Thrombopoiesis-stimulating Peptibody Research Articles

Development of Romiplostim for Treatment of Primary Immune Thrombocytopenia From a Pharmacokinetic and Pharmacodynamic Perspective.

Romiplostim is a novel thrombopoiesis-stimulating peptibody consisting of a carrier Fc domain and a peptide domain that binds to the thrombopoietin receptor (TPOR) on platelets and platelet precursors. Similar to endogenous thrombopoietin, romiplostim activates the TPOR to stimulate the growth and maturation of megakaryocytes, resulting in increased production of platelets in the circulation. Binding of romiplostim to TPOR on the platelets and megakaryocytes presumably triggers subsequent internalization and degradation. Therefore, increased platelet counts following romiplostim treatment results in increased elimination of the drug. The TPOR target-mediated process is saturable, resulting in nonlinear volume of distribution and clearance of romiplostim. Therefore, target-mediated disposition plays a decreasing role in drug elimination with increasing romiplostim serum concentration. Conversely, nonspecific elimination processes such as renal clearance play an increasing role with increasing romiplostim serum concentration. Limited pharmacokinetics data demonstrated that the exposure to romiplostim was lower after multiple dose administrations than after the first dose, although large inter-subject variability was observed. Large inter- and intra-subject variability in the platelet response was also observed at a given dose. These findings suggest considerable heterogeneity of disease in patients with primary immune thrombocytopenia and support the need for individual dose adjustments based on platelet counts.

Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined. The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, RO(thr), and K(D) parameters were determinants of drug potency, whereas S(max) reflected drug efficacy. The model implicated that receptor-mediated clearance was negligible. RO(thr) estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of K(D) were 4.05, 2320, and 429ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship. The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys, and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.

Romiplostim therapy in children with unresponsive chronic immune thrombocytopenia

Romiplostim, a thrombopoiesis-stimulating peptibody, represents a new therapeutic option in adult refractory chronic immune thrombocytopenia (ITP). This study aimed to assess the short-term efficacy and safety of romiplostim in children with chronic ITP. Eight non-splenectomized patients with chronic ITP refractory to standard lines of medical therapy were recruited from the Pediatric Hematology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt. One patient was initially excluded because of increased bone marrow reticulin (grade 3). Therapy was initiated in seven patients, aged 3.4–15.2 years (median 5.5 years), and the disease duration ranged from 13 months to 7.3 years (median 2.4 years); none were splenectomized. Romiplostim dose was started as 1 µgm/kg/week and the dose escalated by 1 µgm/kg/week according to platelet count. The duration of therapy varied between 1 and 22 weeks (median 12 weeks). Results revealed that four out of the seven patients achieved variable response. Four patients demonstrated rapid increase in platelet count when pulse steroid therapy was added. Most reported adverse events were mild and transient. This case series study reveals variable response rate in children with chronic ITP to romiplostim therapy; addition of steroids especially in emergency bleeding situations could potentiate romiplostim thrombopoietic effect even in patients initially refractory to steroids. Romiplostim safety and efficacy in pediatric ITP needs further long-term studies.

Romiplostim – A Thrombopoiesis-stimulating Peptibody for the Management of Chronic Immune Thrombocytopenic Purpura in Adults

Romiplostim – A Thrombopoiesis-stimulating Peptibody for the Management of Chronic Immune Thrombocytopenic Purpura in Adults

Pharmacodynamics and Pharmacokinetics of AMG 531, a Thrombopoiesis‐Stimulating Peptibody, in Healthy Japanese Subjects: A Randomized, Placebo‐Controlled Study

AMG 531 is a novel thrombopoiesis-stimulating peptibody being investigated for the treatment of chronic immune thrombocytopenic purpura. This double-blind, phase I study evaluated the safety, pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531/placebo) to receive 1 dose of AMG 531 (0.3, 1, or 2 microg/kg) or placebo by subcutaneous injection; subjects were evaluated for 6 weeks. AMG 531 was generally well tolerated, with adverse events similar to placebo. Treatment-related adverse events (headache, "feeling hot," malaise) were reported for 5 of 24 AMG 531-treated subjects. Platelets generated after exposure to AMG 531 functioned normally. Four of 8 subjects receiving 1 microg/kg and 7 of 8 receiving 2 microg/kg had platelet count increases > or =1.5-fold over baseline, an effect similar to that seen in non-Japanese subjects. Serum AMG 531 concentrations were below the lower limit of quantification in all but 2 subjects receiving 2 microg/kg.

Phase 1/2 Study of AMG 531 in Thrombocytopenic Patients (pts) with Low-Risk Myelodysplastic Syndrome (MDS): Update Including Extended Treatment.

Background: AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. This report updates outcomes in Part A of the study as of May 2007 on pts who continued into the extension phase of this ongoing phase 1/2, open-label, sequential-cohort, dose-escalation study to evaluate the safety and efficacy of AMG 531 in low risk MDS pts with severe thrombocytopenia (Kantarjian et al., ASCO, 2007).Methods: Pts with low- risk MDS (IPSS Low or Intermediate-1, excluding CMML), a mean baseline platelet count ≤50×109/L, and only receiving supportive care were eligible to enter this study. Pts were enrolled into sequential cohorts of 300, 700, 1000, and 1500μg, receiving 3 weekly subcutaneous injections of AMG 531. After evaluation of platelet response at week 4, pts could continue AMG 531 in an optional treatment extension at their assigned dose or dose adjust to achieve or maintain a response.Results: The mean duration of exposure to AMG 531 was 23±15.5 (SD) weeks. Of 44 pts enrolled, 40 continued into the extension phase; 16 pts remain on treatment. Eighteen pts (41%) achieved a durable platelet response (per IWG 2006 criteria for at least 8 consecutive weeks). Evaluation of durable responses based on baseline platelet count showed that responses occurred in 12/29 (41%) pts with a baseline count of ≥20×109/L, and in 6/15 (40%) pts with a baseline count of <20×109/L. The mean duration of the platelet response was 22.8±13.3 (SD) weeks. A total of 104 platelet transfusions were given to 17/44 (39%) pts during this study; of these transfusions, 7 were given in 3/18 (17%) pts who achieved a durable response. Treatment-related AEs were reported in 17 pts. There were 3 deaths unrelated to treatment. Two confirmed cases of transformation to AML were reported. These two pts received maximum doses of 300 and 1000μg. Six pts were confirmed to have temporary blast cell increases, three of whom had increases above 20%. Of the 6, 4 were receiving 1500μg and 2 were receiving 1000μg. In all 6 pts, blast cell counts were observed to have fallen upon follow-up assessments within 7 weeks after treatment discontinuation. In one case, treatment was reinitiated at 700μg.Conclusions: In this study, AMG 531 appeared to be well-tolerated in severely thrombocytopenic low-risk MDS pts, and resulted in increased and sustained platelet counts in the responding pts. AMG 531 may have a role in the treatment of low-risk MDS pts who are thrombocytopenic or have a history of bleeding. These data suggest that further exploration is merited in this pt population. Pt recruitment is ongoing until reaching the planned 84 pts.

A Phase 2 Open-Label, Sequential-Cohort, Dose-Escalation Study of AMG 531 in Japanese Patients with Chronic Immune Thrombocytopenic Purpura (ITP).

AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. [Display omitted]

Reduction in Immunoglobulin (IVIG or Anti D) Use in Patients with Chronic Immune Thrombocytopenic Purpura (ITP) Receiving AMG 531: Results from Two Phase 3 Randomized Placebo-Controlled Trials.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. We report pooled data on acute use of immunoglobulin (IVIG or Anti D) in both splenectomized and nonsplenectomized patients from 2 randomized, double blind, placebo-controlled Phase 3 studies designed to evaluate the efficacy and safety of AMG 531 in adult patients with chronic ITP. Patients were randomized to receive either AMG 531 or placebo at a 2:1 ratio, and concomitant medications were continued. Of the 125 patients enrolled, 63 were splenectomized (placebo, 21; AMG 531, 42), and 62 were nonsplenectomized (placebo, 21; AMG 531, 41) with a median age of 52 years (range 21 to 88) and a mean baseline platelet count of 16.5x109/L. Immunoglobulin was allowed as rescue medication when medically necessary at the discretion of the physician. For both trial arms, we calculated the percentage of patients requiring immunoglobulin intervention in each month of treatment, and the age and sex-adjusted 24-week cumulative probability of immunoglobulin use. No difference was observed between splenectomized and nonsplenectomized patients; therefore pooled results are shown. Fisher's exact tests and Log-Rank tests were used to compare the between-arm differences. We also performed subgroup analyses of immunoglobulin use in overall responders (defined as either platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24-week treatment period in the absence of rescue medications at any point in the study, or ≥4 weekly platelet counts ≥50x109/L in the absence of rescue medications in the previous 8 weeks), and placebo patients. In the 24-week study period, there were 19 immunoglobulin administrations among 83 AMG 531 patients, and 68 immunoglobulin administrations among 42 placebo patients. The cumulative probability of incurring immunoglobulin use in 24 weeks was 0.51 (SE: 0.08) for the placebo arm and 0.13 (SE: 0.04) for the AMG 531 arm (see Figure), with a hazard ratio of 5.31 (95% CI: 2.55–11.06, p<0.001). Per-cycle immunoglobulin use ranged from 19% to 29% in the placebo arm, and from 0% to 6% in the AMG 531 arm (p≤0.01 in all cycles). Subgroup analysis showed that compared to placebo patients, overall responders of AMG 531 had even greater reduction in immunoglobulin use in each cycle (0 to 4%, p<0.006). AMG 531 treatment was associated with significantly reduced immunoglobulin use in both splenectomized and nonsplenectomized patients with chronic ITP. Moreover, placebo patients were 5 times more likely to receive immunoglobulin therapy compared to AMG 531-treated patients. [Display omitted]

Health-Related Quality of Life (HRQoL) in Patients (Pts) with Chronic Immune Thrombocytopenic Purpura (ITP): Results from Two Placebo-Controlled Phase 3 Studies of AMG 531.

Pt-reported outcomes (PROs) are important tools for understanding the effects of treatment for various diseases. We developed the ITP Pt Assessment Questionnaire (ITP-PAQ) as the first disease-specific PRO instrument for adult chronic ITP. Further evaluation of its validity was assessed in ITP pts receiving AMG 531. AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. The ITP-PAQ was used to examine HRQoL changes in both splenectomized and nonsplenectomized pts from 2 randomized, double blind, placebo-controlled Phase 3 studies of AMG 531 in adult pts with chronic ITP. It contains 44 items and 10 scales including Symptoms, Bother, Fatigue, Activity, Fear, Psychological, Work, Social Activity, Women's Reproductive Health, and Overall Quality of Life. Pts were blinded to their platelet counts before completing the ITP-PAQ. Changes in mean scores from baseline to week 24 were calculated for each ITP-PAQ scale by treatment arm, with positive values indicating improvement in HRQoL. Independent two-tailed t-tests were used to test differences. Specific items within each scale were also analyzed to provide further insights into the disease-specific areas of most concern for pts. Of the 125 pts enrolled, 63 were splenectomized (placebo, 21; AMG 531, 42), and 62 were nonsplenectomized (placebo, 21; AMG 531, 41). At baseline, splenectomized pts had lower scores on all ITP-PAQ scales than nonsplenectomized pts, especially Bother (51.0 vs 66.7), Fear (69.4 vs 81.3), Work (62.4 vs 77.5), and Overall Quality of Life (40.3 vs 56.5). Over the 24-week study, AMG 531-treated pts reported significantly greater improvement relative to placebo on 5 of 10 scales. Among splenectomized pts, significantly greater improvements in mean scores from baseline were found in the AMG 531 arm for Symptoms (placebo vs AMG 531; 0.2 vs 10.8, p=0.02), Bother (4.5 vs 24.6, p=0.009), Social Activity (−2.1 vs 16.9, p=0.017), and Women's Reproductive Health (−11.9 vs 10.1, p=0.027). Among nonsplenectomized pts, significantly greater improvement was found in AMG 531 pts for Activity (−1.8 vs 23.7, p=0.016). Particular improvements in items shown by both splenectomized and nonsplenectomized AMG 531-treated pts included bleeding (Symptoms), bruising (Symptoms), feeling unattractive due to bruising (Bother), and fear of infections (Fear). In summary, lower HRQoL was reported in splenectomized compared to nonsplenectomized pts with ITP, reflecting potentially different clinical needs for these 2 pt populations. Pts treated with AMG 531 showed greater improvement in HRQoL relative to placebo pts on most ITP-PAQ scales, and significant improvements were more common in splenectomized pts. Results from these 2 trials have provided further validation of the ITP-PAQ and can inform selection of key endpoints for future studies.

Health-Related Quality of Life (HRQoL) in Patients with Chronic Immune Thrombocytopenic Purpura (ITP): Interim Results from an Open-Label Study of AMG 531.

The ITP Patient Assessment Questionnaire (ITP-PAQ) was developed to complement clinical data by assessing multiple facets of disease-specific HRQoL in adult patients with chronic ITP (Mathias et al., Health Qual Life Outcomes, 2007). Here we present interim results from an ongoing, open-label extension study that will evaluate the ability of AMG 531 to improve their HRQoL in the long-term. AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. Adult chronic ITP patients receiving AMG 531 completed the ITP- PAQ at baseline, and weeks 4, 12, 24, and every 12 weeks thereafter. The ITP-PAQ consists of 44 items and 10 scales. Data have been assessed for this interim analysis through week 48, a time-point with reasonable patient numbers at the time of the data cut-off. Mean scores at each assessment, and changes in mean scores from baseline to week 48 were calculated, with positive changes in mean score indicating improvement in HRQoL. Compliance rates for the ITP-PAQ were 95% at baseline, 93% at week 4, and 83% at week 48. Over the 48-week period, results demonstrated an upward trend for the scale scores (see Table). The greatest improvements were reported in the Symptoms, Bother, Activity, Reproductive Health, and Overall Quality of Life scales, particularly during the first 4 weeks of the study. Changes in mean score from baseline to week 48 were significantly increased for Symptoms, Bother, Fatigue, Activity, Fear, Psychological Health, Work, Social Activity, and Overall Quality of Life. ITP patients receiving AMG 531 had an initial, yet sustained, improvement in ITP-PAQ scores. Subsequent analyses of results collected in this ongoing study will be used to substantiate our findings, and the therapeutic benefit of AMG 531 on HRQoL in patients with chronic ITP will be provided by correlations with clinical data. [Display omitted]

Evaluation of AMG 531 Efficacy in Splenectomized Patients with Chronic Immune Thrombocytopenic Purpura (ITP) in a Randomized Placebo-Controlled Phase 3 Study.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that acts by stimulating the thrombopoietin (TPO) receptor. We report efficacy data in splenectomized patients from a randomized, double blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of AMG 531 in patients with chronic ITP. Sixty-three splenectomized patients were enrolled (placebo, 21; AMG 531, 42), with a median age of 52 years (range 26 to 88) and a mean baseline platelet count 14.7x109/L. Subcutaneous AMG 531 or placebo was administered weekly for 24 weeks at a starting dose of 1μg/kg, and adjusted to maintain a target platelet count of 50–200x109/L. The primary study endpoint was the incidence of a durable platelet response, defined as a platelet count ≥50x109/L for ≥6 weeks during the last 8 weeks of the 24 week treatment period in the absence of rescue medications. Sixteen of the 42 splenectomized patients (38.1%) receiving AMG 531 achieved a durable platelet response compared to 0/21 (0.0%) receiving placebo (p=0.0013). Overall response, defined as either durable or transient platelet response (≥4 weekly platelet responses), was observed in 33/42 (78.6%) patients receiving AMG 531, compared to 0/21 (0%) placebo patients. The mean number of weekly platelet responses (platelet count ≥50x109/L) was significantly greater in patients receiving AMG 531 (12.3/24 weeks, 51%) compared to placebo (0.2/24 weeks, 1%) (p<0.0001). AMG 531 reduced the proportion of patients requiring ITP rescue medications, defined as either increase from baseline in dose of concurrent medication or use of new medication to increase platelet counts. Twelve of 21 (57.1%) placebo-treated patients received rescue medications compared to just 11/42 (26.2%) AMG 531-treated patients (p=0.0175). In addition, 12/12 (100.0%) AMG 531-treated patients compared to 1/6 (16.7%) placebo-treated patients either discontinued or reduced by >25% their concurrent ITP medications. AMG 531 was well-tolerated. There were 2 treatment-related serious adverse events; 1 patient with elevated bone marrow reticulin that returned to baseline 3 months after withdrawal of AMG 531, and 1 patient experienced thrombosis that was successfully treated allowing study continuation. No patient developed neutralizing antibodies against either AMG 531 or endogenous TPO. In summary, AMG 531 was well-tolerated, and effectively increased and sustained platelet counts in splenectomized patients with ITP. AMG 531-treated patients required less frequent rescue medications in comparison to those receiving placebo, and were able to reduce their use of concurrent therapies.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 2-Year Update.

AMG 531, a novel thrombopoiesis-stimulating peptibody, increases platelet production by stimulating the TPO receptor. This study is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, SC administration of AMG 531 in patients with chronic ITP who completed a previous AMG 531 study. Patients previously treated with AMG 531 received the same starting dose as the final dose given in the previous study; placebo-treated patients began the extension at 1μg/kg. Doses could be adjusted based on platelet response. As of an April 2007 analysis, 137 patients were enrolled and 136 had received AMG 531. The longest treatment duration was 122 weeks; 22 patients were followed for 96 weeks or longer. At baseline, 91 women and 46 men had a mean age of 53±15(SD) years and a median (range) platelet count of 18(1–50)x109/L; 82 patients (60%) had undergone splenectomy. The most frequently reported adverse events (AEs) were headache (overall incidence 31%), contusion (27%), fatigue (24%), diarrhea (24%), epistaxis (23%), nasopharyngitis (21%), and arthralgia (20%). Exposure-adjusted analysis showed no trend for AEs to increase in frequency with increased drug exposure (table). Eleven patients had serious AEs judged by investigators as treatment-related including 3 withdrawn from study (vaginal hemorrhage, increased reticulin in the bone marrow reported as myelofibrosis, and initial report of multiple myeloma later reclassified as monoclonal gammopathy of undetermined significance - 1 report each) and 8 who continued on-study (bone marrow disorder/reticulin fibrosis - 3, unacceptably high platelet count - 2, thrombosis - 2, and cerebral thrombosis/papilloedema/temporary blindness - 1). One patient developed neutralizing antibodies to AMG 531 (absent on retesting 4 months after drug cessation), with no clinical sequelae and no cross-reactive antibodies to TPO. Overall, 112 patients (82%) achieved a platelet response (≥50x109/L and doubling of baseline). From week 4 onward, weekly incidence of platelet response ranged from 52–73% (figure). Median number of weeks to first response was 2 (median dose 3μg/kg). Of 30 patients with baseline use of concurrent ITP therapies, 13 were able to discontinue them and 6 additional patients had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for long-term treatment of chronic ITP. The safety profile has been acceptable, and most patients have been able to maintain a platelet response and discontinue or reduce concurrent ITP therapies. [Display omitted] [Display omitted]

Evaluating safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study

7032 Background: The prevalence of thrombocytopenia in MDS ranges from 40% to 65%, hemorrhagic complications range from 3% to 53%, and hemorrhagic deaths range from 14% to 24% (Kantarjian 2006). Platelet transfusion can lead to reactions, infection, and alloimmunization. AMG 531 is a thrombopoiesis-stimulating peptibody that increases platelet production. This phase 1/2 study evaluated the safety and efficacy of AMG 531 in thrombocytopenic MDS patients. Methods: A minimum of 5 subjects with low risk MDS (IPSS low or intermediate-1) and a platelet count of = 50×109/L were enrolled to receive 3 QW SC injections of AMG 531 in each of 4 sequential dose cohorts. After evaluation at week 4, subjects could continue AMG 531 in an optional treatment extension at their assigned dose or escalated to a responding dose. Erythroid growth factors were allowed, but no other active treatment. Results: 28 subjects (9 transfusion-dependent) have been enrolled to date. All subjects were evaluable for response and entered the extension; 17 continue treatment. Dose-limiting toxicity (DLT) was defined as a drug-related grade 3 or 4 adverse event (AE) or a platelet count ≥ 600×109/L. Two DLTs occurred, both due to elevated platelet counts. No treatment-related severe AEs occurred. There was 1 treatment-unrelated death. Overall, 17 subjects (61%) achieved a platelet response. Median baseline platelet count for responders was 25×109/L with a median peak platelet count of 130×109/L during the 4 week treatment period. Of the 18 subjects to date completing at least 12 weeks of treatment, 11 (48%) achieved a durable response of at least 8 consecutive weeks (revised IWG criteria, Cheson 2006). A total of 90 clinically significant thrombocytopenic events (39 bleeding, 51 transfusions) were observed over both treatment phases. There were 16 such events (12 bleeding, 4 transfusions) in 6 subjects with a durable response, 6 events (6 minor bleeds, 0 transfusions) during the durable response period. There were 74 events (27 bleeding, 47 transfusions) in 11 subjects without a durable response. Conclusions: These preliminary data suggest that bleeding and transfusion events can be reduced in thrombocytopenic low risk MDS patients who respond to AMG 531. [Table: see text]

Platelet Aggregation Analysis of AMG 531 in a Randomized, Placebo-Controlled Study in Healthy Japanese Subjects.

AMG 531 is a novel thrombopoiesis-stimulating peptibody currently being investigated for the treatment of chronic immune thrombocytopenic purpura. This study was a double-blind, phase 1 evaluation of safety (including a platelet aggregation analysis), pharmacodynamics, and pharmacokinetics of AMG 531 in healthy Japanese men. Thirty subjects were randomly assigned 4:1 (AMG 531:placebo) to each of 3 sequential dose cohorts (0.3, 1, and 2 μg/kg) of 10 subjects each. A single dose of AMG 531 or placebo was administered by subcutaneous injection, and subjects were evaluated for 6 weeks. Concentrations of 0.2 and 2 μg/mL collagen and 0.5 and 2 μmol/L adenosine phosphate were used as reagents in the platelet aggregation analysis conducted on day -1, day 2, day 15, and at the end of the study. No enhancement or reduction in platelet aggregation was detected in samples collected from subjects treated with AMG 531 compared with either pretreatment or placebo samples. Overall, adverse events were similar between the AMG 531 and placebo groups. Treatment-related adverse events (headache, “feeling hot,” migraine without aura, and/or malaise) were reported for 5 of 24 subjects treated with AMG 531. Four of 8 subjects who received the 1 μg/kg dose and 7 of 8 subjects who received the 2 μg/kg dose had platelet count increases ≥ 1.5-fold over baseline, and 3 of 8 subjects who received the 2 μg/kg dose had platelet count increases ≥ 2-fold over baseline, a pharmacodynamic effect similar to that seen in previous studies of non-Japanese subjects. Serum concentrations of AMG 531 were below the lower limit of quantification in all but 2 subjects who received the 2 μg/kg dose. In summary, platelets in subjects treated with AMG 531 functioned normally compared with pretreatment and placebo samples. AMG 531 was generally well tolerated and was effective at raising platelet counts after a single subcutaneous administration.

Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

An open‐label, unit dose‐finding study of AMG 531, a novel thrombopoiesis‐stimulating peptibody, in patients with immune thrombocytopenic purpura

Abstract The objective of this open label, phase 1-2, multicentre trial was to evaluate the safety of AMG 531, a novel thrombopoiesis-stimulating peptibody, and its effect on platelet counts in adults with immune thrombocytopenic purpura. Four patients were assigned to each of four unit-dose cohorts: 30, 100, 300 or 500 microg, administered subcutaneously on days 1 and 15 (or day 22 if the day 15 platelet count was >50 x 10(9)/l). Safety was assessed by adverse event (AE) monitoring, clinical laboratory studies and antibody assays. Platelet response was defined as a platelet count double the baseline value and between 50 and 450 x 10(9)/l. Sixteen patients (10 women) were enrolled. The 500-microg cohort was discontinued because the first patient's platelet count became unacceptably high. AEs were generally expected and mild or moderate; the most frequent was headache (eight of 16 patients). Two patients experienced serious AEs related to AMG 531 (severe headache and elevated serum lactic dehydrogenase; thrombocytopenia). Platelet responses occurred with all doses and with a dose equivalent to >/=1 microg/kg in eight of 11 patients. In summary, patients tolerated AMG 531 well at the doses tested. No anti-AMG or antithrombopoietin antibodies were detected. Doses equivalent to >/=1 microg/kg increased platelet counts.