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Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors

Shapiro, Amy D. ; Angchaisuksiri, Pantep ; Astermark, Jan LU ; Benson, Gary ; Castaman, Giancarlo ; Eichler, Hermann ; Jiménez-Yuste, Victor ; Kavakli, Kaan ; Matsushita, Tadashi and Poulsen, Lone Hvitfeldt , et al. (2022) In Blood Advances 6(11). p.3422-3432
Abstract

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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
6
issue
11
pages
11 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85132337451
  • pmid:35290453
ISSN
2473-9529
DOI
10.1182/bloodadvances.2021006403
language
English
LU publication?
yes
id
dccecfa2-6d3f-4c06-ac0c-5a990abcf92c
date added to LUP
2022-10-04 11:07:28
date last changed
2024-06-13 16:20:37
@article{dccecfa2-6d3f-4c06-ac0c-5a990abcf92c,
  abstract     = {{<p>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.</p>}},
  author       = {{Shapiro, Amy D. and Angchaisuksiri, Pantep and Astermark, Jan and Benson, Gary and Castaman, Giancarlo and Eichler, Hermann and Jiménez-Yuste, Victor and Kavakli, Kaan and Matsushita, Tadashi and Poulsen, Lone Hvitfeldt and Wheeler, Allison P. and Young, Guy and Zupančić-Šalek, Silva and Oldenburg, Johannes and Chowdary, Pratima}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{3422--3432}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2021006403}},
  doi          = {{10.1182/bloodadvances.2021006403}},
  volume       = {{6}},
  year         = {{2022}},
}