TY - JOUR
T1 - Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors
AU - Shapiro, Amy D.
AU - Angchaisuksiri, Pantep
AU - Astermark, Jan
AU - Benson, Gary
AU - Castaman, Giancarlo
AU - Eichler, Hermann
AU - Jiménez-Yuste, Victor
AU - Kavakli, Kaan
AU - Matsushita, Tadashi
AU - Poulsen, Lone Hvitfeldt
AU - Wheeler, Allison P.
AU - Young, Guy
AU - Zupančić-Šalek, Silva
AU - Oldenburg, Johannes
AU - Chowdary, Pratima
PY - 2022/6/14
Y1 - 2022/6/14
N2 - Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main ($24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced $3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main 1 extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main 1 extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes.
AB - Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main ($24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced $3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main 1 extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main 1 extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes.
U2 - 10.1182/bloodadvances.2021006403
DO - 10.1182/bloodadvances.2021006403
M3 - Article
C2 - 35290453
AN - SCOPUS:85132337451
SN - 2473-9529
VL - 6
SP - 3422
EP - 3432
JO - Blood Advances
JF - Blood Advances
IS - 11
ER -