Table 1.

Published studies of the second-generation thrombopoietic agents.

Agent, structure; route and frequency of administrationRef.TrialNo. of patientsBaseline platelet countsDoseTreatment periodTime to responsePlatelet responseToxicityThrombotic events?
Abbreviations: HEP C-ITP, hepatitis C virus–associated thrombocytopenia 
AMG531 Recombinant TPO-R protein with carrier Fc domain; Once weekly subcutaneous injection 53  Phase 1 48 healthy controls NA 0.3 to 10 mg/kg IV or 0.1 to 2.0 mg/kg SC or placebo Single dose Peak response 12–16 d NA Well tolerated, no serious adverse events. Most common toxicity mild headache or sore throat. No 
 12  Phase 1 24 Median platelet count 11 x 109/mL All had platelets <30 x 109/L Cohorts ranging from 0.2 to 10 mg/kg/wk 6 wks Median time to targeted response 5–10 d Platelet count of > 50 x 109/L achieved in 7/12 patients at doses >3 mg Well tolerated, most frequent adverse effect was self-limiting mild headache. 4 had worsening of thrombocytopenia after treatment. No 
 12  Phase 2 21 Median platelet count 16 x 109/mL All had platelets <30 x 109/L Randomly assigned to 1, 2 or 6 μg/kg/wk 6 wks Median time to response 5–10 d 10/16 achieved target platelet count (50–450 x 109/L) with 1 or 3 mg/kg/wk  No 
 13  Phase 1–2 16 Median platelet count 14.5; all had platelets <30 x 109/L Cohorts ranging from 30 to 500 mg/wk 3 wks Median of 10 d (range 5–13 d) Platelet counts in 12/15 patients increased to > 20 and in 8/15 to > 100 x 109/L Generally well tolerated, most common effect mild-mod headache. 1 patient had worsening of thrombocytopenia after treatment and 1 had transient increase in serum lactate dehydrogenase No 
 54  Phase 3 104 enrolled; study ongoing — — up to 96 wks — Mean platelet count 100 wk 1–24 x 109/L and 131 x 109/L wk 25–48; 6/12 pt able to discontinue concurrent steroids Headache most common adverse event. 4 pts had serious treatment- related adverse events, 3 of whom were withdrawn. Transverse sinus thrombosis in 1 pt 
Eltrombopag Small-molecule, nonpeptide TPO-R agonist; Once daily, oral capsule (on empty stomach) 58  Phase 1 73 healthy male controls NA Cohorts of 5–75 mg/d with placebo 10 d Consistent increase started after 8 days of daily dosing; 16 days to peak increase NA No treatment-related adverse events reported. No; no effect of treatment on platelet aggregation and activation 
 14  Phase 2 117 Platelets ≤30 x 109/L Randomly assigned to placebo, 30 mg, 50 mg or 75 mg 6 wks Preliminary results encouraging, no major toxicity — — No 
 16  Phase 2 74 HEP C-ITP Platelets 20–70 x 109/L Randomly assigned to placebo, 30 mg, 50 mg or 75 mg 4 wks Preliminary results encouraging, no major toxicity — — No 
AKR-501 Small-molecule TPO-R agonist; Oral, once daily 59  Phase 1 63 healthy volunteers NA Cohorts of 3–100 mg or placebo 14 d Dose-dependent increases seen NA No serious drug-related adverse experiences reported at any dose. No 
Agent, structure; route and frequency of administrationRef.TrialNo. of patientsBaseline platelet countsDoseTreatment periodTime to responsePlatelet responseToxicityThrombotic events?
Abbreviations: HEP C-ITP, hepatitis C virus–associated thrombocytopenia 
AMG531 Recombinant TPO-R protein with carrier Fc domain; Once weekly subcutaneous injection 53  Phase 1 48 healthy controls NA 0.3 to 10 mg/kg IV or 0.1 to 2.0 mg/kg SC or placebo Single dose Peak response 12–16 d NA Well tolerated, no serious adverse events. Most common toxicity mild headache or sore throat. No 
 12  Phase 1 24 Median platelet count 11 x 109/mL All had platelets <30 x 109/L Cohorts ranging from 0.2 to 10 mg/kg/wk 6 wks Median time to targeted response 5–10 d Platelet count of > 50 x 109/L achieved in 7/12 patients at doses >3 mg Well tolerated, most frequent adverse effect was self-limiting mild headache. 4 had worsening of thrombocytopenia after treatment. No 
 12  Phase 2 21 Median platelet count 16 x 109/mL All had platelets <30 x 109/L Randomly assigned to 1, 2 or 6 μg/kg/wk 6 wks Median time to response 5–10 d 10/16 achieved target platelet count (50–450 x 109/L) with 1 or 3 mg/kg/wk  No 
 13  Phase 1–2 16 Median platelet count 14.5; all had platelets <30 x 109/L Cohorts ranging from 30 to 500 mg/wk 3 wks Median of 10 d (range 5–13 d) Platelet counts in 12/15 patients increased to > 20 and in 8/15 to > 100 x 109/L Generally well tolerated, most common effect mild-mod headache. 1 patient had worsening of thrombocytopenia after treatment and 1 had transient increase in serum lactate dehydrogenase No 
 54  Phase 3 104 enrolled; study ongoing — — up to 96 wks — Mean platelet count 100 wk 1–24 x 109/L and 131 x 109/L wk 25–48; 6/12 pt able to discontinue concurrent steroids Headache most common adverse event. 4 pts had serious treatment- related adverse events, 3 of whom were withdrawn. Transverse sinus thrombosis in 1 pt 
Eltrombopag Small-molecule, nonpeptide TPO-R agonist; Once daily, oral capsule (on empty stomach) 58  Phase 1 73 healthy male controls NA Cohorts of 5–75 mg/d with placebo 10 d Consistent increase started after 8 days of daily dosing; 16 days to peak increase NA No treatment-related adverse events reported. No; no effect of treatment on platelet aggregation and activation 
 14  Phase 2 117 Platelets ≤30 x 109/L Randomly assigned to placebo, 30 mg, 50 mg or 75 mg 6 wks Preliminary results encouraging, no major toxicity — — No 
 16  Phase 2 74 HEP C-ITP Platelets 20–70 x 109/L Randomly assigned to placebo, 30 mg, 50 mg or 75 mg 4 wks Preliminary results encouraging, no major toxicity — — No 
AKR-501 Small-molecule TPO-R agonist; Oral, once daily 59  Phase 1 63 healthy volunteers NA Cohorts of 3–100 mg or placebo 14 d Dose-dependent increases seen NA No serious drug-related adverse experiences reported at any dose. No 
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