Switching from eltrombopag to hetrombopag in patients with primary immune thrombocytopenia: a post-hoc analysis of a multicenter, randomized phase III trial.

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.

A phase I, single-sequence, open-label study to evaluate the drug-drug interaction between hetrombopag and cyclosporine in healthy Chinese subjects.

AIMS: This study aims to evaluate the drug-drug interaction (DDI) between hetrombopag and cyclosporine in healthy Chinese subjects. METHODS: Twenty-six eligible subjects enrolled in this single-centre, single-sequence, open-label, DDI study with 3 treatment periods, receiving 5 mg hetrombopag once on Day 1, 100 mg cyclosporine twice daily from Day 11 to Day 15 and 5 mg hetrombopag + 100 mg cyclosporine on Day 16. Serial blood samples were collected for pharmacokinetic evaluation. Adverse events were monitored throughout the study. RESULTS: The plasma hetrombopag geometric mean ratios (90% confidence interval) of maximum plasma concentration, area under the plasma concentration-time curve (AUC) from predose to time of last quantifiable sample and AUC to infinity of coadministration of hetrombopag with cyclosporine vs. hetrombopag alone were 95.97% (70.08-131.43%), 105.75% (75.04-149.04%) and 104.19% (74.71-145.32%), respectively, indicating multiple doses of cyclosporine had minimal effects on hetrombopag exposure. The geometric mean ratios (90% confidence interval) of maximum blood concentration and AUC at steady state during a dosing interval for blood cyclosporine of coadministration vs. cyclosporine alone were 100.49% (91.89-109.89%) and 100.81% (107.88-103.82%), respectively, suggesting a single dose of hetrombopag had no impact on the exposure of cyclosporine. Coadministration of hetrombopag with cyclosporine was generally well tolerated. CONCLUSION: No clinically significant DDI was observed when coadministration of hetrombopag with cyclosporine. The results of this study will inform the appropriate use of this combination therapy both in clinical trials and clinical settings.

Treatment of immune thrombocytopenia with hetrombopag olamine tablets in a Kabuki syndrome patient with new KMT2D mutations.

Kabuki syndrome (KS) is a rare multisystem-affecting genetic disorder, and usually accompanied with autoimmune disorders such as immune thrombocytopenic purpura (ITP). Here, we report a 16-year-old patient with Kabuki syndrome with ITP and observe the therapeutic effect of TPO agonist hetrombopag olamine tablets. The duration of maintenance therapy and follow up were both 17 months. Whole exon sequencing (WES) of the patient's peripheral blood showed c.5775_5778del (p. Leu1926LysfsTer120) heterozygous mutation in the KMT2D gene, which was not reported before.

Iron chelation of hetrombopag in aplastic anemia: a post hoc analysis of a phase II study.

Hetrombopag is the only CFDA-approved thrombopoietin (TPO) receptor agonist for severe aplastic anemia (SAA) in China. Its chemical structure has an iron chelation domain. To explore the iron chelation effect of hetrombopag, we performed a post hoc analysis of the phase II clinical trial (NCT03557099). Thirty-five immunosuppressive therapy (IST)-refractory SAA patients were enrolled in the study, and the longitudinal changes of serum ferritin (SF) were assessed. At 18 weeks post-hetrombopag initiation, 51.4% of patients showed decreased SF levels by a median of 49.0 (18.1-95.5) % from baseline (median ΔSF decrease value, 917.2 ng/ml, range from 104.0 to 7030.0 ng/ml). A decrease in SF was found in 75.0% of hematologic responders and 31.6% of non-responders. Among the 24 patients with iron overload, 12 had decreased SF levels by up to 51% of the baseline. Patients with normal SF levels also showed decreased SF levels, and iron deficiency occurred in two patients. In conclusion, hetrombopag showed a powerful and rapid iron chelation effect.

Impact of target-mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura.

AIMS: The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag. METHODS: Nonlinear mixed-effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness-of-fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study. RESULTS: The pharmacokinetic data of hetrombopag were well described by a modified target-mediated drug disposition (TMDD) model with dual sequential first-order absorption. Mean parameter estimates (interindividual variability) were CL/F 7.66 L/h (63.5%), Vc /F 30.0 L (77.2%) and Kdeg 0.693/h (87.1%). The pharmacodynamic profile was well described by a five-compartment lifespan model with four-transit and one-platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once-daily hetrombopag would able to achieve an ideal platelet count level (50-200 × 109 /L). CONCLUSION: TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once-daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.

Effect of postdose fasting duration on hetrombopag olamine pharmacokinetics and pharmacodynamics in healthy volunteers.

AIMS: Hetrombopag olamine is a novel small-molecule, nonpeptide thrombopoietin receptor agonist developed for immune thrombocytopenia treatment. This study aims to determine the safety and the effect of fasting duration after administration of hetrombopag on pharmacokinetics and pharmacodynamics in Chinese healthy subjects. METHODS: A randomized, open-label, single-dose, 3-period crossover, self-control trial was conducted. 15 eligible subjects were enrolled and received hetrombopag 7.5 mg at day 1 of each period followed by a standard meal 4 hours postdose (treatment A/fasting condition), or a high-calorie, high-fat meal 1 hour postdose (treatment B), or a high-calorie, high-fat meal 2 hours postdose (treatment C). The plasma concentrations of hetrombopag were determined by validated liquid chromatography-tandem mass spectrometry, platelet counts were quantified by blood test. Analysis was performed using a mixed model, including treatment, period as fixed effects and participant as a random effect. RESULTS: Compared with treatment A, peak concentration and area under concentration-time curve extrapolated to infinity decreased by 56 and 74.6%, and 44 and 61% in treatments B and C, respectively. The mean platelet number on day 6 increased by 15.8, 6.96 and 10.26%, respectively, in treatments A, B and C in comparison with baseline platelet level. No severe adverse events happened in any of the 3 treatments. CONCLUSION: Hetrombopag was well tolerated in healthy male subjects under fasted/fed conditions. The shorter fasting duration resulted in lower hetrombopag exposure, corresponding to a lower level of platelet elevation. Therefore, we recommended oral administration of hetrombopag on an empty stomach (fasting condition) or at least 2 hours before a meal to achieve maximum bioavailability.

Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist.

Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small-molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR-expressing cells, including 32D-MPL and human hematopoietic stem cells, with low nanomolar EC50 values through stimulation of STAT, PI3K and ERK signalling pathways. Notably, hetrombopag effectively up-regulated G1 -phase-related proteins, including p-RB, Cyclin D1 and CDK4/6, normalized progression of the cell cycle, and prevented apoptosis by modulating BCL-XL/BAK expression in 32D-MPL cells. Moreover, hetrombopag and TPO acted additively in stimulating TPOR-dependent signalling, promoting cell viability, and preventing apoptosis. Orally administered hetrombopag specifically promoted the viability and growth of 32D-MPL cells in hollow fibres implanted into nude mice with much higher potency than that of the well-known TPOR agonist, eltrombopag, in association with activation of TPOR-dependent signal transduction in vivo. Taken together, our findings indicate that, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small-molecule TPOR agonist for patients with thrombocytopenia.

Hetrombopag, a Thrombopoietin Receptor Agonist, Protects Cardiomyocyte Survival from Oxidative Stress Damage as an Enhancer of Stem Cells.

PURPOSE: Current human umbilical cord blood stem cell therapy faces the great challenges, because the stem cells are scarce and cannot survive for a long time. Here we describe how hetrombopag, an orally-active TPO receptor agonists, enhanced ex vivo expansion of human UCB stem cells, and protected cardiac myocytes from the damage caused by oxidative stress. METHODS: Ex vivo expansion of stem cells were performed in serum-free medium supplemented with rhSCF and rhFL plus hetrombopag for 7 days. The percentage and number of stem cell subsets were determined by flow cytometry. Rat cardiac myocytes, ex vivo expanded stem cells, or cardiac myocytes plus ex vivo expanded stem cells were serum starved for 24 hours, and were then subjected to H2O2, hetrombopag or both for 12 hours at the indicated concentrations. Cell viability assays, protein microarrays and western blots were then performed in each group. RESULTS: Our studies first revealed that the combination of hetrombopag and rhTPO manifested additive effect on ex vivo expansion of human UCB stem cells. Besides, hetrombopag dose-dependently enhanced the beneficial effects of ex vivo expanded human UCB MNCs in increasing the survival of injured cardiomyocytes during free oxygen radical stress. CONCLUSION: These data, for the first time, uncovered a novel function of non-peptide small molecular TPO receptor agonists as enhancers of stem cells in protecting cardiac myocyte survival from oxidative stress damage, which might provide a new therapeutic avenue for the treatment of oxidative stress-related cardiovascular disease. Graphical abstract ᅟ.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study.

Hetrombopag, a small molecular thrombopoietin-receptor agonist, has shown encouraging efficiency in immunosuppressive therapy refractory or relapsed severe aplastic anaemia. To investigate the response rate of hetrombopag combined with IST as first-line treatment, we designed a prospective pilot study including 32 patients with SAA treated with anti-human T lymphocyte porcine immunoglobulin (p-ATG), cyclosporine, and hetrombopag. In addition, 96 patients with SAA treated with p-ATG and cyclosporine alone were matched as controls. In total, 21.9% of patients treated with hetrombopag achieved complete response (CR) at 3 months, while 5.2% of patients achieved CR in the control group (P = 0.005). At 6 months, the CR rates were 34.4% in the hetrombopag group and 14.6% in the control group (P = 0.015). The overall response rates at 6 months were 68.7% and 50.0% in the hetrombopag and control groups, respectively. The median time to haematologic response was 56 days and 77 days, and to CR was 96 days and 214 days in the hetrombopag and control groups, respectively. In conclusion, adding hetrombopag to IST as first-line treatment resulted in faster and better haematologic response in SAA.

Hetrombopag plus recombinant human thrombopoietin for chemotherapy-induced thrombocytopenia in patients with solid tumors.

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common hematological complication in patients with cancer. Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO). Objectives: This multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT. Methods: A total of 294 patients with solid tumors and CIT (platelet count, <50 × 109/L) who received either rhTPO plus hetrombopag (146 patients) or rhTPO alone (148 patients) at 3 centers from January to December 2022 were included in the study. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days. Chemotherapy dose reductions/delays, bleeding, and adverse events were reported. Results: One hundred twenty patients (82.2%) in the rhTPO-hetrombopag group vs 100 patients (67.6%) in the rhTPO group achieved the primary outcome (P = .005). This significant difference persisted in adjusted analysis (odds ratio, 2.01; 95% CI, 1.12-3.60). A total of 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 patients (68.2%) in the rhTPO group avoided chemotherapy dose reductions/delays (P = .041). There was no significant difference in bleeding rates, and adverse events were mild and similar between the 2 groups. No deaths occurred. Conclusion: Compared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.

Safety of non­peptide thrombopoietin receptor agonists in patients with immune thrombocytopenia: A systematic review and meta­analysis of short­term double­blind randomized clinical trials.

The aim of the present study was to analyze the safety of non-peptide thrombopoietin receptor agonists (TPO-RAs) for immune thrombocytopenia (ITP) treatment. All studies reporting adverse events (AEs) in relation to ITP treatment with eltrombopag, avatrombopag, and hetrombopag were retrieved from PubMed, Web of Science, and Embase databases. RevMan 5.4.1 was used for meta-analysis, heterogeneity and bias analyses. A total of 1,078 patients from seven eligible studies were enrolled. In the enrolled clinical trials, the double-blind period was between 6 weeks and 6 months. The results revealed that the chances of any AEs [relative risk (RR)=1.16; 95% confidence interval (CI), 0.90-1.51; I2=78%; P=0.26], grade 3/4 AEs (RR=1.07; 95% CI, 0.63-1.80; I2=0%; P=0.81), elevated transaminase levels (RR=1.09; 95% CI, 0.68-1.74; I2=0%; P=0.72), thrombosis (RR=1.92; 95% CI, 0.55-6.66; I2=0%; P=0.31) and cataracts (RR=0.83; 95% CI, 0.38-1.83; I2=0%; P=0.65) were not significantly higher in patients with ITP that received non-peptide TPO-RAs compared with patients with ITP treated with a placebo. The present study indicated that non-peptide TPO-RAs were relatively safe for patients with ITP, at least within 6 months of administration.

Dose tapering to withdrawal stage and long-term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open-label extension study.

BACKGROUND: The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). OBJECTIVE: This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. PATIENTS/METHODS: Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. RESULTS: Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30 × 109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n = 339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. CONCLUSION: The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy.

Background: In this single-arm phase II study (NCT03557099), we evaluated the efficacy and safety of hetrombopag, a small molecule thrombopoietin (TPO) receptor agonist, in patients with severe aplastic anemia (SAA) who were refractory to standard first-line immunosuppressive therapy (IST). Methods: SAA patients who were refractory to standard first-line IST were given hetrombopag orally at an initial dose of 7.5 mg once daily to a maximum of 15 mg once daily, for a total of 52 weeks. The primary endpoint was proportion of patients achieving hematologic responses in ⩾1 lineage at week 18. Results: A total of 55 eligible patients were enrolled and received hetrombopag treatment. This study met its primary endpoint, with 23 [41.8%, 95% confidence interval (CI) = 28.7-55.9] patients achieving hematologic response in ⩾1 lineage at week 18 after initiation of hetrombopag treatment. Twenty-four (43.6%, 95% CI = 30.3-57.7) and 27 (49.1%, 95% CI = 35.4-62.9) of the 55 patients responded in ⩾1 lineage at weeks 24 and 52, respectively. Median time to initial hematologic response was 7.9 weeks (range = 2.0-32.1). The responses were durable, with a 12-month relapse-free survival rate of 82.2% (95% CI = 62.2-92.2). Adverse events occurred in 54 (98.2%) patients, and 28 (50.9%) patients had treatment-related adverse events. Seventeen (30.9%) patients had adverse events of grade ⩾3. Serious adverse events occurred in 15 (27.3%) patients and three deaths (5.5%) were reported. Conclusion: Hetrombopag showed encouraging efficacy with durable hematologic responses in patients with SAA who were refractory to IST. Hetrombopag was well tolerant and safe for long-term use. ClinicalTrialsgov identifier: NCT03557099.

Safety and efficacy of hetrombopag in patients with chronic immune thrombocytopenia: a single-arm, open-label, multi-center phase 1 study.

Background: Thrombopoietin receptor agonists (TPO-RAs) are promising therapeutic strategy for patients with immune thrombocytopenia (ITP). We conducted this phase 1 trial (NCT02614846) to evaluate the preliminary efficacy and safety of hetrombopag (a TPO-RA) in patients with ITP. Methods: Patients with ITP who had an insufficient response or had progressed on at least one standard treatment for ITP were given hetrombopag orally at an initial dose of 5 mg once daily for up to 6 weeks. The primary endpoint was the proportion of patients who achieved platelet counts of ≥50×109/L at week 6. Results: A total of 37 eligible patients received hetrombopag treatment. This study met its primary endpoint, 22 (59.5%, 95% CI: 42.1-75.3) patients responded to hetrombopag, achieving platelet counts ≥50×109/L at week 6. Of the 29 (78.4%, 95% CI: 61.8-90.2%) patients who responded at least once during the study, the median time from treatment initiation to first response was 2.1 weeks (95% CI: 1.3-4.1 weeks). The median accumulative response duration was 3.1 weeks [interquartile range (IQR), 2.1-4.1 weeks]. The incidence of bleeding was reduced with hetrombopag treatment compared to the baseline. Adverse events (AEs) occurred in 32 (86.5%) patients and treatment-related AEs occurred in 13 (35.1%) patients. Two (5.4%) serious AEs were reported, but neither were treatment related. The dose was modified in one (2.7%) patient due to an AE. There were no incidences of treatment discontinuation/interruption or death. Conclusions: Hetrombopag showed preliminary activity in elevating platelet counts and reducing bleeding in patients with chronic ITP who had received at least one standard therapy. It was well-tolerated.

A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia.

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 × 109/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.

Effect of Food on the Pharmacokinetic and Pharmacodynamic Profiles of Hetrombopag in Healthy Volunteers.

PURPOSE: Hetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers. METHODS: An independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model. FINDINGS: Twelve Chinese healthy volunteers were enrolled. Mean plasma AUC0-t and Cmax decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition. IMPLICATIONS: High-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394.

First-in-patient study of hetrombopag in patients with chronic idiopathic thrombocytopenic purpura.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP). OBJECTIVES: This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients. METHODS: In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks. RESULTS: Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 109 /L on day 28. CONCLUSION: Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag.

Development and validation of a LC-MS/MS method for quantification of hetrombopag for pharmacokinetics study.

Hetrombopag as the derivative of ethylidene hydrazine carboxamide was recently developed into a novel patented non-peptide thrombopoietin mimetic and thrombopoietin receptor agonist to treat idiopathic thrombocytopenic purpura. To study the pharmacokinetics of hetrombopag, a highly sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of hetrombopag in rat plasma. After protein precipitation extraction, the chromatography separation of analyte and internal standard named eltrombopag as an marketed analog of hetrombopag was performed on an Synergi Polar-RP column at the flow rate of 0.5 mL/min, and the determination was conducted on an API4000 triple quadrupole mass spectrometry in the multiple reaction monitoring mode using the respective [M+H](+) ions m/z 459.2 â†’ 200.9 for hetrombopag and m/z 443.2 â†’ 229.0 for IS. The lower limit of quantification was established to be 1 ng/mL, and the linear scope of standard curve was 1-1000 ng/mL. Both the precision (RSD%) and accuracy (RE%) were within the acceptable criterion of below 15 %. The validated method was successfully applied to quantify hetrombopag in the rat plasma and investigate the pharmacokinetics.