Abstract
Background
Hetrombopag has been approved for chronic ITP (duration >12 months). However, its efficacy and safety in persistent ITP (duration 3–12 months) remain unexplored.
Objectives
This post-hoc analysis aimed to evaluate the efficacy and safety of hetrombopag in persistent ITP patients and compare outcomes with chronic ITP and overall ITP patients, based on existing clinical data.
Methods
Data were derived from a registration phase Ⅲ trial (NCT03222843), which included a 10-week randomized, double-blind, placebo-controlled treatment period (initial dose: hetrombopag 2.5 mg as HETROM-2.5 group, hetrombopag 5.0 mg as HETROM-5.0 group, or placebo once daily), a 14-week open-label treatment period, a dose tapering to withdrawal period and a 24-week single-arm extension period. The primary endpoint was the proportion of responders (a platelet count of ≥ 50 × 109/L) after 8 weeks of treatments.
Results
Of 395 who completed the double-blinded treatment, 80 patients had persistent ITP. The proportion of patients with persistent ITP who achieved primary endpoint was 68.8% in the HETROM-2.5 group and 74.3% in the HETROM-5.0 group, significantly higher than 7.7% in the placebo group. Hetrombopag also demonstrated other therapeutic benefits over placebo including reduced bleeding risk and rescue therapy need. Similar efficacy results were observed in both the chronic ITP and the overall ITP population. Furthermore, hetrombopag manifested favorable safety profile in patients with persistent ITP, and safety outcomes were comparable with those in chronic and overall ITP populations.
Conclusion
Hetrombopag showed favorable safe and efficacy profile in patients with persistent ITP, aligning with results observed in patients with chronic ITP and overall ITP.
Keywords: hetrombopag, persistent immune thrombocytopenia, platelet response, thrombopoietin receptor agonist
Essentials
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Evidence of hetrombopag in persistent primary immune thrombocytopenia (ITP) remain limited.
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This post hoc study analyzed data from a phase III trial of hetrombopag in patients with ITP.
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Hetrombopag increased platelet counts, reduced bleeding and rescue therapy in persistent ITP.
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Findings suggest hetrombopag is effective and safe for patients with persistent ITP.
1. Introduction
Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder characterized by isolated thrombocytopenia without identifiable etiologies. Based on the duration, ITP is classified into newly diagnosed ITP (disease duration <3 months), persistent ITP (disease duration, 3-12 months), and chronic ITP (disease duration >12 months). The global incidence of ITP ranges from 2 to 10 per 100,000 individuals, predominantly affecting individuals aged >60 years, with a slightly higher incidence among women of reproductive age compared with men of the same age group [1]. Clinical manifestations vary widely, ranging from asymptomatic thrombocytopenia to skin and mucosal bleeding, severe gastrointestinal hemorrhage, or even life-threatening intracranial hemorrhage. A population-based study revealed that adult patients with ITP have significantly higher mortality rates due to bleeding, infections, and cardiovascular events than the general population, with the considerable negative impact on the quality of life [2,3].
The primary therapeutic goal for ITP is to elevate platelet counts to a safe level, reduce bleeding events, and improve health-related quality of life, all while minimizing treatment-related adverse effects. Currently, first-line treatments include corticosteroids (dexamethasone or prednisone) and intravenous immunoglobulin. Nonetheless, the number of patients who truly benefit from these 2 types of treatments is limited owing to the intolerance to adverse effects and the inability to achieve sustained remission [1,4,5]. For second-line therapies, recommendations involve thrombopoietin receptor agonists (TPO-RAs), recombinant human TPO, rituximab, and splenectomy. TPO-RAs, by binding to the transmembrane domain of the TPO receptor, stimulate the proliferation and differentiation of megakaryocytes, thereby enhancing platelet production. With rapid onset (1-2 weeks), higher sustained response rates than other second-line treatments and favorable safety profiles, TPO-RAs such as romiplostim and eltrombopag are endorsed as the preferred second-line treatments recommended by major clinical guidelines [4,6].
Hetrombopag is a novel oral, small-molecule, nonpeptide TPO-RA approved in China for the treatment of chronic ITP. The first-in-human trial (NCT02403440) demonstrated that hetrombopag (2.5-7.5 mg daily) increased platelet counts in a dose-dependent manner with an acceptable safety profile in patients with chronic ITP [7]. A subsequent randomized, double-blind, placebo-controlled, multicenter phase Ⅲ trial (NCT03222843) further evaluated its efficacy. After 8 weeks of treatment, the proportion of patients achieving the primary endpoint, platelet count of ≥ 50 × 109/L, was markedly higher in the hetrombopag 2.5-mg (HETROM-2.5) and 5.0-mg (HETROM-5.0) groups than that in the placebo group, with response rates of 58.9% and 64.3% vs 5.9%, respectively (all P < .0001). Hetrombopag also displayed superiority in reducing bleeding risk and rescue treatment use. Common adverse events included upper respiratory tract infections, urinary tract infections, immune thrombocytopenic purpura, and hematuria, indicating the overall manageable safety profile [8].
Although robust clinical data support the approval of hetrombopag for chronic ITP, evidence regarding its efficacy and safety in other subtypes, such as persistent ITP, remains constrained. Globally, only eltrombopag and romiplostim have been approved for the treatment of persistent ITP, and even these approvals were primarily based on retrospective data, with limited prospective evidence specifically addressing the persistent ITP population. Meanwhile, clinical guidelines offer few detailed recommendations for this phase of disease, and treatment decisions are often empirical. As a result, patients with persistent ITP, who may exhibit different disease dynamics and treatment responses, remain underserved, highlighting an area of unmet therapeutic need. Considering these challenges, it is crucial to explore the potential value of hetrombopag in this particular subgroup. In the aforementioned phase Ⅲ trial (NCT03222843), patients with persistent ITP were included as part of the study population, but their outcomes were not separately analyzed. To address this gap, the current study conducted a post hoc analysis of existing clinical data to evaluate the efficacy and safety of hetrombopag in patients with persistent ITP. Furthermore, comparisons were drawn with results in patients with chronic ITP and the overall study population, aiming to offer further insights into the therapeutic potential of hetrombopag for this underserved subgroup.
2. Methods
2.1. Study design and patients
Data of this post hoc analysis were derived from a randomized, double-blind, placebo-controlled, multicenter phase Ⅲ clinical trial (NCT03222843) that investigate the efficacy and safety of hetrombopag in adult patients with ITP [8]. Eligible patients included those diagnosed with primary ITP for at least 6 months prior to randomization and a platelet count of < 30 × 109/L within 48 hours before receiving the first dose of the treatment. The trial consisted of 4 periods: a 10-week randomized, double-blind, placebo-controlled treatment period (8 weeks of treatment followed by 2 weeks for data cleaning), during which patients were assigned to receive hetrombopag with an initial dose of either 2.5-mg (HETROM-2.5) or 5.0-mg (HETROM-5.0) or placebo, administered orally once daily under fasting condition; a 14-week open-label treatment period for patients who did not meet withdrawal criteria after the first period; a dose tapering to withdrawal period lasting up to 6 weeks; and a 24-week single-arm extension period to assess the long-term safety and efficacy of hetrombopag. The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines, with ethics committee approvals obtained at all participating centers. Written informed consent was provided by all patients before any study-related procedures.
In this post hoc analysis, patients with persistent ITP were those who had a disease duration of at least 6 months but <1 year, as determined by the eligibility criteria of the original phase Ⅲ clinical trial mentioned earlier. The primary objective was to assess the efficacy of 8-week hetrombopag treatment in patients with persistent ITP and compare the results with those in chronic ITP and the overall ITP population of the original trial. Secondary objectives included exploring the therapeutic performance of hetrombopag during the double-blind period (10 weeks) in the persistent ITP subgroup and its safety profile during the first 24 weeks of treatment (the double-blind and the open-label periods) while further examining the consistency of findings with those observed in patients with chronic ITP and the overall ITP population.
2.2. Assessments and outcomes
Efficacy was assessed by monitoring platelet counts at different intervals: weekly during the double-blind period, every 2 weeks during the open-label period, and every 4 weeks during the extension period. Response to treatment was defined as a platelet count of ≥ 50 × 109/L. The primary efficacy endpoint was the proportion of responders after 8 weeks of treatments during the double-blind period. Secondary efficacy endpoints, all assessed during the double-blinded period, included the proportion of responders after 3, 4, 5, 6, 7, and 8 weeks of treatment, the proportion of patients who responded at least once, the proportion of patients who achieved a platelet count of ≥ 30 × 109/L at least once with 2-fold increase from baseline, the time since the first dose to first response, the proportion of patients who responded for ≥75% of the assessments, the proportion of patients requiring rescue therapy (defined as either platelet transfusion or intravenous immunoglobulin at the discretion of the investigators based on the clinical assessment), the incidence and severity of bleeding symptoms assessed using the World Health Organization (WHO) bleeding scores, and the maximum continuous duration of response.
Adverse events (AEs) were tracked constantly throughout the study. Comprehensive clinical assessments including laboratory evaluations, physical examinations, electrocardiograms, ophthalmologic assessments, and bone marrow biopsies were conducted and recorded at all scheduled visits during the double-blinded treatment period and open-label treatment period. AEs of special interest are potential drug-induced liver injury. All AEs were coded to preferred terms of the Medical Dictionary of Regulatory Activities (MedDRA, v22.0).
2.3. Statistical analyses
The full-analysis set comprised all randomized patients who received at least 1 dose of the study treatment and had at least 1 assessment of the platelet count after randomization. The safety analysis set included all patients who received at least 1 dose of the study treatment.
Efficacy endpoints were analyzed based on full-analysis set. The primary efficacy endpoint of HETROM-2.5 or HETROM-5.0 was compared with that of placebo group using a logistic regression model to adjust baseline platelet count, as predefined in the original phase III trial protocol to address key prognostic imbalance. No further covariates were adjusted for. A noncompleter considered failure imputation was applied for patients who withdrew early from the study or patients with missing platelet count values at scheduled visits. The odds ratio (OR) and 95% CIs were provided. Logistic regression model was also applied in the analysis of secondary endpoints such as the comparation of the proportion of patients who responded at least once, the proportion of patients who achieved platelet count ≥ 30 × 109/L at least once with 2-fold increase from baseline, the proportion of patients who responded for ≥75% of the assessments. The proportions of responders after 3, 4, 5, 6, 7, and 8 weeks of treatment in the first period were compared between HETROM-2.5 or HETROM-5.0 group and placebo group via conducting a repeated measures model for binary data with time, treatment, and treatment-by-time interaction as fixed effects and platelet count as a covariate. The generalized estimating equation with the compound symmetry correlation structure was used to estimate the regression model parameters, and corresponding OR and 95% CI were calculated. Kaplan–Meier method was carried out to estimate the time since the first dose to first response. The proportion of patients requiring rescue therapy and the incidence of bleeding symptoms were compared via Fisher exact test. The 95% CIs for the proportion of patients with a response in each group were computed by the Clopper–Pearson method if applicable. Given the exploratory nature of this post hoc analysis, no formal adjustment for multiple comparisons was performed. P values for subgroup analyses and secondary endpoints are presented descriptively. All statistical analyses were executed with SAS software (SAS; version 9.4).
3. Results
3.1. Patients
A total of 578 patients were screened for the study, of whom 424 were eligible and randomized. Among these qualified participants, 80 were patients with persistent ITP (18.9%): 32 in the HETROM-2.5 group (40.0%), 35 in the HETROM-5.0 group (43.75%), and 13 in the placebo group (16.25%). In the open-label treatment period, 338 patients completed the study, including 64 with persistent ITP, of whom 54 were in the hetrombopag group and 10 in the eltrombopag group (Figure 1).
Figure 1.
Patient flowchart. HETROM-2.5, the dose was titrated from an initial dosage of once daily 2.5-mg hetrombopag; HETROM-5.0, the dose was titrated from an initial dosage of once daily 5-mg hetrombopag; ITP, immune thrombocytopenia.
As shown in Table 1, key baseline characteristics, such as demographics, baseline platelet counts, prior splenectomy, and concomitant ITP medication at baseline, were generally balanced among persistent ITP, chronic ITP, and overall ITP population. The median age of patients with persistent ITP in the placebo group was 53.0 years (range, 21-67 years), numerically higher compared with those in the HETROM-2.5 group (37.0 years; range, 19-67 years) and in the HETROM-5.0 group (44.0 years; range, 18-74 years). This difference may be attributed to the relatively small sample size of the placebo arm (n = 13). Meanwhile, the median ages across the placebo, HETROM-2.5, and HETROM-5.0 groups were comparable among patient with chronic ITP or the overall ITP. Besides, female participants were predominant across all 3 types of populations. Median baseline platelet counts in the patient with persistent ITP were 16.7 × 109/L (range, 5.0-28.0 × 109/L) in the placebo group, 10.00 × 109/L (range, 1.0-27.0 × 109/L) in the HETROM-2.5 group, and 15.00 × 109/L (range, 2.0-28.0 × 109/L) in the HETROM-5.0 group, basically aligning with the baseline platelet levels of the chronic ITP and overall ITP population. All participants with persistent ITP had undergone prior first-line treatment or splenectomy, consistent with patients with chronic or overall ITP. It is worth noting that splenectomy was more frequent in treating chronic ITP than in treating the persistent ITP. Moreover, a substantial proportion of patients, whether with persistent or chronic ITP, were receiving concomitant ITP medication.
Table 1.
Baseline characteristics.
| Characteristic | Persistent ITP |
Chronic ITP |
Overall ITP |
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|---|---|---|---|---|---|---|---|---|---|
| Placebo (n = 13) | HETROM-2.5 (n = 32) | HETROM-5.0 (n = 35) | Placebo (n = 72) | HETROM-2.5 (n = 136) | HETROM-5.0 (n = 136) | Placebo (n = 85) | HETROM-2.5 (n = 168) | HETROM-5.0 (n = 171) | |
| Age (y) | 53.0 (21-67) | 37.0 (19-67) | 44.0 (18-74) | 42.0 (18-71) | 38.0 (19-70) | 40.0 (18-70) | 42.0 (18-71) | 38.0 (19-70) | 41.0 (18-74) |
| Height (cm) | 160.00 (152.0-170.0) | 162.00 (149.0-174.6) | 160.00 (150.0-178.0) | 162.50 (150.0-185.5) | 163.00 (147.0-182.0) | 162.00 (147.0-182.0) | 162.00 (150.0-185.5) | 162.50 (147.0-182.0) | 161.00 (147.0-182.0) |
| Weight (kg) | 61.00 (54.0-71.0) | 62.00 (46.0-85.0) | 61.70 (43.5-95.9) | 63.00 (44.5-88.0) | 61.00 (39.0-115.0) | 63.00 (44.7-110.0) | 63.00 (44.5-88.0) | 61.00 (39.0-115.0) | 62.50 (43.5-110.0) |
| BMI (kg/m2) | 23.530 (21.19-28.57) | 23.317 (19.15-34.48) | 24.112 (18.11-30.27) | 23.673 (17.99-30.49) | 23.437 (16.88-37.55) | 24.403 (17.31-35.86) | 23.634 (17.99-30.49) | 23.437 (16.88-37.55) | 24.369 (17.31-35.86) |
| Female | 9 (69.2) | 23 (71.9) | 22 (62.9) | 51 (70.8) | 99 (72.8) | 97 (71.3) | 60 (70.6) | 122 (72.6) | 119 (69.6) |
| Baseline platelet count (×109/L) | 16.70 (5.0-28.0) | 10.00 (1.0-27.0) | 15.00 (2.0-28.0) | 12.25 (1.0-29.0) | 13.50 (1.0-29.0) | 13.00 (2.0-29.0) | 13.00 (1.0-29.0) | 13.00 (1.0-29.0) | 13.00 (2.0-29.0) |
| Prior first-line therapy or splenectomy | 13 (100.0) | 32 (100.0) | 35 (100.0) | 72 (100.0) | 136 (100.0) | 136 (100.0) | 85 (100.0) | 168 (100.0) | 171 (100.0) |
| Splenectomy | 0 | 0 | 1 (2.9) | 4 (5.6) | 14 (10.3) | 14 (10.3) | 4 (4.7) | 14 (8.3) | 15 (8.8) |
| Bleeding (WHO bleeding scale grade 1-4) | 7 (53.8) | 26 (81.3) | 16 (45.7) | 46 (63.9) | 82 (60.3) | 77 (56.6) | 52 (61.2) | 108 (64.3) | 93 (54.4) |
| Concomitant ITP medication | 12 (92.3) | 32 (100.0) | 34 (97.1) | 71 (98.6) | 135 (99.3) | 133 (97.8) | 83 (97.6) | 168 (100.0) | 168 (98.2) |
Values are median (range) or n (%).
BMI, body mass index; HETROM-2.5, starting dose of 2.5 mg hetrombopag once daily; HETROM-5.0, starting dose of 5.0 mg hetrombopag once daily; ITP, immune thrombocytopenia; WHO, World Health Organization.
3.2. Primary efficacy outcome
Among the persistent ITP participants, the proportion of patients who responded (defined as a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment was 68.8% (22/32) in the HETROM-2.5 group and 74.3% (26/35) in the HETROM-5.0 group, significantly higher than in the placebo group (7.7% [1/13]; HETROM-2.5 vs placebo: OR, 63.89; 95% CI, 5.78-705.95; HETROM-5 vs placebo: OR, 55.42; 95% CI, 5.50-558.01; all P < .0001) (Table 2), indicating that higher doses may be associated with better efficacy. Similar outcomes were observed in both the chronic ITP and the overall population. The proportion of responders after 8 weeks of treatment were 5.6%, 56.6%, and 61.8% in the chronic ITP subgroup and 5.9%, 58.9%, and 64.3% in the overall population for the placebo, HETROM-2.5, and HETROM-5.0 groups, respectively. Forest plot (Figure 2) shown that the efficacy benefit of hetrombopag to patients with persistent ITP was comparable with that observed to chronic ITP or the overall population, illustrating the stable and predictable efficacy across different disease stages of ITP.
Table 2.
Primary endpoint within 8 wk in patients with persistent immune thrombocytopenia.
| Group | n (%) | Hetrombopag vs placebo |
||
|---|---|---|---|---|
| Intergroup difference (95% CI) | OR (95% CI) | 2-sided P | ||
| Placebo (n = 13) | 1 (7.7) | — | — | — |
| HETROM-2.5 (n = 32) | 22 (68.8) | 61.06 (39.43-82.68) | 63.89 (5.78-705.95) | .0007 |
| HETROM-5.0 (n = 35) | 26 (74.3) | 66.59 (46.11-87.07) | 55.42 (5.50-558.01) | .0007 |
HETROM-2.5, dosage titrated from an initial dose of once daily 2.5 mg hetrombopag; HETROM-5.0, dosage titrated from an initial dose of once daily 5.0 mg hetrombopag; OR, odd ratio.
Figure 2.
Forest plot of the primary endpoint in patients with persistent ITP, chronic ITP, and overall ITP within 8 weeks. HETROM-2.5 and HETROM-5.0 refer to patients who received initial doses of 2.5 mg and 5.0 mg hetrombopag once daily, respectively; ITP, immune thrombocytopenia.
3.3. Secondary efficacy outcomes
Other secondary efficacy endpoints yielded consistent results across the persistent, chronic, and overall ITP population as well. Patients with persistent ITP in HETROM-2.5 or HETROM-5.0 group exhibited significantly higher proportion of response after 3, 4, 5, 6, 7, and 8 weeks of treatment than those in placebo group (Supplementary Table 1). Furthermore, the proportion of patients who responded at least once, the proportion of patients who achieved platelet count ≥ 30 × 109/L at least once with 2-fold increase from baseline and the proportion of patients who responded for ≥75% of the assessments in HETROM-2.5 or HETROM-5.0 group were all notably greater than those in placebo group. These findings were uniformly validated in the chronic and overall ITP population (Table 3). Forest plots further confirmed similar therapeutic outcomes among the persistent, chronic, and overall ITP population (Supplementary Figures 1-9).
Table 3.
Secondary endpoints within 8 week of treatment.
| Secondary endpoints | Persistent ITP |
Chronic ITP |
Overall ITP |
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|---|---|---|---|---|---|---|---|---|---|
| Placebo | HETROM-2.5 | HETROM-5.0 | Placebo | HETROM-2.5 | HETROM-5.0 | Placebo | HETROM-2.5 | HETROM-5.0 | |
| Proportion of patients who responded at least once | |||||||||
| % (n) | 38.55 (5/13) | 93.8 (30/32) | 91.4 (32/35) | 19.4 (14/72) | 82.4 (112/136) | 85.3 (116/136) | 22.4 (19/85) | 84.5 (142/168) | 86.5 (148/171) |
| OR (95% CI) | — | 30.13 (4.25-213.33) | 18.39 (3.48-97.17) | — | 24.00 (10.77-53.48) | 31.95 (14.01-72.87) | — | 24.11 (11.76-49.60) | 27.83 (13.49-57.40) |
| Intergroup difference (95% CI) | — | 55.29 (27.54-83.03) | 52.97 (24.94-80.99) | — | 62.91 (51.75-74.07) | 65.85 (54.94-76.76) | — | 62.17 (51.76-72.58) | 64.20 (53.97-74.42) |
| Two-sided P | — | .0006 | .0006 | — | <.0001 | <.0001 | — | <.0001 | <.0001 |
| Proportion of patients achieving platelet counts of ≥30 × 109/L at least once with 2-fold increase from baseline | |||||||||
| % (n) | 38.5 (5/13) | 93.8 (30/32) | 94.3 (33/35) | 26.4 (19/72) | 86.0 (117/136) | 89.7 (122/136) | 28.2 (24/85) | 87.5 (147/168) | 90.6 (155/171) |
| OR (95% CI) | — | 21.29 (3.36-134.95) | 26.40 (4.28-162.96) | — | 17.61 (8.57-36.21) | 24.60 (11.46-52.84) | — | 18.01 (9.31-34.85) | 24.93 (12.37-50.24) |
| Intergroup difference (95% CI) | — | 55.29 (27.54-83.03) | 55.82 (28.28-83.37) | — | 59.64 (47.91-71.37) | 63.32 (51.93-74.71) | — | 59.26 (48.47-70.06) | 62.41 (51.89-72.89) |
| Two-sided P | — | .0012 | .0004 | — | <.0001 | <.0001 | — | <.0001 | <.0001 |
| Proportion of patients who responded for ≥75% of the assessments | |||||||||
| % (n) | 7.7 (1/13) | 31.3 (10/32) | 60.0 (21/35) | 1.4 (1/72) | 33.1 (45/136) | 56.6 (77/136) | 2.4 (2/85) | 32.7 (55/168) | 57.3 (98/171) |
| OR (95% CI) | — | 13.63 (1.30-143.04) | 33.56 (3.32-338.83) | — | 38.00 (5.03-286.86) | 125.84 (16.55-956.98) | — | 24.63 (5.71-106.21) | 79.65 (18.36-345.53) |
| Intergroup difference (95% CI) | — | 23.56 (1.93-45.18) | 52.31 (30.55-74.06) | — | 31.70 (23.34-40.06) | 55.23 (46.47-63.99) | — | 30.39 (22.59. 38.18) | 54.96 (46.87-63.04) |
| Two-sided P | — | .0294 | .0029 | — | .0004 | <.0001 | — | <.0001 | <.0001 |
| Proportion of patients requiring rescue therapy | |||||||||
| % (n) | 30.8 (4/13) | 12.5 (4/32) | 8.6 (3/35) | 38.9 (28/72) | 13.2 (18/136) | 11.0 (15/136) | 37.6 (32/85) | 13.1 (22/168) | 10.5 (18/171) |
| 95% CI | 9.1-16.4 | 3.5-29.0 | 1.8-23.1 | 27.6-51.1 | 8.0-20.1 | 6.3-17.5 | 27.4-48.8 | 8.4-19.2 | 6.4-16.1 |
| Bleeding (WHO bleeding scale > 0) | |||||||||
| % (n) | 69.2 (9/13) | 65.6 (21/32) | 45.7 (16/35) | 80.6 (58/72) | 63.7 (86/136) | 58.8 (80/136) | 78.8 (67/85) | 64.1 (107/168) | 56.1 (96/171) |
| 95% CI | 38.6-90.9 | 46.8-81.4 | 28.8-63.4 | 69.5-88.9 | 55.0-71.8 | 50.1-67.2 | 68.6-86.9 | 56.3-71.3 | 48.4-63.7 |
| Maximum continuous duration of response (d) | |||||||||
| n | 1 | 26 | 31 | 5 | 99 | 107 | 6 | 125 | 138 |
| Median (minimum-maximum) | 36.0 (36-36) | 17.0 (6-43) | 22.0 (7-52) | 8 (7-42) | 22 (8-53) | 22 (6-54) | 8.5 (7-42) | 22 (6-53) | 22 (6-54) |
HETROM-2.5, dosage titrated from an initial dose of once daily 2.5-mg hetrombopag; HETROM-5.0, dosage titrated from an initial dose of once daily 5-mg hetrombopag; ITP, immune thrombocytopenia; OR, odd ratio; WHO, World Health Organization.
The median time since the first dose to first response in the patients with persistent ITP was 8 days in HETROM-5.0 group, shorter than 21 days in HETROM-2.5 group. Similarly, in the chronic and overall ITP population, the HETROM-5.0 group achieved 14 days, while the HETROM-2.5 group required 21 days (Figure 3).
Figure 3.
Time since the first dose to first response (platelet count of ≥ 50 × 109/L) in patients with persistent, chronic, and overall ITP during the 8-week double-blind treatment period. HETROM-2.5 and HETROM-5.0 refer to patients who received initial doses of 2.5 mg and 5.0 mg hetrombopag once daily, respectively; ITP, immune thrombocytopenia.
Regarding patients with persistent ITP who required rescue therapy, 4 (12.5%) in HETROM-2.5 group and 3 (8.6%) in HETROM-5.0 group received protocol-defined rescue therapy within 8 weeks, lower than that of placebo group (30.8%). Similar proportions were observed in chronic and overall ITP population as well (Table 3). In patients with persistent ITP, fewer, in both HETROM-2.5 group (65.6%) and HETROM-5.0 group (45.7%), had bleeding symptoms (WHO bleeding grades 1-4) compared with placebo group (69.2%) within 8 weeks of treatments (Supplementary Table 2). Comparable outcomes were obtained in chronic and overall ITP population (Table 3). These findings illustrated the aligned efficacy of hetrombopag in lowering bleeding risk and minimizing the demand for rescue therapy.
Additionally, the median maximum continuous duration of response in patients with persistent ITP were 36, 17, and 22 days in placebo group, HETROM-2.5 group, and HETROM-5.0 group, respectively. What is worth noting is that there was only 1 patient of 13 patients in placebo group who achieved response, which is not statistically significant. In the chronic and overall ITP population, the median maximum continuous duration of response was 22 days in both HETROM-2.5 group and HETROM-5.0 group, longer than that in placebo group (8 and 8.5 days in chronic ITP and overall population, respectively) (Table 3), hinting the concordance of hetromopag’s capacity to maintain platelet elevation across persistent, chronic, and overall ITP populations.
3.4. Adverse events
During the 24-week treatment encompassing the double-blinded and open-label periods, 67 patients (100%) in the persistent ITP group, 265 patients (97.4%) in the chronic ITP group, and 332 patients (97.9%) in the overall population experienced at least 1 treatment-emergent AE. The incidence of treatment-related adverse events (TRAEs) was 62.7%, 50.7%, and 53.1% in the persistent, chronic, and all ITP population, respectively. Common TRAEs included increased platelet counts (persistent ITP, 7.5%; chronic ITP, 11.8%; overall, 10.9%), increased blood lactate dehydrogenase levels (10.4%; 7.7%; and 8.3%, respectively), elevated alanine aminotransferase (9.0%; 7.7%; and 8.0%, respectively), and increased aspartate aminotransferase (9.0%; 6.6%; and 7.1%, respectively). Details of TRAEs with an incidence of ≥5% were provided in Table 4 and Supplementary Table 3.
Table 4.
Treatment-related adverse events of any severity occurring at least 5% of patients.
| TRAEs | Persistent ITP, hetrombopag (n = 67) | Chronic ITP, hetrombopag (n = 272) | Overall ITP, hetrombopag (n = 339) |
|---|---|---|---|
| Any TRAE | 28 (41.8) | 82 (30.1) | 102 (30.1) |
| Platelet count increased | 5 (7.5) | 32 (11.8) | 37 (10.9) |
| Blood lactate dehydrogenase increased | 7 (10.4) | 21 (7.7) | 28 (8.3) |
| ALT increased | 6 (9.0) | 21 (7.7) | 27 (8.0) |
| AST increased | 6 (9.0) | 18 (6.6) | 24 (7.1) |
| Blood bilirubin increased | 5 (7.5) | ||
| Hepatic function abnormal | 5 (7.5) | ||
| Hyperuricemia | 4 (6.0) |
Values are n (%).
Blank cells indicate that the incidence of the corresponding TRAE was <5% in that subgroup.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ITP, immune thrombocytopenia; TRAE, treatment-related adverse events.
Serious AEs were reported in 12 patients (17.9%) in the persistent ITP group, 37 patients (13.6%) in the chronic ITP group, and 49 patients (14.5%) in the overall population. Among these, only 1 serious AE case (acute myocardial infarction) was deemed treatment-related, occurring in the chronic ITP population within 2 weeks after the first dose.
One death was reported in persistent ITP participants caused by infectious pneumonia and hypoxia. Two deaths occurred in patients with chronic ITP: one was due to pneumonia and the other was led by gastrointestinal hemorrhage and hemorrhagic shock. All deaths were determined to be unrelated to the treatment.
Treatment discontinuation attributed to AEs occurred in 3 patients (4.5%) in the persistent ITP group, 8 patients (2.9%) in the chronic ITP group, and 11 patients (3.2%) in the overall population. Additionally, 9 patients (13.4%) in the persistent ITP group, 38 patients (14.0%) in the chronic ITP group, and 47 patients (13.9%) in the overall group had their treatment paused or doses reduced due to AEs.
Most reported AEs were of mild to moderate severity. AEs of special interest were reported in 1 patient from the persistent ITP group and 1 from the chronic ITP group during the open-label treatment period.
5. Discussion
Patients with ITP are classified as persistent subtype when the duration lasts 3-12 months without spontaneous remission and maintenance of complete remission after discontinuing treatment. Compared with chronic ITP, persistent ITP has shorter disease course, and immune dysfunction in some patients has not yet fully stabilized, leaving a potential for spontaneous remission, which is particularly true for those with recent diagnosis (3-6 months), mild bleeding symptoms (platelet count ≥ 30 × 109/L), and no comorbid autoimmune diseases (eg, systemic lupus erythematosus) [9]. However, as the disease progresses, patients with persistently low platelet counts (< 10-20 × 109/L), severe or recurrent bleeding, and treatment dependence, such as relapsing immediately after stopping corticosteroids or intravenous immunoglobulin, exhibit increased disease activity and more stable immune destruction mechanism [10]. Without timely intervention at this stage, the risk of severe bleeding may increase, and the optimal therapeutic window could be missed, ultimately resulting in progression to chronic ITP. Therefore, early identification of high-risk features and individualized interventions are crucial to breaking the cycle of disease activity and preventing progression to chronicity.
Given the instability of disease progression and immune function, treatment strategies for persistent ITP remain challenging. First-line therapies such as corticosteroids and immunoglobulins are effective for acute episodes such as intracranial hemorrhage but are often insufficient in terms of long-term efficacy and safety. Since the pathological characteristics of chronic ITP are more clearly defined than those of persistent ITP, research on second-line therapies, particularly TPO-RAs, has largely focused on chronic ITP. Consequently, studies on the safety and efficacy of TPO-RAs in persistent ITP are not abundant. Although no prospective, randomized, placebo-controlled trials have exclusively targeted patients with persistent ITP, these individuals have been included as part of broader clinical studies including the phase Ⅲ registration trial (NCT03222843) of hetrombopag [11], which serves as the data source for this post hoc analysis. This analysis further evaluated the safety and efficacy of hetrombopag in patients with persistent ITP and compared the findings with those in chronic ITP and the overall ITP population. Results indicated that hetrombopag significantly improved and sustained platelet levels in patients with persistent ITP compared with the placebo group, with benefits comparable with those observed in chronic ITP and the overall population. While no formal statistical comparison was performed between persistent and chronic ITP subgroups, the proportion of responders after 8 weeks of treatments during the double-blinded period appeared numerically higher in patients with persistent ITP. This observation may suggest a potential clinical benefit associated with earlier initiation of hetrombopag, although further validation is warranted. Although clinical guidelines on the initiation timing of TPO-RA are confined, existing evidence supports that greater therapeutic outcomes could be obtained when TPO-RAs are introduced early (within 3 months after first-line treatment failure) [4]. Meanwhile, this analysis confirmed that hetrombopag manifested the comparable safety characteristics in patients with persistent ITP with those in chronic and overall ITP populations, with no new safety signals identified during the 24-week treatment (double-blinded and open-label period). Most AEs were manageable, highlighting that hetrombopag not only achieved rapid platelet response but also demonstrated a favorable safety profile, providing additional support for its clinical application in patients with persistent ITP.
Eltrombopag, the first oral TPO-RA approved globally, was initially indicated for patients with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. In 2021, its indications were expanded to persistent ITP. Clinical studies have provided some insights: Study 773B included 60 patients with documented since diagnosis, of whom approximately 17% met the definition of persistent ITP (3-12 months postdiagnosis). Study 773A included 51 such patients, with 14% meeting this definition. In the RAISE (RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag) trial (NCT00370331), of 145 patients with documented since diagnosis, 19% classified as persistent ITP. However, none of these studies separately analyzed safety and efficacy in this subgroup. A retrospective study involving 220 patients with ITP, including 30 with persistent ITP, reported no significant difference in treatment response (defined as platelet count ≥ 30 × 109/L at least once with 2-fold increase from baseline) proportions between persistent and chronic ITP patients after a 15-month follow-up (83.3% vs 79.4%). The incidence of AEs and the types of common AEs such as headache, liver function abnormalities, and upper respiratory infections were also similar between the groups, suggesting eltrombopag was equally safe and effective for both [12]. In this post hoc analysis, the proportions of patients who achieved a platelet count of ≥ 30 × 109/L at least once with 2-fold increase from baseline, one of the secondary endpoints, were 93.8% and 94.3% in HETROM-2.5 group and HETROM-5.0 group in patients with persistent ITP, respectively, merely within 8 weeks of treatment. These findings may suggest a rapid response with hetrombopag in the short term. Nevertheless, it is important to stress that these comparisons are based on indirect, cross-trial observations. Given the differences in study designs, follow-up durations, baseline characteristics of participants, and assessment criteria, such comparisons should be interpreted with caution and are not intended to imply superiority.
This post hoc analysis provided preliminary evidence supporting the application of hetrombopag in patients with persistent ITP; however, several limitations inherent to post hoc analyses must be considered. First, the post hoc design and small sample size of patients with persistent ITP (n = 80) may reduce statistical power and generalizability. Second, the analysis only assessed treatment over a short duration, precluding the exploration of long-term therapeutic efficiency and safety including durability of response and cumulative risks. Third, the logistic regression approach did not adjust for potential confounders beyond platelet counts (eg, age and prior treatments), which may limit causal interpretation of treatment effect. Additionally, we acknowledged that the original trial only enrolled patients with a disease duration of ≥6 months; therefore, outcomes from patients with 3-5 months of persistent ITP were not available in this analysis, which may limit the applicability of our findings to the full spectrum of the persistent ITP population. The absence of multiplicity correction also increases the risk of false-positive findings; consequently, the efficacy and safety outcomes reported in this study must be viewed as exploratory and hypothesis generating, requiring validation in future prospective studies.
5. Conclusion
This post hoc analysis, on the basis of outcomes from the phase Ⅲ registrational study of hetrombopag (NCT03222843), evaluated and analyzed the efficacy and safety of hetrombopag in patients with persistent ITP, chronic ITP, and the overall ITP population. The findings preliminarily proved that hetrombopag effectively increased and sustained platelet levels in patients with persistent ITP, with benefits comparable with those observed in chronic and overall ITP populations. Moreover, hetrombopag exhibited a reassuring safety profile, underscoring its potential advantage in managing persistent ITP. Prospective, randomized, controlled trials focusing specifically on patients with persistent ITP, along with real-world data, are needed to thoroughly assess the long-term efficacy, safety, and treatment response patterns across different patient subgroups, thereby providing a stronger guidance for clinical practice.
Acknowledgments
We thank all patients who participated in this study and their families. We also thank Du Wang (Jiangsu Hengrui Pharmaceuticals Co, Ltd) for her statistical support and Shanshan Liu and Jie Shi (Jiangsu Hengrui Pharmaceuticals Co, Ltd) for medical writing assistance.
Funding
The work was supported by Jiangsu Hengrui Pharmaceuticals Co, Ltd.
Author contributions
Y.H., R.Y., and T.N. designed the study. H.M., X.L., Y.L., H.Z., Y.H., R.Y., T.N., Y.F., G.G., P.C., R.H., L.Y., J.H., M.H., Y.Y., L.L., Y.W., D.W., X.S., J.J., J.L., Y.Z., X.Z., R.X., Z.J., Y.B., and L.W. conducted the study including patient treatment and data collection. H.M. analyzed the data and wrote the manuscript with support from the sponsor. All authors critically reviewed the manuscript, participated in the data interpretation, and approved the content.
Relationship Disclosure
LW is an employee from Jiangsu Hengrui Pharmaceuticals Co, Ltd. All other coauthors declare no competing interests.
Footnotes
Handling editor: John Semple
Heng Mei, Xiaofan Liu, Yan Li, and Hu Zhou contributed equally to this work.
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2025.103205
Contributor Information
Ting Niu, Email: tingniu@sina.com.
Renchi Yang, Email: rcyang65@163.com.
Yu Hu, Email: dr_huyu@126.com.
Supplementary material
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