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Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients

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Abstract

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab’s efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab’s efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040

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References

  1. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028. https://doi.org/10.1038/nrdp.2017.28.

    Article  PubMed  Google Scholar 

  2. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124:2804–11. https://doi.org/10.1182/blood-2014-02-522128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore). 2004;83:193–207. https://doi.org/10.1097/01.md.0000126763.68170.46.

    Article  Google Scholar 

  4. Sakurai M, Jang JH, Chou WC, Kim JS, Wilson A, Nishimura JI, et al. Comparative study on baseline clinical characteristics of Asian versus non-Asian patients with paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2019;110:411–8. https://doi.org/10.1007/s12185-019-02699-7.

    Article  CAS  PubMed  Google Scholar 

  5. Soliris [prescribing information]. Alexion Pharmaceuticals, Inc.: New Haven, CT; 2019.

  6. Soliris [summary of product characteristics]. Alexion Europe SAS: Paris, France; 2017.

  7. Alexion accelerates plans to launch Soliris® (eculizumab) in Japan [news release]. Cheshire, CN: Alexion Pharmaceuticals, Inc. June 2, 2010. https://ir.alexion.com/news-releases/news-release-details/alexion-accelerates-plans-launch-solirisr-eculizumab-japan. Accessed 14 Aug 2020.

  8. Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233–43. https://doi.org/10.1056/NEJMoa061648.

    Article  CAS  PubMed  Google Scholar 

  9. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840–7. https://doi.org/10.1182/blood-2007-06-094136.

    Article  CAS  PubMed  Google Scholar 

  10. Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110:4123–8. https://doi.org/10.1182/blood-2007-06-095646.

    Article  CAS  PubMed  Google Scholar 

  11. Loschi M, Porcher R, Barraco F, Terriou L, Mohty M, de Guibert S, et al. Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study. Am J Hematol. 2016;91:366–70. https://doi.org/10.1002/ajh.24278.

    Article  CAS  PubMed  Google Scholar 

  12. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117:6786–92. https://doi.org/10.1182/blood-2011-02-333997.

    Article  CAS  PubMed  Google Scholar 

  13. Hillmen P, Muus P, Roth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162:62–73. https://doi.org/10.1111/bjh.12347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee JW, Jang JH, Kim JS, Yoon SS, Lee JH, Kim YK, et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013;97:749–57. https://doi.org/10.1007/s12185-013-1346-4.

    Article  PubMed  Google Scholar 

  15. Yenerel MN, Muus P, Wilson A, Szer J. Clinical course and disease burden in patients with paroxysmal nocturnal hemoglobinuria by hemolytic status. Blood Cells Mol Dis. 2017;65:29–34. https://doi.org/10.1016/j.bcmd.2017.03.013.

    Article  PubMed  Google Scholar 

  16. Ultomiris [prescribing information]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2018.

  17. Brazilian Health Authority. Ultomiris approval Brazil. In: Brazilian Health Authority Diario Oficial da Uniao (Suplemento), No. 169, September 2, 2019:46-47. ISSN 1677-7042.

  18. Health Canada. Ultomiris approval Canada: Health Canada; 2019. https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?linkID=RDS00547. Accessed 14 Aug 2020.

  19. Ultomiris® (ravulizumab) receives marketing authorization from European commission for adults with paroxysmal nocturnal hemoglobinuria (PNH) [press release]. Boston, MA: Alexion Pharmaceuticals, Inc. July 3, 2019. https://www.biospace.com/article/ultomiris-ravulizumab-receives-marketing-authorization-from-european-commission-for-adults-with-paroxysmal-nocturnal-hemoglobinuria-pnh-/. Accessed 14 Aug 2020.

  20. Australian Product Information—Ultomiris (Ravulizumab RCH) Concentrated Solution for Intravenous Infusion. https://www.tga.gov.au/sites/default/files/auspar-ravulizumab-191113-pi.pdf. Published 13 Nov 2019. Accessed 4 Feb 2020.

  21. Sahelijo L, Mujeebuddin A, Mitchell D, Larouche R, Yu Z-X, Zhang Y, et al. First in human single-ascending dose study: safety, biomarker, pharmacokinetics and exposure-response relationships of ALXN1210, a humanized monoclonal antibody to C5, with marked half-life extension and potential for significantly longer dosing intervals. Blood. 2015;126(23) (Abstract 4777)

  22. Roth A, Rottinghaus ST, Hill A, Bachman ES, Kim JS, Schrezenmeier H, et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2018;2:2176–85. https://doi.org/10.1182/bloodadvances.2018020644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee JW, de Fontbrune Sicre F, Wong Lee L, Pessoa V, Gualandro S, Fureder W, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019;133:530–9. https://doi.org/10.1182/blood-2018-09-876136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133:540–9. https://doi.org/10.1182/blood-2018-09-876805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol. 2011;93:36–46. https://doi.org/10.1007/s12185-010-0748-9.

    Article  CAS  PubMed  Google Scholar 

  26. Ninomiya H, Obara N, Chiba S, Usuki K, Nishiwaki K, Matsumura I, et al. Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan. Int J Hematol. 2016;104:548–58. https://doi.org/10.1007/s12185-016-2065-4.

    Article  CAS  PubMed  Google Scholar 

  27. Ueda Y, Obara N, Yonemura Y, Noji H, Masuko M, Seki Y, et al. Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan. Int J Hematol. 2018;107:656–65. https://doi.org/10.1007/s12185-018-2409-3.

    Article  CAS  PubMed  Google Scholar 

  28. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370:632–9. https://doi.org/10.1056/NEJMoa1311084.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all the patients and investigators who participated in and contributed to this study. In addition, the authors thank Takahisa Matsuda and Akihiko Shimono of Alexion Pharma G.K for critical review and discussion of the manuscript. Medical writing and editorial support were provided by ApotheCom (Yardley, PA, USA) and was funded by Alexion Pharma G.K. (Tokyo, Japan). The content of this article, the ultimate data interpretation, and the decision to submit it for publication in International Journal of Hematology were made by the authors.

Author information

Author notes

  1. Tetsuya Fukuda

    Present address: Department of Hematology, Tottori University Hospital, Tottori, Japan

  2. Hideyoshi Noji

    Present address: Minami Fukushima Cardiovascular Hospital, Fukushima, Japan

  3. Yuzuru Kanakura

    Present address: Sumitomo Hospital, Osaka, Japan

Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan

    Ken Ishiyama & Shinji Nakao

  2. Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan

    Kensuke Usuki

  3. Department of Transfusion Medicine and Cell Therapy, Kumamoto University Hospital, Kumamoto, Japan

    Yuji Yonemura

  4. Department of Hematology, Fukushima Medical University, Fukushima, Japan

    Takayuki Ikezoe & Hideyoshi Noji

  5. Department of Hematology, Japanese Red Cross Society Suwa Hospital, Suwa, Japan

    Michihiro Uchiyama

  6. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    Yasuo Mori

  7. Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan

    Tetsuya Fukuda

  8. Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

    Masaya Okada

  9. Division of Hematology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan

    Shin-ichiro Fujiwara

  10. Alexion Pharmaceuticals, Inc, Boston, MA, USA

    Scott Rottinghaus & Rasha Aguzzi

  11. Alexion Pharma G.K, Tokyo, Japan

    Jun Yokosawa

  12. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan

    Jun-Ichi Nishimura & Yuzuru Kanakura

  13. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Shinichiro Okamoto

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  1. Ken Ishiyama
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Corresponding author

Correspondence to Shinji Nakao.

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Conflict of interest

This study was funded by Alexion Pharmaceuticals, Inc., Boston, MA, USA. Ken Ishiyama has received research funding from Alexion Pharma G. K. Shinji Nakao has received honoraria from Alexion Pharmaceuticals, Inc. Kensuke Usuki has received honoraria and speakers bureau fees from Alexion Pharmaceuticals, Inc. Yuji Yonemura has received honoraria and research funding from Alexion Pharmaceuticals, Inc. Shin-ichiro Fujiwara has received personal fees from Alexion Pharma G. K. Scott Rottinghaus and Rasha Aguzzi are employees and stockholders of Alexion Pharmaceuticals, Inc. Jun Yokosawa is an employee of Alexion Pharma G. K. and owns stock/stock options in the company. Jun-Ichi Nishimura has received grants and personal fees from Alexion Pharma G. K. Yuzuru Kanakura has received grants from Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceuticals, Eisai, Janssen Pharmaceuticals K. K., the Japan Blood Products Organization, Kyowa Hakko Kirin Pharmaceuticals, Nippon Shinyaku, Novartis Pharma K. K., Ono Pharmaceuticals, Pfizer, Shionogi Pharmaceuticals, Taiho Pharmaceuticals, Takeda Pharmaceuticals, and Teijin Pharma. Shinichiro Okamoto has received honoraria and research funding from Alexion Pharma G. K. Takayuki Ikezoe, Michihiro Uchiyama, Yasuo Mori, Tetsuya Fukuda, Masaya Okada, and Hideyoshi Noji have nothing to disclose.

Informed consent

Informed consent was obtained from all patients.

IRB approval

The protocol was approved by the institutional review board and the designs of both studies were approved by local ethics committees and trials were conducted in accordance with the principles of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines.

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Ishiyama, K., Nakao, S., Usuki, K. et al. Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients. Int J Hematol 112, 466–476 (2020). https://doi.org/10.1007/s12185-020-02934-6

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