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Peer-reviewedCC BY 4.0Journal of Clinical Medicine

Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison

  • Noriko Aramaki-Hattori1
  • Satoru Sasaki2
  • Naoki Murao2
  • Taiki Nozaki3
  • Akihiro Fujino4
  • Ayato Hayashi5
  • Michio Ozeki6
  • Saori Endo6
  • Shimpei Akiyama7
  • Tadashi Nomura8,9
  • Shunsuke Sakakibara8
  • Yoshihisa Kawakami10,11
4 more authors
  • Ai Morita10
  • Junko Ochi12
  • Motoki Akamatsu13
  • Sadanori Akita14,15
15 affiliations
  1. 1Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
  2. 2Department of Plastic Surgery, Tonan Hospital, Sapporo 060-0004, Japan
  3. 3Department of Radiology, Keio University School of Medicine, Tokyo 160-8582, Japan
  4. 4Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
  5. 5Department of Plastic and Reconstructive Surgery, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
  6. 6Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
  7. 7Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
  8. 8Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
  9. 9Department of Plastic Surgery, National Hospital Organization Kobe Medical Center, Kobe 654-0155, Japan
  10. 10Department of Plastic Surgery, Fukuoka Children’s Hospital, Fukuoka 813-0017, Japan
  11. 11Department of Plastic and Reconstructive Surgery, Osaka Rosai Hospital, Sakai 591-8025, Japan
  12. 12Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
  13. 13Kaken Pharmaceutical Co., Ltd., Tokyo 113-8650, Japan
  14. 14Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
  15. 15Department of Plastic Surgery, Tamaki Aozora Hospital, Tokushima 779-3125, Japan
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Abstract

Background/Objectives: Slow-flow vascular malformations, including venous malformation (VM), lymphatic malformation (LM), and Klippel–Trenaunay syndrome (KTS), are rare, symptomatic disorders with limited treatment options. This study evaluated the efficacy and safety of serabelisib, an orally available selective phosphoinositide 3-kinase α inhibitor, in these patients. Methods: This phase 3, multicenter, single-arm, confirmatory study was conducted in Japan (September 2023–June 2025). Patients aged ≥2 years received oral serabelisib once daily (100 mg for body weight ≥ 40 kg; 60 mg/m2 for <40 kg) for up to 52 weeks. The primary endpoint was the response rate at the final evaluation (≥24 weeks), defined as the proportion of patients achieving a ≥20% reduction from baseline in target lesion volume on blinded, centrally reviewed magnetic resonance imaging. The response rate was compared with a natural history-based null rate of 6.7% (exact binomial test). Trial registration: jRCT2041230064. Results: Thirty-six patients received serabelisib. The response rate was 30.6% (11/36; 95% confidence interval, 16.3–48.1%; p < 0.001) and remained significant in post hoc sensitivity analyses for null rates of up to 16%. Response rates were 19.0% (VM), 33.3% (LM), and 50.0% (KTS). Quality of life did not improve consistently. Adverse drug reactions (ADRs) occurred in 52.8% of patients (grade 3 or 4, 22.2%), most commonly hyperinsulinemia (13.9%), nausea (11.1%), and liver function test abnormal (11.1%); most hepatic ADRs (13 of 15 events) resolved after dose interruption or discontinuation. One death (tubulointerstitial nephritis) was judged unrelated to treatment. Conclusions: Serabelisib produced radiological responses exceeding a natural history benchmark in refractory VM, LM, and KTS, with hepatic toxicity requiring monitoring. Larger controlled studies with longer follow-up are needed to confirm its clinical benefit and long-term safety.

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Cite

BibTeXRIS
BibTeX
@article{aramakihattori2026serabelisib,
  title = {{Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison}},
  author = {Noriko Aramaki-Hattori and Satoru Sasaki and Naoki Murao and Taiki Nozaki and Akihiro Fujino and Ayato Hayashi and Michio Ozeki and Saori Endo and Shimpei Akiyama and Tadashi Nomura and Shunsuke Sakakibara and Yoshihisa Kawakami and Ai Morita and Junko Ochi and Motoki Akamatsu and Sadanori Akita},
  journal = {Journal of Clinical Medicine},
  year = {2026},
  month = nov,
  doi = {10.3390/jcm15218624},
  url = {https://www.mdpi.com/2077-0383/15/21/8624},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Serabelisib, a Selective PI3Kα Inhibitor, for Slow-Flow Vascular Malformations in a Phase 3 Multicenter Single-Arm Study with Natural History Comparison
AU  - Noriko Aramaki-Hattori
AU  - Satoru Sasaki
AU  - Naoki Murao
AU  - Taiki Nozaki
AU  - Akihiro Fujino
AU  - Ayato Hayashi
AU  - Michio Ozeki
AU  - Saori Endo
AU  - Shimpei Akiyama
AU  - Tadashi Nomura
AU  - Shunsuke Sakakibara
AU  - Yoshihisa Kawakami
AU  - Ai Morita
AU  - Junko Ochi
AU  - Motoki Akamatsu
AU  - Sadanori Akita
PY  - 2026
DA  - 2026/11/05
JO  - Journal of Clinical Medicine
DO  - 10.3390/jcm15218624
UR  - https://www.mdpi.com/2077-0383/15/21/8624
AB  - Background/Objectives: Slow-flow vascular malformations, including venous malformation (VM), lymphatic malformation (LM), and Klippel–Trenaunay syndrome (KTS), are rare, symptomatic disorders with limited treatment options. This study evaluated the efficacy and safety of serabelisib, an orally available selective phosphoinositide 3-kinase α inhibitor, in these patients. Methods: This phase 3, multicenter, single-arm, confirmatory study was conducted in Japan (September 2023–June 2025). Patients aged ≥2 years received oral serabelisib once daily (100 mg for body weight ≥ 40 kg; 60 mg/m2 for <40 kg) for up to 52 weeks. The primary endpoint was the response rate at the final evaluation (≥24 weeks), defined as the proportion of patients achieving a ≥20% reduction from baseline in target lesion volume on blinded, centrally reviewed magnetic resonance imaging. The response rate was compared with a natural history-based null rate of 6.7% (exact binomial test). Trial registration: jRCT2041230064. Results: Thirty-six patients received serabelisib. The response rate was 30.6% (11/36; 95% confidence interval, 16.3–48.1%; p < 0.001) and remained significant in post hoc sensitivity analyses for null rates of up to 16%. Response rates were 19.0% (VM), 33.3% (LM), and 50.0% (KTS). Quality of life did not improve consistently. Adverse drug reactions (ADRs) occurred in 52.8% of patients (grade 3 or 4, 22.2%), most commonly hyperinsulinemia (13.9%), nausea (11.1%), and liver function test abnormal (11.1%); most hepatic ADRs (13 of 15 events) resolved after dose interruption or discontinuation. One death (tubulointerstitial nephritis) was judged unrelated to treatment. Conclusions: Serabelisib produced radiological responses exceeding a natural history benchmark in refractory VM, LM, and KTS, with hepatic toxicity requiring monitoring. Larger controlled studies with longer follow-up are needed to confirm its clinical benefit and long-term safety.
SN  - 2077-0383
ER  -