Eltrombopag, a novel, oral platelet growth factor, increases platelet counts in thrombocytopenic patients and healthy subjects

8602 Background: Eltrombopag (SB-497115) is a novel, first in class, orally bioavailable, thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocyte progenitors and has been shown to increase platelet counts in preclinical and clinical studies. Methods: In two randomized, placebo-controlled trials, eltrombopag was administered as oral tablets, once daily for 10 days to 73 healthy male subjects at doses of 5–75mg in an ascending dose cohort study, and to 103 (64 female/39 male) adult chronic immune thrombocytopenic purpura (ITP) patients, with a platelet count of <30×109/L, once daily for 6 weeks at doses of 30–75mg in a parallel dose cohort study. The primary efficacy endpoint in the Phase II ITP trial was the proportion of subjects with a platelet count >50×109/L after 6 weeks of dosing. Results: In healthy subjects, eltrombopag induced a dose dependent increase in the platelet counts. Mean maximal platelet count increases were 24.1 % at 30mg, 42.9 % at 50mg, and 50.4 % at 75mg. In 95 eligible ITP patients, platelet counts increased from <30 to >50×109/L in 16% (4/25) of subjects on placebo, and in the eltrombopag groups in 28% (7/25, p=ns) on 30mg, 67% (16/24, p<0.001) on 50mg and 86% (18/21, p<0.001) on 75mg eltrombopag. The median platelet counts in each treatment arm after 6 weeks of dosing were 16×109/L on placebo, 29×109/L on 30mg, 132×109L on 50mg, and 202×109/L on 75mg. The dose dependent effect was not significantly affected by the splenectomy status, background immunosuppressant use, or baseline platelet count (greater than or less than 15×109/L). Conclusions: The platelet count data from these clinical studies suggests that eltrombopag could be an effective therapy for the treatment of thrombocytopenia. Eltrombopag is being tested in further studies involving patients with ITP and chronic liver disease, and cancer patients receiving thrombocytopenic chemotherapy. [Table: see text]

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Studies on Reference Intervals for Platelet Counts in Three Cities in China and one in Japan

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613162 ◽

2002 ◽

Vol 88 (07) ◽

pp. 111-114 ◽

Cited By ~ 3

Author(s):

Changgeng Ruan ◽

Yun Wu ◽

Tokuhiro Okada ◽

Shigemi Motoi ◽

Tamiaki Kondo ◽

...

Keyword(s):

Platelet Count ◽

Mean Platelet Volume ◽

Healthy Subjects ◽

Hematological Parameters ◽

Reference Interval ◽

Reference Intervals ◽

Sichuan Province ◽

Jiangsu Province ◽

Platelet Volume ◽

Platelet Counts

SummaryHematological parameters including platelet counts, etc. were determined in 1,140 healthy subjects living in four cities: Suzhou (Jiangsu Province), Chengdu (Sichuan Province) and Harbin (Heilongjang Province) in China, and Kobe in Japan. Then, the reference intervals for platelet counts were calculated and compared. The reference interval for platelet count of subjects aged between 18 and 60 years was 60-259 × 109/L in Suzhou and 52–202 × 109/L in Chengdu, and subjects with platelet counts of 100 × 109/L or less accounted for about 30% of the subjects examined in these cities. The reference intervals in Harbin and Kobe were within the range of 150–350 × 109/L, and no subject having a platelets count of 100 × 109/L or less was detected. Mean platelet volume (MPV) determined concurrently was negatively correlated with platelet count, and the reference intervals for MPV in Chengdu and Suzhou were higher than those in Harbin and Kobe.

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Effects of biological variations on platelet count in healthy subjects in China

Thrombosis and Haemostasis ◽

10.1160/th03-05-0276 ◽

2004 ◽

Vol 91 (02) ◽

pp. 367-372 ◽

Cited By ~ 18

Author(s):

Jing Yang ◽

Xiaojun Lu ◽

Tokuhiro Okada ◽

Tamiaki Kondo ◽

Changgeng Ruan ◽

...

Keyword(s):

Platelet Count ◽

Mean Platelet Volume ◽

Healthy Subjects ◽

Bleeding Time ◽

Platelet Volume ◽

Platelet Counts ◽

Normal Platelet Count ◽

Normal Platelet ◽

Low Platelet Count ◽

The Mean

SummaryThe effects of biological variations on platelet counts were investigated in 694 healthy subjects aged 18 to 60 years living in three cities including Chengdu (Sichuan Province), Suzhou (Jiangsu Province) and Harbin (Heilongjang Province) in China. Platelet counts in healthy subjects were significantly lower in Chengdu (52∼202 X 109/L) and Suzhou (60∼259 X 109/L) than in Harbin (154∼348 X 109/L)(p <0.0001), but the mean platelet volume (MPV) determined concurrently was negatively correlated with platelet count, the MPV values were significantly higher in Chengdu (11.8∼15.6 fl) and Suzhou (10.9∼15.8 fl) than in Harbin (9.5∼12.9 fl) (p < 0.0001). Platelet counts were significantly higher in summer (73∼289 X 109/L) than in winter (52∼202 X 109/L) (p <0.0001), but the MPV values were lower in summer (11.2∼14.7 fl) than in winter (11.8∼15.6 fl) (p <0.05) in Chengdu. Platelet associated immunoglobulin (PA-IgG) in Chengdu was revealed to be significantly higher in the low platelet count group (<150 X 109/L, 13.5 ± 7.1 ng/107 PLT) than in the normal platelet count group (≥150 X 109/L, 8.3 ± 2.7 ng/107 PLT)(p <0.0001). Similar results were observed in Suzhou for the reticulated platelet ratio, which was significantly higher in the low platelet count group (19.5 ± 7.1%) than in the normal platelet count group (11.6 ± 2.7%)(p <0.01). The bleeding time in Chengdu showed a significantly longer time in the low platelet count group (8.6 ± 2.3 min) than in the normal platelet count group (6.0 ± 1.2 min)(p <0.01). With regard to the effects of lipids on platelet counts, the HDL values were significantly higher in the normal platelet count group (1.60 ± 0.76 mmol/L) than the low platelet count group (1.23 ± 0.31 mmol/L) (p <0.01); but no significant differences in cholesterol and triglycerides values between the normal and low platelet count groups (p >0.05) were recorded. These findings suggest that the platelet counts could be greatly influenced in healthy subjects by biological variations such as geographical, seasonal, and lipid variations.

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An Oral, Non-Petide, Small Molecule Thrombopoietin Receptor Agonist Increases Platelet Counts in Healthy Subjects.

Blood ◽

10.1182/blood.v104.11.2916.2916 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2916-2916 ◽

Cited By ~ 13

Author(s):

Julian Jenkins ◽

Richard Nicholl ◽

Daphne Williams ◽

Charlotte Baidoo ◽

Jennifer Phillips ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Small Molecule ◽

Receptor Agonist ◽

Once Daily ◽

Thrombopoietin Receptor ◽

Thrombopoietin Receptor Agonist ◽

Orally Bioavailable ◽

Dose Dependent Increase ◽

Dose Dependent

Abstract SB497115, is an orally bioavailable, small molecule thrombopoietin receptor agonist that induces differentiation and proliferation of megakaryocytes. In a randomized, single blind, placebo-controlled, parallel group, phase I study conducted in the UK in 72 healthy male subjects, SB497115 was administered as oral capsules once daily for 1 day and, after a 1 week washout, for 10 days at doses of 5 to 75 mg. Subjects were randomized into six groups of 12 subjects to receive either active or placebo medication in a ratio of 9:3. The study was conducted according to Good Clinical Practice and all subjects gave their written informed consent to participate in the study. SB497115 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB497115 was shown to be orally bioavailable in humans with a linear pharmacokinetic profile suitable for a once daily oral medication. When administered at oral doses of 30mg and above for 10 days a dose dependent increase in the platelet count was observed, maximum platelet count was observed on days 14 to 16 following initiation of dosing. The dose dependent increase in platelet count is shown in the table below. On the basis of these safety, pharmacokinetic and pharmacodynamic data the oral thrombopoietin receptor agonist, SB497115, will be studied in phase II trials involving thrombocytopenic patients. Preliminary Data: Mean Platelet Count (platelets/uL) Oral Dose Baseline (Day 1) Maximum (Day 14 or 16) Change from Baseline Placebo 234000 255000 21000 5 mg 217000 249000 32000 10 mg 251000 291000 40000 20 mg 236000 279000 43000 30 mg 249000 323000 74000 50 mg 254000 356000 102000 75 mg 239000 357000 118000

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Single Oral Doses of a Novel Thrombopoietin Mimetic ONO-7746 Increase Platelet Counts In Healthy Subjects

Blood ◽

10.1182/blood.v118.21.4827.4827 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4827-4827

Author(s):

Thomas L Hunt ◽

Ming Q. Lu ◽

Yasushi Kawasaki ◽

John P. Hall ◽

Junji Komaba ◽

...

Keyword(s):

Adverse Event ◽

Platelet Count ◽

Single Dose ◽

Dose Escalation ◽

Healthy Subjects ◽

Dose Range ◽

Plasma Concentrations ◽

Stopping Rules ◽

Platelet Counts ◽

The Mean

Abstract Abstract 4827 Objective: A novel orally administered small-molecule thrombopoietin receptor (c-Mpl) agonist, ONO-7746, was investigated in a double-blind, placebo-controlled single dose escalation study for its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects. Methods: A total of 48 subjects were enrolled into 6 cohorts of 8 subjects each. For each cohort, subjects were randomly assigned to receive ONO-7746 or placebo in a 3:1 ratio. After a single dose of study drug on Day 1 of each cohort, all subjects in a cohort were assessed on Day 21 for their overall safety, tolerability and changes in platelet count prior to proceeding to the next higher dose. The doses of ONO-7746 applied for each successive cohort were adjusted per Dose-Escalation and Stopping Rules, i.e. the successive dose was only a 1.5-fold increase from the previous dose if either of the following were observed: Two subjects had a platelet count increase greater than 400 × 109/L, or had a platelet count doubling from Baseline. Further dose escalation was terminated if 50% of the subjects in a cohort (4 subjects) demonstrated a platelet count increase > 400 × 109/L or doubling from Baseline. This study completed a total of 6 cohorts including 5, 10, 20, 50, 100, and 150 mg. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results: Dose escalation was only increased 1.5-fold after the 100-mg cohort because of increases in platelet count, and dose escalation was ultimately terminated after the 150-mg cohort because 50% of subjects had a platelet count increase to > 400 × 109/L or doubling from Baseline. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 9 and 11, decreased from Days 11 or 13, and returned to baseline levels by Day 28. Maximum platelet count, change from Baseline values increased with ascending ONO-7746 dose level. The largest percent change from Baseline in platelet count (117.0%) was observed in the 150-mg cohort, compared with 14.7% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. The PK profile of ONO-7746 showed that the plasma concentrations reached Cmax at a median Tmax of 3.0 to 4.0 hours. The mean T1/2 ranged from 22 to 27 hours. The PK of ONO-7746 was linear in the dose range of 5 to 100 mg. In the dose range of 100 to 150 mg, Cmax and AUCinf increased greater than dose proportionally. One subject in the 150-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L that was considered mild in severity. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, vital sign measurements, 12-lead ECG and telemetry results. Conclusion: The above observations indicate that ONO-7746 could increase platelet count even with a single dose. ONO-7746 is a potent once-daily oral c-Mpl agonist with demonstrated thrombopoietic activity in human subjects, safe and well tolerated at all the tested dose levels (5, 10, 20, 50, 100 and 150 mg). Observed Platelet Count by Study Day Disclosures: Hunt: ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:ONO Pharma USA: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

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2-O, 3-O-Desulfated Heparin (ODSH) Mitigates Chemotherapy-Induced Thrombocytopenia (CIT) by Blocking the Negative Paracrine Effect of Platelet Factor 4 (PF4) On Megakaryopoiesis

Blood ◽

10.1182/blood.v120.21.386.386 ◽

2012 ◽

Vol 120 (21) ◽

pp. 386-386 ◽

Cited By ~ 1

Author(s):

Michele Lambert ◽

Samriddhi S Sharma ◽

Liqing Xiao ◽

Stephen Marcus ◽

Mortimer Poncz

Keyword(s):

Platelet Count ◽

Steady State ◽

Unfractionated Heparin ◽

Clinical Studies ◽

Myelosuppressive Chemotherapy ◽

Platelet Counts ◽

Cell Counts ◽

Count Recovery

Abstract Abstract 386 Thrombocytopenia is a significant complication of myelosuppressive chemotherapy treatments, which are a mainstay in cancer therapy. We and others have previously shown that PF4 is a negative paracrine affecting megakaryocyte number in culture. In murine studies we showed that platelet PF4 levels are inversely related to steady-state platelet counts and is a major contributor to the duration and severity of CIT. Recently, we have shown that PF4 influences both steady-state platelet count and platelet count recovery in pediatric patients treated for acute lymphoblastic leukemia. Pre-clinical studies in murine models suggest that blocking the effect of PF4 (using polyclonal anti-PF4 antibodies) can mitigate the effect of PF4 on megakaryopoiesis and results in a shortened time to platelet count recovery and higher nadir platelet count. Heparin is known to bind PF4 tightly and can clear PF4 from the vascular endothelium. Pre-clinical studies using heparin to mitigate CIT failed to show an effect, but were limited by dose considerations due to the anti-coagulant effect of unfractionated heparin (UFH) and likely by the inability of this highly negative polysaccharide to reach the intramedullary space in high enough amounts to alter available PF4. ODSH does not exhibit the same effect as unfractionated heparin (UFH) in enhancing antithrombin effects and may allow studies of non-anticoagulant pharmacologic effects of heparin. For example, ODSH retains UFH's anti-inflammatory effects and its ability to bind tightly to PF4. In preliminary results of a clinical trial using ODSH in conjunction with myelosuppressive chemotherapy in patients with metastatic pancreatic cancer, there was a striking lack of clinically significant CIT as will be reported separately at this meeting. This prompted our evaluation of whether ODSH affects CIT and modulates platelet count recovery and whether this is through its interaction with PF4. We first examined the ability of ODSH to prevent the PF4 effect on megakaryopoiesis in vitro. Using a megakaryocyte colony assay, we show that PF4 treatment of PF4null murine megakaryocytes decreases megakaryocyte colony numbers (54±3% control vs. 23±6% PF4-treated, p<0.001) and treatment with ODSH completely blocks the PF4 effect (55±9% ODSH/PF4-treated, p<0.001 vs. PF4-treated). This suggested that the major mechanism by which ODSH prevents CIT is through inhibition of the PF4 effect. We then examined the effect of ODSH on liquid murine bone marrow culture and showed that ODSH treatment (50 μg/mL) was able to improve cell counts in the presence of added recombinant human PF4 (50 μg/mL) (9.2±3.3 × 104 cells/mL in PF4-treated cells vs. 19.3±4.2 × 104 cells/mL in ODSH+PF4-treated cells, p<0.01). Finally, we examined the in vivo effect of ODSH on CIT in a murine model of chemotherapy in transgenic mice that overexpress human (h) PF4. In these hPF4 mice, endogenous PF4 levels significantly affect enhances the degree and duration of 5FU-induced CIT. We previously reported that treatment of animals with anti-hPF4 antibodies was able to completely abolish the PF4 effect. Using the same model, injecting 180 mg/kg 5-fluourouracil (5-FU) intraperitoneally on day 0, we examined the effect on platelet counts of treatment with 2 clinically relevant doses of ODSH (25 mg/kg/dose) given subcutaneously 30 minutes and 24 hours after injection of 5-FU. hPF4 mice treated with 5-FU and ODSH had a higher platelet count nadir (70±14% versus vs. 44±1% of baseline). The nadir platelet count in the ODSH-treated mice was similar to that in mPF4null mice (57±20% of baseline). In addition, animals treated with ODSH recovered approximately 2 days earlier. In summary, ODSH mitigates CIT resulting in decreased severity and duration of thrombocytopenia. These studies suggest that this effect is mediated in large part by PF4 as in vitro experiments show that ODSH completely blocks the effect of PF4 on megakaryopoiesis. The in vivo studies support that sufficient ODSH reaches the marrow to block intramedullary-released PF4 and prevents its inhibition of megakaryopoiesis. This drug is already in clinical trials in humans and may be the first clinically relevant inhibitor of CIT. Further studies will examine its effect in other thrombocytopenic settings. Disclosures: Marcus: Paringenix: Employment, Equity Ownership.

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Effect of Eltrombopag on Platelet Response and Safety Results in Chinese Adults with Chronic ITP-Primary Result of a Phase III Study

Blood ◽

10.1182/blood.v124.21.1464.1464 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1464-1464 ◽

Cited By ~ 3

Author(s):

Renchi Yang ◽

Ming Hou ◽

Junmin Li ◽

Jie Jin ◽

Meijuan Huang ◽

...

Keyword(s):

Platelet Count ◽

Placebo Group ◽

Adverse Events ◽

Initial Dose ◽

East Asian ◽

Chinese Adults ◽

Once Daily ◽

Platelet Counts ◽

Chronic Itp ◽

To Receive

Abstract INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline) is a non peptide, oral thrombopoietin receptor agonist which promotes the differentiation and proliferation of megakaryocytes and increases platelet counts. In previous studies, East Asians ITP subjects had an approximately 1.85 fold higher plasma eltrombopag AUC (0-τ) and 1.6 fold higher plasma eltrombopag Cmax than non-East Asian ITP subjects who were predominantly Caucasian. An initial dose of 25mg once daily has not been studied in a randomized fashion in East Asian subjects with ITP. METHODS: This is a randomized study comprising a double-blind (DB), placebo (PBO)-controlled phase, followed by an open-label (OL) phase in previously treated Chinese patients with chronic ITP who had failed ≥1 previous treatment. Subjects were stratified at baseline by use of ITP medication, splenectomy status and platelet count ≤15×109/L. In the DB phase, Chinese Adults with Chronic ITP and platelet counts <30 ×109/L received standard of care and were randomized (2:1) to receive either an initial dose of 25mg of eltrombopag or matching placebo once daily. The dose was increased every 2 weeks by 25 mg once daily increments up to a maximum of 75 mg once daily if the desired platelet response (> 50×109/L) was not achieved. The primary efficacy endpoint was the proportion of patients achieving a platelet count of ≥50×109/L and ≤250×109/L after the first 6 weeks of study treatment using a logistic regression model adjusted for stratification factors . All subjects completing the DB phase entered the OL phase where they initiated (if they were on placebo) or continued (if they were on eltrombopag) to receive eltrombopag (25, 50 or 75 mg/day) based on individual platelet counts. RESULTS: 155 subjects were randomized to receive 6 weeks of once daily eltrombopag (n=104) or matching placebo (n=51) in 2:1 ratio. Of 155 subjects randomized, 81 subjects (52.3%) were receiving concomitant ITP medication at baseline, 25 subjects (16.1%) had prior splenectomy, and 82 subjects (52.9%) had baseline platelet count ≤15×109/L. A total of 53/104 (51%) subjects on eltrombopag were receiving concomitant ITP medication at baseline vs 28/51 (54.9%) subjects on placebo. A total of 18/104 (17.3%) subjects on eltrombopag had prior splenectomy vs 7/51 (13.7%) subjects on placebo. A total of 54/104 (51.9%) subjects on eltrombopag had baseline platelet counts ≤15×109/L vs 28/51 (54.9%) subjects on placebo. The primary efficacy analysis showed that eltrombopag statistically significantly increased platelet counts in patients with chronic ITP: 57.7% (60/104) of subjects in eltrombopag group, and 6% (3/50) of subjects in placebo group achieved a platelet count of ≥50×109/L after the first 6 weeks of study treatment. (Odds ratio= 26.08, 95% CI [7.29, 93.26]; p <0.001). 63.5% (66/104) of patients in eltrombopag group and 66.7% (34/51) of patients in placebo group experienced adverse events. The most common (≥3% total incidence) adverse events are hypokalaemia [10.6% (11/104) in eltrombopag group, 15.7% (8/51) in placebo group], alanine aminotransferase increased [8.7% (9/104) in eltrombopag group, 15.7% (8/51) in placebo group], and nasopharyngitis [10.6% (11/104) in eltrombopag group, 9.8% (5/51) in placebo group]. The AEs were mostly mild to moderate. Only 4.9% (4/104) of patients on eltrombopag and 9.8% (5/51) of patients on placebo experienced serious adverse events. Additional safety and efficacy results will be presented at meeting. CONCLUSION: This is the first study to evaluate eltrombopag at an initial dose of 25mg once daily in a randomized fashion in East Asian patients with previously treated chronic ITP. Eltrombopag statistically significantly increased platelet counts in Chinese adults with chronic ITP when compared to placebo. Eltrombopag was well-tolerated and these results are consistent with the known clinical benefit: risk profile of eltrombopag in patients with chronic ITP. Eltrombopag may be a new treatment option for Chinese patients with chronic ITP. Disclosures No relevant conflicts of interest to declare.

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Cancer incidence following a high-normal platelet count: cohort study using electronic healthcare records from English primary care

British Journal of General Practice ◽

10.3399/bjgp20x710957 ◽

2020 ◽

Vol 70 (698) ◽

pp. e622-e628

Author(s):

Luke TA Mounce ◽

Willie Hamilton ◽

Sarah ER Bailey

Keyword(s):

Primary Care ◽

Cohort Study ◽

Platelet Count ◽

Cancer Incidence ◽

Clinical Practice Research Datalink ◽

Normal Range ◽

Platelet Counts ◽

Normal Platelet Count ◽

Normal Platelet ◽

One Year

BackgroundA raised platelet count (thrombocytosis) measuring >400 × 109/l is associated with high cancer incidence. It is uncertain whether platelet counts at the upper end of the normal range (high-normal: 326–400 × 109/l) are also associated with cancer.AimTo investigate cancer incidence following a normal platelet count in primary care.Design and settingA prospective cohort study was undertaken using data from the Clinical Practice Research Datalink and National Cancer Registration and Analysis Service, dating from 1 May 2005 to 30 April 2014.MethodOne-year cancer incidence was estimated for 295 312 patients with normal platelet counts (150–400 × 109/l). Patients with platelet counts >325 × 109/l were oversampled to maximise precision of estimates of cancer incidence. All patients were aged ≥40 years with no prior cancer diagnoses. The effects of age, sex, and smoking were explored. Non-melanoma skin cancers were omitted from exclusions and incidence.ResultsOne-year cancer incidence increased greatly with age, male sex, and higher platelet count. Males aged ≥60 years with a high-normal count had an incidence of 4.2% (95% confidence interval [CI] = 4.0 to 4.4). The highest incidence of 6.7% (95% CI = 5.3 to 8.4) was found in males aged ≥80 years, who had platelets in the range of 376–400 × 109/l; this was 3.1 percentage points higher than the incidence for patients in the same age group with lower-normal counts of 150–325 × 109/l. Risks for all female subgroups were <3%. Patients with high-normal platelet counts were most at risk of lung and colorectal cancers and, in general, had advanced-stage cancer at diagnosis.ConclusionPlatelet counts at the high-normal range in males aged ≥60 years may be indicative of an underlying malignancy, and referral for further investigation should be considered.

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Platelet Response to Avatrombopag in Patients with Chronic Immune Thrombocytopenia: Additional Analyses from a Phase 3 Study and Its Extension

Blood ◽

10.1182/blood-2019-130963 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1071-1071 ◽

Cited By ~ 1

Author(s):

Srikanth Nagalla ◽

Michael Vredenburg ◽

Wei Tian ◽

Lee F. Allen

Keyword(s):

Platelet Count ◽

Clinical Studies ◽

Immune Thrombocytopenia ◽

Complete Response ◽

Extension Phase ◽

Phase 3 ◽

Platelet Counts ◽

The Core ◽

Core Study ◽

Chronic Immune Thrombocytopenia

Background: Avatrombopag (AVA) is a novel, oral thrombopoietin receptor agonist (TPO-RA) recently FDA approved for the treatment of chronic immune thrombocytopenia (ITP) in patients who have not responded to prior therapies. Additionally, AVA is approved for the treatment of thrombocytopenia in chronic liver disease patients undergoing a procedure. AVA is unique in that it does not have a boxed safety warning for hepatoxicity, is administered with food, and does not have any dietary restrictions. Further, it does not interact with polyvalent cations (calcium, magnesium, iron, selenium, zinc, etc.) in foods, mineral supplements, or antacids that could reduce systemic exposure and efficacy. Methods and Aims: A 6-month, multicenter, randomized, double-blind, Phase 3 study (Core Study) enrolled 32 AVA- and 17 placebo (PBO)-treated patients with ITP. The mean platelet count at Baseline was 13,600/µL for the study population. The starting dose for AVA was 20 mg QD, with subsequent dose titration (5 to 40 mg) to maintain platelet counts between 50,000 to 150,000/µL. The primary endpoint was the median cumulative number of weeks achieving a platelet count ≥50,000/µL, and AVA was shown to be superior to PBO (12.4 vs. 0.0 weeks, p<0.0001). Achieving a platelet count of ≥50,000/µL on Day 8 was a key secondary endpoint with 65.6% of AVA-treated patients meeting this endpoint versus 0% for PBO (p<0.0001). AVA had a favorable safety profile with the most frequently reported adverse events including headache, fatigue, contusion, epistaxis and upper respiratory tract infection. In addition, patients could enter the Extension Phase if they completed the 6-month Core Study, or if they experienced a lack of efficacy during that period. Reaching a target platelet count of ≥50,000/µL at any time is a common endpoint for therapies in clinical studies as well as in clinical practice, with a platelet count of ≥100,000/µL often being defined as a complete response. The objective of the analyses of these endpoints for the Phase 3 study was to provide previously unreported data, and further evaluate the efficacy of AVA in patients with ITP, i.e., the percentage of patients who achieved platelet counts ≥50,000/µL or ≥100,000/µL at any time during the Core Study and its Extension Phase. Results: In the Core Study, a high proportion of AVA patients achieved a platelet count ≥50,000/µL relative to PBO by Day 28 (84.4% vs. 0.0%, respectively) and Week 26 (87.5% vs. 5.9%). In an integrated analysis of the Core Study and its Extension Phase, 93.8% of patients initially randomized to AVA achieved a platelet count of ≥50,000/µL at any time, and 64.7% of PBO patients who rolled-over to AVA in the Extension Phase also reached this metric. In addition, a high proportion of patients in the Core Study achieved platelet counts categorized as a complete response, with 81.3% of patients reaching a platelet count ≥100,000/µL at any time by Month 6, versus 5.9% with PBO. Across the Core Study and its Extension Phase, 84.4% of patients initially randomized to AVA and 58.8% of those who initially received PBO achieved a complete response at any time. During the Extension Phase out through 36 weeks, both patients who were initially randomized to AVA and the PBO patients who rolled over to AVA in the Extension Phase maintained mean platelet counts ≥ 50,000/µL, demonstrating the consistency of efficacy for AVA; i.e., both PBO-treated patients responded to active drug and those previously administered AVA maintained platelet counts in the target range in the Extension Phase. Conclusions: Analysis of these previously unreported alternative efficacy endpoints that are standard across other clinical studies demonstrated a high proportion of AVA-treated patients in the Phase 3 study as responders or complete responders. Further, the integrated analyses of the Phase 3 Core Study and Extension Phase data provides additional information regarding the durability of the AVA response, and illustrates the consistency of effect with PBO-treated patients also responding to subsequent treatment with AVA. Table Disclosures Nagalla: Alnylam: Membership on an entity's Board of Directors or advisory committees. Vredenburg:Dova Pharmaceuticals: Employment, Other: Shareholder. Allen:Dova Pharmaceuticals: Equity Ownership, Other: Chief Medical Officer .

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A Randomized, Double-Blind, Placebo-Controlled Phase II Trial on the Efficacy, Safety and Tolerability of E5501 (AKR501) In Subjects with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v116.21.71.71 ◽

2010 ◽

Vol 116 (21) ◽

pp. 71-71 ◽

Cited By ~ 3

Author(s):

James B. Bussel ◽

Jenny Zhang ◽

Shande Tang ◽

Joe McIntosh ◽

David J. Kuter

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Responder Rate ◽

Dependent Manner ◽

Advisory Committees ◽

Double Blind ◽

Baseline Platelet Count ◽

Platelet Counts ◽

Dose Dependent

Abstract Abstract 71 Chronic immune thrombocytopenia (ITP) is a condition of low platelet counts due to increased autoimmune-mediated platelet destruction and suboptimal platelet production. Thrombopoietin (TPO) receptor agonists are a novel class of agents which increase platelet counts by mimicking the principal physiologic regulator of platelet production, TPO. TPO agonists have demonstrated efficacy in randomized controlled trials in patients with ITP who are refractory to 1st and 2nd line agents. E5501 (previously AKR501) is a novel, orally-active, once-a-day TPO agonist which increased platelet counts in healthy volunteers. Here, we report data from a Phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group 4-week study (501-CL-003) of E5501 in subjects with ITP whose disease was refractory to, or had relapsed after, at least one prior ITP therapy. Subjects were enrolled if they had a baseline platelet count of <30 x109/L, or if they had a baseline platelet count of <50 x109/L and were on stable corticosteroid therapy. Sixty-four subjects were randomized to E5501 (2.5, 5, 10 or 20 mg) or placebo in a 3:3:3:3:1 randomization ratio, respectively. E5501 or placebo was administered orally, once daily for 28 days. Response to E5501 was based on weekly platelet counts. The primary endpoint was responder rate at Day 28. Responders were defined as subjects whose platelet count was ≥50 x109/L and had risen by a minimum of 20 x109/L above baseline. Responder rate increased in subjects receiving E5501 in a dose-dependent manner (Table 1). At Day 28, the responder rate in the E5501 20 mg group was 80% (12 of 15 subjects) vs 0% in the placebo group (p=0.0036). The responder rate was also significantly higher with E5501 20 mg than with E5501 2.5 mg (80% vs 13.3%; p=0.0007). In non-splenectomized subjects, the responder rate at Day 28 was 51.2% in the combined E5501 group and 88.9% in the E5501 20 mg group, compared with 44.4% and 66.7% respectively in splenectomized subjects. Median platelet counts at Day 28, and change in platelet counts above baseline, increased in subjects receiving E5501 in a dose-dependent manner (Table 2). The majority (57.6%) of subjects responded to a dose of ≥5 mg E5501 by Day 7. Subjects treated with E5501 20 mg achieved a 93.3% response rate on Day 7. None of the 5 placebo-treated subjects responded at any time during the study. E5501 was well tolerated, with a similar proportion of subjects showing treatment-emergent adverse events (TEAEs) across all dose groups. Most TEAEs were mild, transient, and resolved completely. TEAEs occurring in ≥10% of E5501-treated subjects were fatigue (20.3%), headache (20.3%) and epistaxis (15.3%). There were no clinically relevant changes in vital signs or physical examination findings. Three subjects (2 in the 2.5 mg and 1 in the 10 mg E5501 group) reported serious TEAEs. Of the two subjects in the 2.5 mg E5501 group, one reported thrombocytopenia and one reported a GI bleed; both had platelet counts <10 x109/L. The one subject in the 10 mg E5501 group, a 72-year-old Hispanic male with a significant history of cardiovascular disease (including myocardial infarction [MI], coronary artery vein bypass graft, 3 prior transient ischemic attacks [TIAs], chronic obstructive pulmonary disease, hypertension, systolic ejection murmur, angioplasty, stent placement, hyperlipidemia, and small vessel disease), had TIA and MI on Day 20 and a retinal artery occlusion 14 days after E5501 was discontinued. At the time of the events his platelet counts were 40–47 x109/L. Three other E5501-treated subjects (6.8% in total) experienced TEAEs leading to study drug withdrawal: 1 receiving 5 mg E5501 had Grade 2 musculoskeletal chest pain; 2 receiving 20 mg E5501 had excessively increased platelet counts with no clinical sequellae. In conclusion, E5501 was effective in increasing platelet counts in subjects with ITP. At 20 mg E5501, 80% of patients had responded at Day 28, with a median platelet count of 95 x109/L, and >90% of patients had responded by Day 7. E5501 was generally well tolerated and had a favorable safety profile. These data support continued development of E5501 as a potentially effective treatment with an acceptable safety profile in non-splenectomized and splenectomized patients with ITP. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy. Zhang:Eisai: Employment. Tang:Eisai: Employment. McIntosh:Eisai: Employment. Kuter:Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Shionogi: Consultancy, Research Funding; Pfizer: Consultancy; Protalix: Consultancy, Research Funding; Risk Managment Foundation: Consultancy.

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Assessment of the Effects of the Nitroimidazo-Oxazine PA-824 on Renal Function in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00112-09 ◽

2009 ◽

Vol 53 (9) ◽

pp. 3726-3733 ◽

Cited By ~ 35

Author(s):

Ann M. Ginsberg ◽

Martino W. Laurenzi ◽

Doris J. Rouse ◽

Karl D. Whitney ◽

Mel K. Spigelman

Keyword(s):

Renal Function ◽

Healthy Subjects ◽

Renal Plasma Flow ◽

Healthy Male ◽

Filtration Fraction ◽

Pathological Effect ◽

Once Daily ◽

Creatinine Excretion ◽

Renal Tubular ◽

Dose Dependent

ABSTRACT The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.

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