without inhibitors1-3 It is approved in the US, Japan and EU for once-daily, subcutaneous prophylaxis in HAwI/HBwI Aim: To assess non-joint bleeds in HAwI/HBwI during concizumab prophylaxis vs on- demand treatment in an exploratory analysis from the prospective, multicenter, open-label, phase 3 explorer7 study (NCT04083781) REFERENCES Shapiro A et al., Blood Adv. 2022;6(11):3422 3432 Matsushita T et al., N Engl J Med. 2023; 389(9):783 794 Chowdary P et al., Lancet Haematol. 2024;11(12):e891-e904

Materials & methods Patients were randomized 1:2 to on-demand treatment or concizumab prophylaxis. On- demand patients switched to concizumab after 24 weeks. After a 1.0 mg/kg concizumab loading dose (Day 1), patients received a 0.20 mg/kg daily dose (Day 2+), with potential dose adjustment (5 8 weeks) to 0.15/0.25 mg/kg daily based on concizumab plasma concentration measured after week 4 Here, we describe the location and number of non-joint bleeds during on-demand or concizumab treatment at the 32- and 56-week cut-offs in explorer7, and annualized bleeding rates (ABRs) for treated spontaneous and traumatic muscle bleeding episodes (including re-bleeds and bleeds occurring contemporaneously) at the 32-week cut-off Informed consent and ethics committee approval were obtained

Results This exploratory analysis included 19 patients receiving on-demand treatment and 33 patients on concizumab prophylaxis Patients on on-demand treatment had 11.6 patient years of exposure (PYE) cumulated after the switch to concizumab, and patients on concizumab had 24.2 PYE at the 32-week cut-off

Location of treated bleeds in patients with hemophilia A/B with inhibitors Breakdown of non-joint bleeds in explorer7 Low numbers of non-joint bleeds reported with concizumab at the 32- and 56-week cut-offs 60 Total n=182 Muscular Skin Gastrointestinal Mouth, gum or nose Urinary system CNS Other 50 200 11 2 All treated bleeds 54 150 40 5 Non-joint bleeds Total n=96 4 100 Total n=66 30 22 128 14 50 74 4 20 52 1 32 1 2 0 1 On-demand Concizumab Concizumab 1 On-demand 32-week cut-off (n=17/19 with bleeds) Concizumab 32-week cut-off (n=15/33 with bleeds) Concizumab 56-week cut-off (n=19/33 with bleeds) 10 9 8 5 4 0 Joint bleeds Non-joint bleeds On-demand 32-week cut-off (n=19) Concizumab 32-week cut-off (n=33) Concizumab 56-week cut-off (n=33) All treated bleeds with either of the four causes (spontaneous, traumatic, surgical or missing) were counted when checking whether patient had any bleeds. Bleeds with multiple locations are counted in all of these locations. The 32- and 56-week cut-offs were defined as when all patients had completed the visit after 32 or 56 weeks respectively, or permanently discontinued treatment. CNS, central nervous system.

Estimated ABR for treated muscle bleeding episodes at the 32-week cut-off in explorer7 Lower muscle bleed ABR in patients on concizumab vs on-demand treatment (ABR ratio: 0.05 [95% CI 0.01;0.22]) On-demand Estimated 1.5 ABR Concizumab 0.1 Muscle bleeds along with joint bleeds affect patient mobility and can thus lead to a reduced quality of life

Origin and severity of treated muscle bleeds at the 32-week cut-off in explorer7 Mostly mild/moderate muscle bleeds reported in patients on demand Severe bleeds Traumatic n=15/32 (46.9%) n=2/32 (6.3%) On-demand bleeds Concizumab n=1/4 (25%) n=2/4 (50.0%) Mild/moderate Spontaneous n=17/32 (53.1%) n=30/32 (93.8%) bleeds bleeds n=3/4 (75.0%) n=2/4 (50.0%) Hemostatic therapies used to treat muscle bleeds: aPCC (Feiba) rFVIIa (NovoSeven/Coagil-VII/Eptacog alfa) The 32-week cut-off was defined as when all patients had completed the visit after 32 weeks, or permanently discontinued treatment.

Conclusions Few non-joint bleeds were reported with concizumab prophylaxis in explorer7 at the 32- and 56-week cut-offs The ABR for treated muscle bleeding episodes was reduced in patients on concizumab compared with on-demand treatment at the 32-week cut-off At the explorer7 32-week cut-off: Patients Patients 33 19 On-demand On concizumab experienced: Muscle bleeds Muscle bleeds 4 32 Other treated bleeds Other treated bleeds Estimated ABR 1.5 0.1

Acknowledgements The authors thank the patients, their families and all physicians for their participation and support. Medical writing support was provided by Ashfield MedComms GmbH (Mannheim, Germany), an Inizio company, and sponsored by Novo Nordisk

Disclosures A.S.: Speakers Bureau and/or Advisory Board of Novo Nordisk, Pfizer, Genentech/Roche, Kedrion Biopharma, Sanofi- Genzyme/Bioverativ, Hema Biologics, Be Biopharma, BioMarin; research funding from Novo Nordisk, Pfizer, Genentech/Roche, Kedrion Biopharma, Sanofi-Genzyme/Bioverativ, Regeneron, Takeda Pharmaceuticals, Pharmacosmos A/S, Centessa Pharmaceuticals/ApcinteX Ltd A.B.: Speakers Bureau and/or Advisory Board of Bayer, CSL Behring, NovoNordisk, Octapharma, Roche, Takeda, Sobi. R.B.F. and S.V.: Employees of Novo Nordisk A/S G.C.:Speakers Bureau or honoraria from Bioviiix, CSL Behring, Biomarin, Sanofi, Novo Nordisk, Takeda, LFB, Roche, Sobi; Data Safety Monitoring Board or Advisory Board of Bayer, CSL Behring, Biomarin, Pfizer, Sanofi, Novo Nordisk, Takeda, LFB, Roche K.H.: Speakers honoraria from Novo Nordisk; Advisory Board of Novo Nordisk, Takeda, Roche K.N.:Honoraria or consultation fees: Novo Nordisk, Chugai, Sanofi, CSL Behring, KM Biologics, Takeda, SEKISUI MEDICAL, Bayer, Fujimoto, Pfizer; research funding from Novo Nordisk, Chugai, Sanofi, CSL Behring, KM Biologics, Takeda, SEKISUI MEDICAL, Bayer, Fujimoto J.S.: Honoraria or consultation fees from ZP, BMS J.W.:Speakers Bureau, Advisory Board, research support and honoraria or consultation fees from Amgen, AstraZeneca, Bayer AG, CSL Behring, LFB, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, Takeda V.J.Y.: Speakers Bureau and consultation fees from Novo Nordisk, Roche, Sobi, Pfizer, LFB, CSL Behring; research funding from Novo Nordisk, Roche, Sobi, Pfizer, Grifols

Disclaimer Concizumab is indicated for hemophilia A and B with inhibitors by the FDA, in Europe, Australia and Japan. It is also indicated for hemophilia A and B without inhibitors in Japan and Australia. Local label may vary, please always check your local prescribing information Concizumab is currently not indicated for hemophilia A and B without inhibitors or any other use by the FDA. There is no guarantee that it will become available commercially for any use under clinical investigation ABBREVIATIONS (all slides) ABR, annualized bleeding rates; aPCC, activated prothrombin complex concentrate; CI, confidence interval; EU, European Union; HAwI, hemophilia A with inhibitors; HBwI, hemophilia B with inhibitors; rFVIIa, recombinant activated factor VII; US, United States of America