Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05.

Mechanism of action
TPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is the endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the human TPO-R and initiates signalling cascades similar but not identical to that of endogenous thrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells.

Clinical efficacy and safety

Immune (primary) thrombocytopenia (ITP) studies
Two phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and TRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) evaluated the safety and efficacy of eltrombopag in adult patients with previously treated ITP.
Overall, eltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least 1 year. The single-arm phase II study TAPER (CETB115J2411) evaluated the safety and efficacy of eltrombopag and its ability to induce sustained response after treatment discontinuation in 105 adult ITP patients who relapsed or failed to respond to first-line corticosteroid treatment.

Double-blind placebo-controlled studies
RAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and randomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline and baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment period based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg.
From Day 29 to the end of treatment, 15 to 28% of eltrombopag-treated patients were maintained on ≤25 mg and 29 to 53% received 75 mg.

In addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments as dictated by local standard of care. More than half of all patients in each treatment group had ≥3 prior ITP therapies and 36% had a prior splenectomy.

Median platelet counts at baseline were 16 000/µl for both treatment groups and in the eltrombopag group were maintained above 50 000/µl at all on-therapy visits starting at Day 15; in contrast, median platelet counts in the placebo group remained <30 000/µl throughout the study.

Platelet count response between 50 000-400 000/µl in the absence of rescue treatment was achieved by significantly more patients in the eltrombopag treated group during the 6 month treatment period, p <0.001. Fifty-four percent of the eltrombopag-treated patients and 13 % of placebo-treated patients achieved this level of response after 6 weeks of treatment. A similar platelet response was maintained throughout the study, with 52 % and 16 % of patients responding at the end of the 6-month treatment period.

Table 9             Secondary efficacy results from RAISE

Eltrombopag             Placebo
N = 135               N = 62
Key secondary endpoints
Number of cumulative weeks with platelet counts                ≥ 50 11.3 (9.46)           2.4 (5.95)
000-400 000/µl, Mean (SD)
Patients with ≥ 75 % of assessments in the target range (50 000 to
51 (38)               4 (7)
400 000/µl), n (%) p-value a                                                                                   < 0.001 Patients with bleeding (WHO Grades 1-4) at any time during 6
106 (79)             56 (93) months, n (%) p-value a                                                                                    0.012 Patients with bleeding (WHO Grades 2-4) at any time during 6                           44 (33)              32 (53) months, n (%) p-value a                                                                                    0.002 Requiring rescue therapy, n (%)                                                        24 (18)              25 (40) p-value a                                                                                    0.001 Patients receiving ITP therapy at baseline (n)                                            63                   31 Patients who attempted to reduce or discontinue baseline therapy, n (%)b                                                                    37 (59)              10 (32) p-value a                                                                                  0.016 a     Logistic regression model adjusted for randomisation stratification variables b     21 out of 63 (33 %) patients treated with eltrombopag who were taking an ITP medicinal product at baseline permanently discontinued all baseline ITP medicinal products.

At baseline, more than 70 % of ITP patients in each treatment group reported any bleeding (WHO Grades 1-4) and more than 20 % reported clinically significant bleeding (WHO Grades 2-4), respectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and clinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50 % from Day 15 to the end of treatment throughout the 6-month treatment period.

TRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP patients who had an increase in platelet counts to ≥ 50 000/µl at Day 43 from a baseline of <30 000/µl; patients who withdrew prematurely due to a platelet count >200 000/µl were considered responders, those that discontinued for any other reason were considered non-responders irrespective of platelet count. A total of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n = 76) to placebo (n = 38).

Table 10            Efficacy results from TRA100773B

Eltrombopag            Placebo
N = 74              N = 38
Key primary endpoints
Eligible for efficacy analysis, n                                                        73               37 Patients with platelet count ≥ 50 000/µl after up to 42 days of dosing (compared to a baseline count of < 30 000/µl), n (%)                         43 (59)             6 (16)  p-valuea                                                       < 0.001 Key secondary endpoints
Patients with a Day 43 bleeding assessment, n                                            51               30 Bleeding (WHO Grades 1-4) n (%)                                                     20 (39)             18 (60)  p-valuea                                                        0.029 a        Logistic regression model adjusted for randomisation stratification variables 
In both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar irrespective of ITP medicinal product use, splenectomy status and baseline platelet count(≤ 15 000/µl, >15 000/µl) at randomisation.

In RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count ≤15 000/μl the median platelet counts did not reach the target level (>50 000/µl), although in both studies 43 % of these patients treated with eltrombopag responded after 6 weeks of treatment. In addition, in the RAISE study, 42 % of patients with baseline platelet count ≤15 000/μl treated with eltrombopag responded at the end of the 6 month treatment period. Forty-two to 60 % of the eltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of treatment.

Open-label non-controlled studies
REPEAT (TRA108057):
This open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off treatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of response.

EXTEND (TRA105325):
Eltrombopag was administered to 302 ITP patients in this open-label extension study, 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 completed 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count was 19 000/µl prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and 7 years on study were 85 000/µl, 85 000/µl, 105 000/µl, 64 000/µl, 75 000/µl, 119,000/µl and 76,000/µl respectively.

TAPER (CETB115J2411):
This was a single-arm phase II study including ITP patients treated with eltrombopag after first-line corticosteroid failure irrespective of time since diagnosis. A total of 105 patients were enrolled on the study and started eltrombopag treatment on 50 mg once daily (25 mg once daily for patients of East- /Southeast-Asian ancestry). The dose of eltrombopag was adjusted during the treatment period based on individual platelet counts with the goal to achieve a platelet count ≥100 000/µl.

Of the 105 patients who were enrolled in the study and who received at least one dose of eltrombopag, 69 patients (65.7%) completed treatment and 36 patients (34.3%) discontinued treatment early.

Analysis of sustained response off treatment
The primary endpoint was the proportion of patients with sustained response off treatment until Month 12. Patients who reached a platelet count of ≥100 000/µl and maintained platelet counts around 100 000/µl for 2 months (no counts below 70 000/µl) were eligible for tapering off eltrombopag and treatment discontinuation. To be considered as having achieved a sustained response off treatment, a patient had to maintain platelet counts ≥30 000/µl, in the absence of bleeding events or the use of rescue therapy, both during the treatment tapering period and following discontinuation of treatment until Month 12.

The duration of tapering was individualised depending on the starting dose and the response of the patient. The tapering schedule recommended dose reductions of 25 mg every 2 weeks if the platelet counts were stable. After the daily dose was reduced to 25 mg for 2 weeks, the dose of 25 mg was then only administered on alternate days for 2 weeks until treatment discontinuation. The tapering was done in smaller decrements of 12.5 mg every second week for patients of East-/Southeast-Asian ancestry. If a relapse (defined as platelet count <30 000/µl) occurred, patients were offered a new course of eltrombopag at the appropriate starting dose.

Eighty-nine patients (84.8%) achieved a complete response (platelet count ≥100 000/µl) (Step 1, Table 12) and 65 patients (61.9%) maintained the complete response for at least 2 months with no platelet counts below 70 000/µl (Step 2, Table 11). Forty-four patients (41.9%) were able to be tapered off eltrombopag until treatment discontinuation while maintaining platelet counts ≥30 000/µl in the absence of bleeding events or the use of rescue therapy (Step 3, Table 11).

The study met the primary objective by demonstrating that eltrombopag was able to induce sustained response off treatment, in the absence of bleeding events or the use of rescue therapy, by Month 12 in 32 of the 105 enrolled patients (30.5%; p<0.0001; 95% CI: 21.9, 40.2) (Step 4, Table 11). By Month 24, 20 of the 105 enrolled patients (19.0%; 95% CI: 12.0, 27.9) maintained sustained response off treatment in the absence of bleeding events or the use of rescue therapy (Step 5, Table 11).

The median duration of sustained response after treatment discontinuation to Month 12 was 33.3 weeks (min-max: 4-51), and the median duration of sustained response after treatment discontinuation to Month 24 was 88.6 weeks (min-max: 57-107).

After tapering off and discontinuation of eltrombopag treatment, 12 patients had a loss of response, 8 of them re-started eltrombopag and 7 had a recovery response.

During the 2-year follow-up, 6 out of 105 patients (5.7%) experienced thromboembolic events, of which 3 patients (2.9%) experienced deep vein thrombosis, 1 patient (1.0%) experienced superficial vein thrombosis, 1 patient (1.0%) experienced cavernous sinus thrombosis, 1 patient (1.0%) experienced cerebrovascular accident and 1 patient (1.0%) experienced pulmonary embolism. Of the 6 patients, 4 patients experienced thromboembolic events that were reported at or greater than Grade 3, and 4 patients experienced thromboembolic event that were reported as serious. No fatal cases were reported.

Twenty out of 105 patients (19.0%) experienced mild to severe haemorrhage events on treatment before tapering started. Five out of 65 patients (7.7%) who started tapering experienced mild to moderate haemorrhage events during tapering. No severe haemorrhage event occurred during tapering.
Two out of 44 patients (4.5%) who tapered off and discontinued eltrombopag treatment experienced mild to moderate haemorrhage events after treatment discontinuation until Month 12. No severe haemorrhage event occurred during this period. None of the patients who discontinued eltrombopag and entered the second year follow-up experienced haemorrhage event during the second year. Two fatal intracranial haemorrhage events were reported during the 2-year follow-up. Both events occurred on treatment, not in the context of tapering. The events were not considered to be related to study treatment.

The overall safety analysis is consistent with previously reported data and the risk-benefit assessment remained unchanged for the use of eltrombopag in patients with ITP.

Table 11        Proportion of patients with sustained response off treatment at Month 12 and at Month 24 (full analysis set) in TAPER

All patients   Hypothesis testing
N=105 n (%)      95% CI   p-value Reject H0
Step 1: Patients who reached platelet count ≥100 000/µl at          89 (84.8) (76.4, least once                                                                     91.0) Step 2: Patients who maintained stable platelet count for           65 (61.9) (51.9, 2 months after reaching 100 000/µl (no counts <70 000/µl)                      71.2)
Step 3: Patients who were able to be tapered off eltrombopag 44 (41.9) (32.3, until treatment discontinuation, maintaining platelet count                    51.9) ≥30 000/µl in the absence of bleeding events or use of any rescue therapy
Step 4: Patients with sustained response off treatment until        32 (30.5) (21.9,    <0.0001* Yes Month 12, with platelet count maintained ≥30 000/µl in the                     40.2) absence of bleeding events or use of any rescue therapy
Step 5: Patients with sustained response off treatment from         20 (19.0) (12.0, Month 12 to Month 24, maintaining platelet count ≥30 000/µl                    27.9) in the absence of bleeding events or use of any rescue therapy
N: The total number of patients in the treatment group. This is the denominator for percentage (%) calculation.
n: Number of patients in the corresponding category.
The 95% CI for the frequency distribution was computed using Clopper-Pearson exact method.
Clopper-Pearson test was used for testing whether the proportion of responders was >15%. CI and p-values are reported.
* Indicates statistical significance (one-sided) at the 0.05 level.

Results of response on treatment analysis by time since ITP diagnosis An ad-hoc analysis was conducted on the n=105 patients by time since ITP diagnosis to assess the response to eltrombopag across four different ITP categories by time since diagnosis (newly diagnosed ITP <3 months, persistent ITP 3 to <6 months, persistent ITP 6 to ≤12 months, and chronic ITP >12 months). 49% of patients (n=51) had an ITP diagnosis of <3 months, 20% (n=21) of 3 to <6 months, 17% (n=18) of 6 to ≤12 months and 14% (n=15) of >12 months.

Until the cut-off date (22-Oct-2021), patients were exposed to eltrombopag for a median (Q1-Q3) duration of 6.2 months (2.3-12.0 months). The median (Q1-Q3) platelet count at baseline was 16 000/฀l (7 800-28 000/฀l).

Platelet count response, defined as a platelet count ≥50 000/฀l at least once by Week 9 without rescue therapy, was achieved in 84% (95% CI: 71% to 93%) of newly diagnosed ITP patients, 91% (95% CI: 70% to 99%) and 94% (95% CI: 73% to 100%) of persistent ITP patients (i.e. with ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and in 87% (95% CI: 60% to 98%) of chronic ITP patients.
The rate of complete response, defined as platelet count ≥100 000/฀l at least once by Week 9 without rescue therapy, was 75% (95% CI: 60% to 86%) in newly diagnosed ITP patients, 76% (95% CI: 53% to 92%) and 72% (95% CI: 47% to 90%) in persistent ITP patients (ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and 87% (95% CI: 60% to 98%) in chronic ITP patients.

The rate of durable response, defined as a platelet count ≥50 000/฀l for at least 6 out of 8 consecutive assessments without rescue therapy during the first 6 months on study, was 71% (95% CI: 56% to 83%) in newly diagnosed ITP patients, 81% (95% CI: 58% to 95%) and 72% (95% CI: 47% to 90.3%) in persistent ITP patients (ITP diagnosis 3 to <6 months and 6 to ≤12 months, respectively), and 80% (95% CI: 52% to 96%) in chronic ITP patients.

When assessed with the WHO Bleeding Scale, the proportion of newly diagnosed and persistent ITP patients without bleeding at Week 4 ranged from 88% to 95% compared to 37% to 57% at baseline.
For chronic ITP patients it was 93% compared to 73% at baseline.

The safety of eltrombopag was consistent across all ITP categories and in line with its known safety profile.


Clinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been conducted. The long-term safety of eltrombopag should be considered prior to starting therapy.

Paediatric population (aged 1 to 17 years)
The safety and efficacy of eltrombopag in paediatric patients have been investigated in two studies.

TRA115450 (PETIT2):
The primary endpoint was a sustained response, defined as the proportion of patients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50 000/μl for at least 6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind randomised period.
Patients were diagnosed with chronic ITP for at least 1 year and were refractory or relapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical reason and had platelet count <30,000/μl. Ninety-two patients were randomised by three age cohort strata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted based on individual platelet counts.

Overall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo patients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p < 0.001) which was similar across the three age cohorts (Table 12).

Table 12             Sustained platelet response rates by age cohort in paediatric patients with chronic ITP

Eltrombopag                 Placebo n/N (%)                  n/N (%)
[95% CI]                 [95% CI]
Cohort 1 (12 to 17 years)                9/23 (39%)               1/10 (10%) [20%, 61%]                [0%, 45%]
Cohort 2 (6 to 11 years)                11/26 (42%)               0/13 (0%) [23%, 63%]                   [N/A]
Cohort 3 (1 to 5 years)                  5/14 (36%)                0/6 (0%) [13%, 65%]                   [N/A]

Statistically fewer eltrombopag patients required rescue treatment during the randomised period compared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032).


At baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any bleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any bleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients reported any bleeding.

Patients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase of the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP therapy, mainly corticosteroids, without needing rescue therapy.

TRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts ≥50 000/µl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed with ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a platelet count <30 000/µl (n=67). During the randomised period of the study, patients were randomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of eltrombopag could be adjusted based on individual platelet counts.

Overall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo patients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011).

Sustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the PETIT 2 study and 15 out of 24 weeks in the PETIT study.

Chronic hepatitis C associated thrombocytopenia studies

The efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV infection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised peginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both studies, patients with a platelet count of <75,000/µl were enrolled and stratified by platelet count (<50 000/µl and ≥50 000/µl to <75 000/µl), screening HCV RNA (< 800 000 IU/ml and ≥800 000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6).

Baseline disease characteristics were similar in both studies and were consistent with compensated cirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had bridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, primarily pegylated interferon plus ribavirin. The median baseline platelet count was 59 500/µl in both treatment groups: 0.8%, 28 % and 72% of the patients recruited had platelet counts <20 000/µl, <50 000/µl and ≥50 000/µl respectively.

The studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase.
In the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet count to ≥90 000/µl for ENABLE 1 and ≥100 000/µl for ENABLE 2. The median time to achieve the target platelet count ≥90 000/µl (ENABLE 1) or ≥100 000/µl (ENABLE 2) was 2 weeks.

The primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the percentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned treatment period.

In both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n = 201, 21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The improvement in the proportion of patients who achieved SVR was consistent across all subgroups in the randomisation strata (baseline platelet counts (<50 000 vs. >50 000), viral load (<800 000 IU/ml vs. ≥800 000 IU/ml) and genotype (2/3 vs. 1/4/6)).

Table 13:           Virologic response in HCV patients in ENABLE 1 and ENABLE 2 
Pooled data               ENABLE 1a                 ENABLE 2b
Patients achieving target platelet counts            1,439/1,520 (95%)                 680/715 (95%)                   759/805 (94%) and initiating antiviral therapy c
Eltrombopag        Placebo      Eltrombopag       Placebo        Eltrombopag     Placebo Total number of                    n = 956          n = 485        n = 450         n = 232         n = 506        n = 253 patients entering antiviral treatment phase
% patients achieving virologic response
Overall SVR d                          21             13          23          14          19                         13 HCV RNA Genotype
Genotype 2/3                           35             25              35              24              34             25 Genotype 1/4/6e                        15              8              18              10              13              7 Albumin levels f
≤ 35g/l                                11              8
> 35g/l                                25             16
MELD scoref
≥ 10                                   18             10
< 10                                   23             17 a   Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1 200 mg daily in 2 divided doses orally) b   Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg /kg once weekly for 48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1 400 mg orally in 2 divided doses) c   Target platelet count was ≥ 90 000/µl for ENABLE 1 and ≥ 100 000/µl for ENABLE 2. For ENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients then withdrew consent prior to receiving antiviral therapy.
d   P-value < 0.05 for eltrombopag versus placebo e   64 % patients participating in ENABLE 1 and ENABLE 2 were genotype 1 f   Post-hoc analyses

Other secondary findings of the studies included the following significantly fewer patients treated with eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, p = <0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose reduction as compared to placebo (45% vs, 27%). Eltrombopag treatment delayed and reduced the number of peginterferon dose reductions.

First-line treatment of severe splastic Anaemia
Eltrombopag in combination with horse antithymocyte globulin (h-ATG) and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anaemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received eltrombopag in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same eltrombopag starting dose but differed by treatment start day and duration. The starting dose of eltrombopag for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East and Southeast Asians), 75 mg once daily for paediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East and Southeast Asians), and 2.5 mg/kg once daily for paediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East and Southeast Asians).
•         Cohort 1 (n=30): Eltrombopag on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine 
•        Cohort 2 (n=31): Eltrombopag on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine
•        Cohort 3 + Extension cohort [Eltrombopag D1-M6 cohort] (n = 92): Eltrombopag on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a haematologic response at 6 months) Eltrombopag dose reductions were conducted for elevated platelet counts and hepatic impairment.
Table 14 includes the dosages of h-ATG and cyclosporine administered in combination with eltrombopag in Study US01T.
Data from the Cohort 3 + Extension cohort support the efficacy of Eltrombopag for the first-line treatment of patients with severe aplastic anaemia (Table 15). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92).
Table 14     Dosages of immunosuppressive therapy administered with eltrombopag in study US01T
Agent                             Dose Administered in the Pivotal Trial Horse antithymocyte globulin           40 mg/kg/day, based on actual body weight, administered (h-ATG)*                               intravenously on Days 1 to 4 of the 6-month treatment period a
Cyclosporine                           Patients 12 years and older (total daily dose of 6 mg/kg/day) (therapeutic dose for 6 months, from   3 mg/kg, based on actual body weight, orally every 12 hours Day 1 to Month 6, adjusted to obtain a for 6 months, starting on Day 1 target therapeutic trough level between 200 mcg/L and 400 mcg/L)       Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile:
3 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1

Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)
6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1

Patients 2 to 11 years of age with a body mass index > 95th percentile:
6 mg/kg, based on adjusted body weightb, orally every 12 hours for 6 months, starting on Day 1
Cyclosporine                                 For patients who achieve a haematologic response at 6 months (maintenance dose, from Month 6 to           2 mg/kg/day administered orally at a fixed dose for an Month 24)                                    additional 18 months a
Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information b
Calculated as the midpoint between the ideal body weight and actual body weight 
* h-ATG was used in the single-arm, single-centre, open-label study. If h-ATG is not available, substitution with the appropriate local immunosuppressive therapy based on physician’s discretion is recommended. The local prescribing information for this therapy/these therapies or local treatment guidelines should be consulted for dosing information.

In the eltrombopag D1-M6 cohort, the median age was 28 years (range 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial.
The efficacy of eltrombopag in combination with h-ATG and cyclosporine was established on the basis of complete haematological response at 6 months. A complete response was defined as haematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109/L and haemoglobin > 10 g/dL. A partial response was defined as blood counts no longer 
meeting the standard criteria for severe pancytopenia in severe aplastic anaemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 109/L, or reticulocyte count >60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses.
Table 15    Study US01T: Haematologic Response in First-Line Treatment of Patients With Severe Aplastic Anaemia
Eltrombopag D1-M6 + h-ATG + cyclosporine n = 92
Month 6, na                                                       87
Overall response, n (%) [95% CI]                            69 (79) [69, 87] Complete response, n (%) [95% CI]                           38 (44) [33, 55] 
Median duration of overall response, nb                                         70 Months (95% CI)                                                          24.3 (21.4, NE) Median duration of complete response, nb                                        46 Months (95% CI)                                                          24.3 (23.0, NE) Abbreviation: NE, not estimable.
a
The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation b
Number of responders at any time
The overall and complete haematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively.

Paediatric patients

The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine for the first-line treatment of severe aplastic anaemia in paediatric patients 2 years and older were evaluated in a single- arm, open-label trial [see sections 4.8 and 5.1]. A total of 26 paediatric patients (ages 2 to < 17 years) were evaluated; 12 children (aged 2 to < 12 years) and 14 adolescents (aged 12 to < 17). See section 4.2 for dosing recommendations for paediatric patients 6 years and older.
The safety and efficacy of eltrombopag in combination with h-ATG and cyclosporine in paediatric patients younger than 2 years for the first-line treatment of severe aplastic anaemia have not yet been established. In patients 2 to 16 years of age, 69% of patients experienced serious adverse events compared to 42% in patients 17 years and older. Among the 12 patients who were 2 to 11 years of age in the eltrombopag D1-M6 cohort and reached the 6-month assessment or withdrew earlier, the complete response rate at Month 6 was 8% versus 46% in patients age 12 to 16 years and 50% in patients 17 years of age and older.

Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 paediatric patients achieved a complete and overall response, respectively, at 6 months.


Refractory Severe aplastic anaemia
Eltrombopag was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anaemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109/L. Eltrombopag was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2 week periods up to a maximum dose of 150 mg once daily. The efficacy of eltrombopag in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Haematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109/L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) haemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC )transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109/L.
Eltrombopag was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial.

The treated population had median age of 45 years (range 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x109/L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109/L and absolute reticulocyte count was 24.3 x109/L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.

Table 16 presents the efficacy results.

Table 16        Study US28T: Haematologic Response in Patients with Severe Aplastic Anaemia eltrombopag
Outcome                                     N = 43
Response ratea, n (%)                                               17 (40) 95% CI (%)                                                       (25, 56) Median of duration of response in months (95%CI)                NRb (3.0, NRb) a
Includes single- and multi-lineage.
b
NR = Not reached due to few events (relapsed).

In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of
208 days.

In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with eltrombopag and maintained the response (median follow up: 8.1 months, range: 7.2 to 10.6 months).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Pharmacokinetics
The plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies TRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a population PK analysis. Plasma eltrombopag AUC(0-τ) and Cmax estimates for ITP patients are presented (Table 17).

Table 17            Geometric mean (95 % confidence intervals) of steady-state plasma eltrombopag pharmacokinetic parameters in adults with ITP

Eltrombopag dose, once       N          AUC(0-τ)a, µg.h/ml                Cmaxa , µg/ml daily
30 mg                28            47 (39, 58)                  3.78 (3.18, 4.49) 50 mg                34           108 (88, 134)                 8.01 (6.73, 9.53) 75 mg                26          168 (143, 198)                 12.7 (11.0, 14.5) a      AUC(0-τ) and Cmax based on population PK post-hoc estimates.



Plasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III studies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients with HCV enrolled in the phase II study TPL102357 and healthy adult patients in a population PK analysis. Plasma eltrombopag Cmax and AUC(0-τ) estimates for patients with HCV enrolled in the phase III studies are presented for each dose studied in Table 18.


Table 18            Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in patients with chronic HCV

Eltrombopag dose             N               AUC(0-τ)                       Cmax (once daily)                             (µg.h/ml)                     (µg/ml) 25 mg                  330               118                          6.40
(109, 128)                  (5.97, 6.86)
50 mg                 119               166                          9.08 (143, 192)                 (7.96, 10.35)
75 mg                 45                301                         16.71 (250, 363)                (14.26, 19.58)
100 mg                96                354                         19.19 (304, 411)                (16.81, 21.91)
Data presented as geometric mean (95% CI).
AUC (0-τ) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each patient

Absorption and bioavailability

Eltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration.
Administration of eltrombopag concomitantly with antacids and other products containing polyvalent cations such as dairy products and mineral supplements significantly reduces eltrombopag exposure (see section 4.2). The absolute oral bioavailability of eltrombopag after administration to humans has not been established. Based on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related material following administration of a single 75 mg eltrombopag solution dose was estimated to be at least 52%.

Distribution

Eltrombopag is highly bound to human plasma proteins (>99.9 %), predominantly to albumin.
Eltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1.
Biotransformation

Eltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronic acid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately 64 % of plasma radiocarbon AUC0-∞. Minor metabolites due to glucuronidation and oxidation were also detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative metabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are responsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for the cleavage pathway.

Elimination

Absorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is via faeces (59 %) with 31 % of the dose found in the urine as metabolites. Unchanged parent compound (eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts 

for approximately 20 % of the dose. The plasma elimination half-life of eltrombopag is approximately 21-32 hours.

Pharmacokinetic interactions

Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of UGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag.

Approximately 21 % of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data (see section 4.5).

In vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an inhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP substrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with eltrombopag, a dose reduction of statins by 50 % was recommended.

Eltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc (see sections 4.2 and 4.5).

In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM [1.2 μg/ml]). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor (IC50 value of 2.7 μM [1.2 μg/ml]).

Special patient populations

Renal impairment
The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with renal impairment. Following administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 32 % to 36 % lower in patients with mild to moderate renal impairment, and 60 % lower in patients with severe renal impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with renal impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured. Patients with impaired renal function should use eltrombopag with caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see section 4.2). The efficacy and safety of eltrombopag have not been established in patients with both moderate to severe renal impairment and hepatic impairment.

Hepatic impairment

The pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0-∞ of eltrombopag was 41 % higher in patients with mild hepatic impairment and 80 % to 93 % higher in patients with moderate to severe hepatic impairment compared with healthy volunteers. There was substantial variability and significant overlap in exposures between patients with hepatic impairment and healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound medicinal product were not measured.


The influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat administration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and 714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver disease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with moderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, patients with mild hepatic impairment had approximately 111 % (95 % CI: 45 % to 283 %) higher plasma eltrombopag AUC (0-τ) values and patients with moderate hepatic impairment had approximately 183 % (95 % CI: 90 % to 459 %) higher plasma eltrombopag AUC(0-τ) values.

Therefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see sections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see section 4.2).

Race

The influence of East Asian ethnicity on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (31 East Asians) and 88 patients with ITP (18 East Asians). Based on estimates from the population pharmacokinetic analysis, East Asian (i.e.
Japanese, Chinese, Taiwanese and Korean) ITP patients had approximately 49 % higher plasma eltrombopag AUC (0-τ) values as compared to non-East Asian patients who were predominantly Caucasian, (see section 4.2).
The influence of East Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 635 patients with HCV (145 East Asians and 69 Southeast Asians). Based on estimates from the population pharmacokinetic analysis, East Asian patients had approximately 55 % higher plasma eltrombopag AUC (0-τ) values as compared to patients of other races who were predominantly Caucasian (see section 4.2).

Gender

The influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females).
Based on estimates from the population pharmacokinetic analysis, female ITP patients had approximately 23 % higher plasma eltrombopag AUC (0- τ) as compared to male patients, without adjustment for body weight differences.

The influence of gender on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female HCV patient had approximately 41 % higher plasma eltrombopag AUC (0- τ) as compared to male patients.

Age

The influence of age on eltrombopag pharmacokinetics was evaluated using population pharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic liver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of eltrombopag in patients ≥ 75 years. Based on model estimate, elderly (≥65 years) patients had approximately 41 % higher plasma eltrombopag AUC (0-฀) as compared to younger patients (see section 4.2).

Paediatric population (aged 1 to 17 years)

The pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once daily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. The effects of race and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult patients. East Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC (0- τ) values as compared to non-East Asian patients. Female paediatric ITP patients had approximately 25% higher plasma eltrombopag AUC(0-τ) values as compared to male patients.

The pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in Table 19.

Table 19            Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic parameters in paediatric patients with ITP (50 mg once daily dosing regimen) 
Age                                           Cmax                          AUC(0-τ) (µg/ml)                        (µg.hr/ml)
12 to 17 years (n=62)                         6.80                             103 (6.17, 7.50)                     (91.1, 116)
6 to 11 years (n=68)                          10.3                             153 (9.42, 11.2)                     (137, 170)
1 to 5 years (n=38)                           11.6                             162 (10.4, 12.9)                     (139, 187)
Data presented as geometric mean (95%CI). AUC (0- τ) and Cmax based on population PK post-hoc estimates.