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Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study
Liu X, Zhou H, Hu Y, Yin J, Li J, Chen W, Huang R, Gong Y, Luo C, Mei H, et al
The Lancet. Haematology. 2023
Abstract
BACKGROUND Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 10(9) platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING HUTCHMED.
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A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia
Mei H, Liu X, Li Y, Zhou H, Feng Y, Gao G, Cheng P, Huang R, Yang L, Hu J, et al
Journal of hematology & oncology. 2021;14(1):37
Abstract
BACKGROUND Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. METHODS Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 10(9)/L) after 8 weeks of treatment. RESULTS The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83-68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39-86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. CONCLUSIONS In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843 , registered July 19, 2017, retrospectively registered.
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Efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia: stage 2 results from a multicenter phase III study
Liu X, Hou M, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Yang R
Platelets. 2020;:1-7
Abstract
This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 10(9)/L and 80 × 10(9)/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 10(9)/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 10(9)/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit-risk ratio in Chinese chronic ITP patients. Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761.
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Therapeutic options for adult patients with previously treated immune thrombocytopenia - a systematic review and network meta-analysis
Yang R, Lin L, Yao H, Ji O, Shen Q
Hematology (Amsterdam, Netherlands). 2019;24(1):290-299
Abstract
OBJECTIVES The great majority of adult patients with immune thrombocytopenia (ITP) who fail to respond to first-line medication or who relapse following response require additional treatment. Although broad guidelines currently exist for second-line and subsequent therapies, none to date have been prescriptive. The purpose of this systematic review and network meta-analysis was to establish a clinically relevant ranking of the efficacy and safety of medications for adults (≥18 years old) with previously treated ITP. METHODS Relevant publications from Medline, Embase, and the Cochrane database were searched from their inceptions through July 31, 2018. The primary outcome was the overall response (OR, defined as a platelet count ≥50 x 10(9)/L at the end of treatment without rescue therapy), while the secondary endpoints included early response (ER; i.e. a platelet count ≥50 x 10(9)/L at week 2 after initiation of treatment) and therapy-related severe adverse events (AEs). RESULTS Thirteen randomized controlled trials (1,202 patients) were included in this study. According to pooled results, romiplostim appears to be the most suitable treatment in terms of OR, followed by avatrombopag, eltrombopag, fostamatinib, and rituximab. Avatrombopag produced more satisfactory outcomes than romiplostim, eltrombopag, and rituximab in terms of ER; severe AEs profiles were similar across all treatment arms. CONCLUSION Romiplostim appears to be the best option for patients who fail to respond to prior treatment or relapse thereafter, while avatrombopag and eltrombopag are reasonable alternatives. Rituximab monotherapy is not recommended, as it produces the lowest OR and ER rates.
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Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia
Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Hou M
British Journal of Haematology. 2016;176((1):):101-110
Abstract
Eltrombopag, a thrombopoietin receptor agonist, raises platelet counts and reduces bleeding in patients with immune thrombocytopenia (ITP). In Chinese patients, eltrombopag was evaluated at an initial dose of 25 mg, vs. 50 mg for non-Asians, because the plasma exposure of eltrombopag is higher in East Asians. A multicentre, double-blind, randomised, placebo-controlled, 8-week, phase III study enrolled 155 patients with chronic, previously treated ITP. Dosage could be adjusted (25-75 mg/day) to maintain platelet counts 50-250 x 109 /l. The primary efficacy endpoint was the proportion of patients with a platelet count ≥50 x 109 /l after Day 42. Pharmacokinetics and pharmacodynamics of eltrombopag were analysed in an open-label extension. After Day 42, 57.7% of eltrombopag-treated and 6.0% of placebo-treated patients achieved platelet counts ≥50 x 109 /l. Odds of achieving a platelet count ≥50 x 109 /l were 26.08 times greater with eltrombopag than placebo (P < 0.001). Compared with placebo, time to response and duration of response were better with eltrombopag (P < 0.001) and the odds of any bleeding were reduced by 72% (P = 0.001). Tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics were similar to previous findings in East Asian patients. In conclusion, in Chinese patients with chronic ITP, eltrombopag 25 mg once daily, elevated platelet counts to a safe range and reduced bleeding.
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Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)
Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou-StoeterD, Maas Enriquez M
Journal of Thrombosis & Haemostasis. 2015;13((3):):360-9.
Abstract
BACKGROUND BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12-65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean +/- SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 +/- 7.2; 3-times-weekly, 4.3 +/- 6.5; combined, 4.9 +/- 6.8) vs. on-demand treatment (57.7 +/- 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.
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Effect of eltrombopag on platelet response and safety results in Chinese adults with chronic ITP - primary result of a phase III study
Yang R, Hou M, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Du X, Niu T, et al
Blood. 2014;124((21)): Abstract No. 1464