Long‐term treatment with fostamatinib in Japanese patients with primary immune thrombocytopenia: An open‐label extension study following a phase 3 placebo‐controlled, double‐blind, parallel‐group study
Authors: Masataka Kuwana, Tomoki Ito, Shugo Kowata, Yoshihiro Hatta, Katsumichi Fujimaki, Kensuke Naito, Shingo Kurahashi, Toshiya Kagoo, Kazuki Tanimoto, So Saotome, Yoshiaki Tomiyama
Journal: American Journal of Hematology (2024)

R788-1301 (NCT04132050) is a phase 3, multicenter, randomized, parallel-group study of fostamatinib, an oral spleen tyrosine kinase inhibitor, in Japanese patients with primary ITP.1 The study consists of four parts: a placebo-controlled, double-blind study of fostamatinib for 24 weeks (Period I), an open-label study of fostamatinib for 28 weeks (Period II), a washout period of up to 4 weeks, and an open-label study of fostamatinib until marketing authorization approval (Period III) (Figure 1A and Data S1). In Period I, fostamatinib demonstrated superior efficacy over placebo and a favorable safety profile.1 Here, we report the long-term efficacy and safety of fostamatinib treatment over a maximum duration of 52 weeks, including a 24-week double-blind Period I and a 28-week open-label extension Period II. We also report the absence of bleeding events after abrupt fostamatinib discontinuation in a pre-defined washout period. A total of 33 patients (Fostamatinib-Fostamatinib [Fos-Fos] group, n = 22 [four men and 18 women, median age 61 years]; Placebo-Fostamatinib [P-Fos] group, n = 11 [three men and eight women, median age 64 years]) were treated with fostamatinib at least once in either Period I or Period II, or both (Figure 1A, Table S1). As nine patients made an early transition to Period II and four patients discontinued fostamatinib, 41% of patients (9/22) in the Fos-Fos group completed Periods I and II (Figure S1). All 11 patients in the P-Fos group who started fostamatinib in Period II completed Period II. The median (range) fostamatinib exposure duration (before an early transition to Period II or fostamatinib discontinuation) was 99 (42–372) days in the Fos-Fos group and 197 (197–204) days in the P-Fos group (Figure 1B). The durable platelet response rate (the percentage of patients with a platelet count of ≥50 × 103/μL at two consecutive visits at least 28 days apart while receiving fostamatinib) was 36% (8/22) in the Fos-Fos group and 27% (3/11) in the P-Fos group (Table S2). The median (range) duration of platelet response was 309 (113–358) days in the Fos-Fos group and 162 (113–168) days in the P-Fos group (Table S2, Figure 1B). Median platelet counts of the responders increased immediately after the first dose of fostamatinib and were sustained thereafter (Figure 1C in responders and Figure S2 in all patients). No patient had an overshoot of a platelet count of >400 × 103/μL (Figure S3). The 4-week washout period was conducted with 12 patients who provided written informed consent to participate in the washout period and had a platelet count of ≥50 × 103/μL at the end of Period II. They were able to withdraw from the washout period and use rescue medication whenever their platelet counts decreased <50 × 103/μL and the investigator considered necessary. Of 12 patients who transitioned to the washout period, four completed the 4-week washout period, and eight made an early transition to Period III because of platelet reduction (Figure S1). Platelet counts decreased in all 12 patients from Day 1 of the washout period, with one patient having post-treatment worsening of thrombocytopenia (i.e., an off-therapy platelet count of <10 × 103/μL and at least 10 × 103/μL less than the baseline value) (Figure S3, #28). Nonetheless, no patients experienced bleeding events, and the proportion of patients with an ITP bleeding score of 0 did not change markedly during the washout period (Figure 1D). The median platelet count change from Day 1 of the washout period was −26 × 103/μL at Week 2 (n = 8), −25 × 103/μL at Week 4 (n = 4), and − 29 × 103/μL at the last observed visit (n = 11) (Table S3). Patients were allowed to use concomitant ITP treatments (glucocorticoids, azathioprine, or danazol) with a fixed dose in Period I and with a flexible dose after transitioning to Period II. Among 14 patients with concomitant glucocorticoid treatment at the beginning of Period II, four reduced (#5, #9, #23, and #28) and two discontinued (#3 and #4) glucocorticoids after responding to fostamatinib treatment (Figure S3). The percentage of patients who did not use rescue medications while receiving fostamatinib was 82% (18/22) of the Fos-Fos group and 73% (8/11) of the P-Fos group. During Periods I and II while receiving fostamatinib, AEs were reported in 95% (21/22) of the Fos-Fos group and 100% (11/11) of the P-Fos group, and treatment-related AEs in 77% (17/22) of the Fos-Fos group and 45% (5/11) of the P-Fos group (Table S4). AEs reported in ≥10% of either group were diarrhea, hypertension, eczema, and neutrophil count decreased. Most AEs were mild or moderate in severity. No patient developed thrombosis, embolism, or thromboembolism. AEs leading to study drug withdrawal were reported in 18% (4/22; hepatic function abnormal, n = 2; hypertension and diarrhea, n = 1; affect lability, n = 1) of the Fos-Fos group and 0% (0/11) of the P-Fos group. No patient died during this study. Serious AEs (SAEs) were reported in 9% (2/22; diarrhea, n = 1; thrombocytopenia, n = 1) of the Fos-Fos group and 27% (3/11; radius fracture, n = 1; cellulitis, n = 1; autoimmune hepatitis, n = 1; herpes zoster, n = 1) of the P-Fos group. The SAEs in the Fos-Fos group were considered as related to the study drug. During the washout period, AEs and treatment-related AEs were reported in 50% (6/12) and 0% (0/12) of patients, respectively (Tables S4 and S5). In the Fos-Fos group, the median immunoglobulin (IgM, IgG, and IgA) levels tended to decrease between Day 1 of Period I and Week 24 but not between Week 24 and Week 52 (Table S6-1). In the P-Fos group, the median immunoglobulin (IgM, IgG, and IgA) levels were stable between Day 1 of Period I and Week 24 but tended to decrease between Week 24 and Week 52. During the washout period, the median IgG levels tended to recover (Table S6-2). During a maximum duration of 52 weeks of fostamatinib treatment, we found that 36% (8/22) of patients in the Fos-Fos group achieved a platelet count of ≥50 × 103/μL at two consecutive visits at least 28 days apart. The global phase 3 and long-term extension study of up to 5 years of fostamatinib treatment showed that 36 of 145 evaluable patients continued to receive treatment (with a median treatment duration of 49 months), 34 of whom had a platelet count of >50 × 103/μL.2 The results of global studies and our present study suggest that fostamatinib elicits a platelet response for at least 52 weeks. In the open-label EXTEND study of eltrombopag, 20% (37/185) of patients had a continuous platelet count of ≥50 × 103/μL or twice the baseline value without rescue therapy for ≥104 weeks.3 The estimated long-term response to rituximab after up to four cycles of standard dose regimen was 31% after 6 years.4 Although assessment methods and time points were different, we believe the platelet response obtained with fostamatinib in the present study and the global phase 3 studies is comparable to that obtained with TPO-RAs and rituximab. The safety profile of long-term fostamatinib treatment in this study was consistent with that of previous global phase 3 studies5 and the placebo-controlled part of this study.1 We found no new safety risks or late-onset AEs specific to Japanese patients. No platelet count overshoot of >400 × 103/μL or thromboembolic events were identified during fostamatinib treatment of up to 52 weeks. IgG levels tended to decrease during the first 24 weeks of fostamatinib treatment, but there was no further decrease in IgG levels nor increase in infectious AEs during this open-label extension. No patients had an IgG of <5 g/L, a level associated with increased infection risk. We speculate that a mild decrease in IgG levels might be linked to the reduction in the pathogenic plasmablast-like B cells without impacting total B cell and lymphocyte counts by spleen tyrosine kinase inhibition, as observed in patients with chronic graft-versus-host disease treated with fostamatinib.6 No patient developed thromboembolism in this study, and the incidence of infection was low. The major limitation of this study was the small number of patients included in the analyses (33 patients in Periods I and II and 12 patients in the washout period). Although this study has the advantage of collecting data prospectively in the placebo-controlled part and the open-label extension part, studies including a larger number of patients over a longer observation period are necessary to further investigate the long-term efficacy and safety of fostamatinib, including the risk of post-treatment worsening of thrombocytopenia, thromboembolism, and infection. In conclusion, this open-label extension part of the phase 3 study of fostamatinib targeting Japanese patients with primary ITP showed a long-lasting platelet response for up to 52 weeks, consistent with previous global phase 3 studies of fostamatinib. This study also demonstrated a favorable safety profile with no new safety risks specific to Japanese patients. These findings will help position fostamatinib as a second-line treatment in patients with primary ITP and develop evidence-based guidelines on selecting treatments for adult primary ITP. Masataka Kuwana and Yoshiaki Tomiyama conceptualized and designed the study and contributed to manuscript writing. Tomoki Ito, Shugo Kowata, Yoshihiro Hatta, Katsumichi Fujimaki, Kensuke Naito, Shingo Kurahashi, Toshiya Kagoo, and Kazuki Tanimoto contributed to the acquisition of data. So Saotome contributed to the analysis. All authors contributed to the critical review and final approval of the manuscript. The authors would like to sincerely thank all the patients and staff that took part in the study and all the co-investigators; Hiroshi Kosugi at Ogaki Municipal Hospital; Michiaki Koike at Juntendo University Shizuoka Hospital; Yuki Nakajima at Yokohama City University Medical Center; Ryosuke Ogawa at Japan Community Health Care Organization Kyushu Hospital, Hiroshi Harada at Showa University Fujigaoka Hospital; Akira Hangaishi at National Center for Global Health and Medicine; Kenji Yokoyama at Tokai University Hachioji Hospital; Ryuko Cho at Chibaken Saiseikai Narashino Hospital; Katsunori Kyoda at Kouseiren Takaoka Hospital; Atsuo Okamura at Kakogawa Central City Hospital; Yasutaka Kakinoki at Asahikawa City Hospital; Masaki Yamaguchi at Ishikawa Prefectural Central Hospital; Masahiro Yoshida at Osaka City General Hospital; Makoto Yoshimitsu at Kagoshima University Hospital; Seiichi Shimizu at Tsuchiura Kyodo General Hospital; Sayuri Motomura at Tokyo Metropolitan Tama-Hokubu Medical Center; Toshiro Ito at National Hospital Organization Matsumoto Medical Center; Hirokazu Kashiwagi at Osaka University Hospital; Jun Yamanouchi at Ehime University Hospital; Keita Kirito at University of Yamanashi; Shinya Katsutani at Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital; Akira Yokota at Chiba Aoba Municipal Hospital; Yasushi Hiramatsu at Japanese Red Cross Society Himeji Hospital; Takahide Kikuchi at Tokyo Saiseikai Central Hospital; Kohsuke Asagoe at Shiga General Hospital; Naoki Harada at Chihaya Hospital; Yutaka Imamura at Our Lady of the Snow Social Medical Corporation St. Mary's Hospital; and Tomofumi Yano at Okayama Rosai Hospital. Medical writing was provided by Yuka Kinoshita, MD, PhD (SunFlare Co., Ltd.), and English language editing was provided by SunFlare Co., Ltd. This study was funded by Kissei Pharmaceutical Co., Ltd. All authors completed the ICMJE disclosure form. Masataka Kuwana has received medical writing support from SunFlare Co., Ltd.; grants or contracts from Boehringer Ingelheim International GmbH and Ono Pharmaceutical Co., Ltd.; royalties or licenses from Medical & Biological Laboratories Co., Ltd.; consulting fees from Kissei Pharmaceutical Co., Ltd., Boehringer Ingelheim International GmbH, and Mochida Pharmaceutical Co., Ltd.; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim International GmbH, Ono Pharmaceutical Co., Ltd., AbbVie Inc., Janssen Global Services, LLC, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd.; participation on a Data Safety Monitoring Board or Advisory Board at argenx. Yoshiaki Tomiyama has received support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from Kissei Pharmaceutical Co., Ltd.; consulting fees from Kissei Pharmaceutical Co., Ltd., Novartis AG, Swedish Orphan Biovitrum AB, Takeda Pharmaceutical, and Megakaryon Corporation; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Kissei Pharmaceutical Co., Ltd., Novartis AG, Kyowa Kirin Co., Ltd., and UCB Japan Co. Ltd.; payment for expert testimony from Swedish Orphan Biovitrum AB and Sanofi; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid at Research on Rare and Intractable Disease supported by Health, Labour and Welfare Science Research Grants. Tomoki Ito, Shugo Kowata, Yoshihiro Hatta, Katsumichi Fujimaki, Kensuke Naito, Shingo Kurahashi, Toshiya Kagoo, and Kazuki Tanimoto do not disclose any conflict of interest. So Saotome is an employee of Kissei Pharmaceutical Co., Ltd. and has received medical writing support from SunFlare Co., Ltd. All authors have agreed to the writer's involvement. All patients gave prior written informed consent before any study procedures were undertaken and again before participating in the washout period and Period III. No material in this manuscript is reproduced or adapted from other published or unpublished sources. The data that support the finding of this study are not available due to a lack of patients' consent to release them to the public. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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