Hemophilia and Rare Bleeding Disorders
Víctor Jiménez Yuste, MD PhD
Head of Hematology
La Paz University Hospital
Madrid, Madrid, Spain
Pantep Angchaisuksiri, MD
Professor of Medicine
Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Bangkok, Krung Thep, Thailand
Giancarlo Castaman
Medical Director
Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy
Florence, Toscana, Italy
Katarina Cepo
International Medical Director
Novo Nordisk A/S
Søborg, Hovedstaden, Denmark
Jesper Haaning
Project Vice President
Novo Nordisk A/S
Søborg, Hovedstaden, Denmark
Sanja H. Jacobsen
Senior Statistician
Novo Nordisk A/S, Søborg, Denmark
Søborg, Hovedstaden, Denmark
Johnny Mahlangu, MD
Professor and Director
Haemophilia Comprehensive Care Centre, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
Johannesburg, Gauteng, South Africa
Tadashi Matsushita
Professor
Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.
Nagoya, Aichi, Japan
Keiji Nogami
Professor
Nara Medical University, Nara, Japan
Nara, Nara, Japan
Amy Shapiro
Medical Director
Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA
Indianapolis, Indiana, United States
Concizumab is a subcutaneously administered anti-tissue factor pathway inhibitor (TFPI) antibody in development as once-daily prophylaxis for all haemophilia patients. explorer7 (NCT04083781) primary analysis results are presented.
Aims:
explorer7 assessed concizumab efficacy and safety in haemophilia A/B with inhibitor (HAwI/HBwI) patients.
Methods:
Patients were randomised 1:2 to no prophylaxis (arm 1; ≥24 weeks) or concizumab prophylaxis (arm 2; ≥32 weeks), or assigned to concizumab prophylaxis (arms 3&4). After treatment restart following pause due to thromboembolic events, patients received a 1.0 mg/kg concizumab loading dose, followed by an initial 0.20 mg/kg daily dose, with potential adjustment to 0.15 or 0.25 mg/kg based on plasma concizumab concentration at week 4. The primary analysis compared number of treated spontaneous and traumatic bleeding episodes between arms 1 and 2 (using negative binomial regression). Safety, patient-reported outcomes, and pharmacokinetics/pharmacodynamics were assessed. Informed consent/ethics committee approval were obtained.
Results:
Of 133 enrolled patients, 33 were randomised to concizumab (arm 2) and 19 to no prophylaxis (arm 1) (28 and 14 completed ≥32/24 weeks of treatment at the primary analysis cut-off, respectively); the remaining 81 were assigned to concizumab (arms 3&4). Estimated mean annualised bleeding rate (ABR) was 1.7 (95% CI, 1.0–2.9) for concizumab versus 11.8 (95% CI, 7.0–19.9) for no prophylaxis (ABR ratio, 0.14 [95% CI, 0.07–0.29]; P< 0.001). Median ABR on concizumab was 0 (Figure 1). Twenty‑one (63.6%) concizumab patients had zero treated bleeds at 24 weeks (including those who discontinued before 24 weeks) versus two (10.5%) on no prophylaxis. No thromboembolic events were reported after treatment restart (Table 1). Positive trends were observed across 36-Item Short-Form Health Survey (SF-36v2) domains with concizumab. Concizumab exposure was stable over time.
Conclusion(s):
Concizumab prophylaxis effectively reduced ABR versus no prophylaxis and was considered safe and well tolerated in HAwI/HBwI patients, the latter of which have the greatest unmet need.