Safety and Efficacy of Extended Treatment with Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2011,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3296-3296 ◽  
Author(s):  
Mansoor N Saleh ◽  
Gregory Cheng ◽  
James B Bussel ◽  
Paul Burgess ◽  
Lisa Marcello ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership ◽  
Clinically Significant

Abstract Abstract 3296 Background: Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). In 6-week, and 6-month, placebo-controlled trials, eltrombopag safely increased platelets and reduced bleeding in patients (pts) with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP pts. Methods: Pts had received eltrombopag or placebo in one of the following studies: TRA100773A or B (6-weeks), RAISE (6-months), or REPEAT (intermittent treatment). The EXTEND study was designed to: 1) identify an individual dose that increases platelets to ≥100,000/μL to support reduction of concomitant ITP medications, 2) identify a minimal dose of eltrombopag and concomitant ITP medication to maintain platelets ≥50,000/μL, and 3) evaluate long-term safety and efficacy. Pts completed the study if they completed ≥2 years of therapy and transitioned off study due to commercial availability of eltrombopag. Results: Of 301 pts enrolled, 21% (63) completed the study, 48% (143) withdrew, and 32% (95) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), pt decision (13%), and lack of efficacy (11%). At baseline, platelet counts were ≤15,000/μL, >15,000-<30,000/μL, 30,000–50,000/μL, and >50,000/μL in 43%, 27%, 17%, and 13% of pts, respectively; 38% were splenectomized, 34% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. As of this report, 252, 215, 176, and 84 pts had been treated for ≥6 months, 1 year, 2 years, and 3 years, respectively. Twenty-three pts (8%) were treated for ≥4 years. Median duration of exposure was 121 weeks (range, 0.3–237 weeks). Overall, 88% (264/301) of pts achieved a platelet count ≥50,000/μL at least once. The proportion of pts achieving on-treatment platelets ≥50,000/μL was similar regardless of the following baseline characteristics: splenectomy vs no splenectomy (85% vs 89%); use vs no use of ITP medication (89% vs 87%); and platelet counts (<30,000/μL, 84%; 30,000–50,000/μL, 98%; >50,000/μL, 95%). Median platelet counts increased to ≥50,000/μL by week 2 and remained consistently ≥50,000/μL through week 208. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 56% at baseline to 16%, 19%, and 9% at weeks 52, 104, and 156, respectively. Clinically significant bleeding (WHO grades 2–4) decreased from 16% at baseline to 3%, 5%, and 0% at weeks 52, 104, and 156, respectively. AEs and serious AEs (SAEs) occurred in 89% (269) and 29% (86) of pts, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (21%). Forty pts (13%) had AEs leading to withdrawal; 28 (9%) had SAEs leading to withdrawal. Twenty-five thromboembolic events (TEEs) have been reported in 19 pts (6%); the incidence rate is 3.02/100 pt years (95% CI [1.82–4.71]). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 pts experienced the TEE at or closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (Center for Drug Evaluation and Research 2009 [FDA]) were reported in 34 pts (11%). None were associated with signs of liver impairment, and most (n=30) resolved either while on treatment or after discontinuation. Eight pts were withdrawn as a result of their HBLA. Two pts were diagnosed with lymphoma and none with leukemia during the 622 pt years of eltrombopag exposure during EXTEND. An independent central review of bone marrow biopsies from >100 pts treated with eltrombopag for 1–4 years, including 39 pts who had ≥2 biopsies during the study, revealed no clinically significant increase in reticulin deposition. Conclusions: Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μL and reducing bleeding symptoms. Eltrombopag was well-tolerated during treatment of pts with chronic ITP with exposures up to 4.5 years. No new safety signals have been observed in this long-term study. Additional long-term safety data continue to be assessed, especially in terms of bone marrow reticulin, HBLAs, and TEEs. Disclosures: Saleh: GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cheng:GlaxoSmithKline: Speakers Bureau. Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Marcello:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

Long-Term Safety and Efficacy of Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP): Report of up to 5.5 Years of Treatment in EXTEND.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2198-2198
Author(s):  
Mansoor N Saleh ◽  
Gregory Cheng ◽  
James B Bussel ◽  
Paul Burgess ◽  
Kalpana Bakshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Drug Induced ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 2198 Background: Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic ITP. Eltrombopag safely increased platelets and reduced bleeding in 6-week and 6-month placebo-controlled trials in patients with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP patients who completed a previous eltrombopag study. Methods: Patients had received eltrombopag or placebo in a prior study. Eltrombopag was started at 50 mg and titrated to between 75 and 25 mg daily or less often, based on platelet counts. Patients were considered to have completed EXTEND if they had received ≥2 years of therapy and transitioned off due to commercial availability of eltrombopag, whether or not they continued with treatment. The study started in June 2006, and an update on long-term safety and efficacy up to February 2012 is presented. Results: Of 302 patients enrolled, 31% (95) completed the study, 48% (146) withdrew, and 20% (61) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), patient decision (14%), and lack of efficacy (11%). Platelet counts at baseline were ≤15,000/μL (43%), >15,000-<30,000/μL (27%), 30,000–50,000/μL (17%), and >50,000/μL (13%); 38% were splenectomized, 33% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. 253 patients were treated for ≥6 months, 217 for ≥1 year, 176 for ≥2 years, and 59 for ≥4 years; 10 patients (3%) were treated for ≥5 years. Median duration of exposure was 121 weeks (range, 0.3–285 weeks), and median average daily dose was 51.4 mg. Overall, 85% (257/302) of patients achieved a platelet count ≥50,000/μL in the absence of rescue therapy, and 62% of patients achieved platelets ≥50,000/μL for ≥50% of on-treatment weeks. The proportion of patients achieving platelets ≥50,000/μL was similar regardless of baseline splenectomy status: splenectomy, 80% vs no splenectomy, 88%. Median platelet counts increased to ≥50,000/μL by Week 2 and remained consistently ≥50,000/μL through Week 241. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 57% at baseline to 16% at Week 52, 19% at Week 104, 12% at Week 156, and 14% at Week 208. Clinically significant bleeding (WHO grades 2–4) decreased from 17% at baseline to 4%, 5%, 0%, and 0% at Weeks 52, 104, 156, and 208, respectively. AEs and serious AEs (SAEs) occurred in 91% (275) and 29% (89) of patients, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (22%). 43 patients (14%) were withdrawn due to AEs, 29 (10%) of which were SAEs. Twenty-five thromboembolic events (TEEs) were reported in 19 patients (6%); the incidence rate is 2.70/100 patient years (95% CI, 1.62–4.21). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 patients experienced the TEE at or shortly after their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (FDA Guidance for Industry Drug-Induced Liver Injury, 2009) were reported in 36 patients (12%). None were associated with signs of liver impairment, and most resolved either while on treatment or after discontinuation. Eight patients were withdrawn as a result of HBLA. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 113 patients treated with eltrombopag for up to 4.75 years revealed no clinically relevant increase in reticulin deposition. 2 patients (2%) had maximum reticulin grade of ≥MF-2 after >24 months on treatment; neither experienced any AE or abnormality in hematologic parameters potentially related to impaired BM function. Conclusions: Eltrombopag was effective in increasing and maintaining platelets ≥50,000/μL and reducing bleeding symptoms in patients with chronic ITP. Eltrombopag was well tolerated with exposures up to 5.5 years. Rates of TEE and HBLA have not increased with longer time on treatment, and analyses of BM biopsies revealed no clinically significant increase in reticulin deposition. No new safety signals were observed in this long-term study. Long-term safety and efficacy continue to be assessed. Disclosures: Cheng: GlaxoSmithKline: Honoraria, Speakers Bureau. 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; IgG of America: 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; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties. Bailey:GlaskoSmithKline: Employment, Equity Ownership.

Cumulative Response to Eltrombopag and Impact of the Number of Prior ITP Therapies: Interim Results of a Long-Term Extension Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3297-3297
Author(s):  
James B Bussel ◽  
Christine K Bailey ◽  
Andres Brainsky
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 3297 Background: Patients with chronic immune thrombocytopenia (ITP) have an increased risk of bleeding, ranging from minor to life-threatening. The goal of treatment is to increase and maintain platelets in a safe range to prevent bleeding. Guidelines state that achieving platelet counts of 30,000/μL to 50,000/μL in patients without other risk factors avoids the most serious complications of ITP, namely intra-cerebral or gastrointestinal hemorrhage (George 1996; Provan 2010). Many patients are refractory or relapse after multiple treatments. Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic ITP. In 6-week, and 6-month, placebo-controlled trials in patients with heavily pre-treated chronic ITP, eltrombopag increased platelets and reduced bleeding and the need for concomitant ITP therapy (Bussel 2007; Bussel 2009; Cheng 2011). Long-term treatment with eltrombopag is being evaluated in EXTEND, an extension study in chronic ITP patients who completed a previous eltrombopag study (Saleh 2010). Aims: To analyze in EXTEND the ability of eltrombopag to increase platelet counts to ≥50,000/μL in >50% and >75% of assessments and to determine whether the number of prior ITP therapies influences this ability. Methods: Patients in EXTEND received eltrombopag or placebo in 1 of the following prior studies of eltrombopag in chronic ITP: a 6-week phase 2 (TRA100773A; Bussel 2007) or phase 3 (TRA100773B; Bussel 2009) study, a 6-month phase 3 study (RAISE; Cheng 2011), or a phase 3 study of intermittent treatment (REPEAT; Psaila 2008). Dosing in EXTEND is individualized in order to maintain platelet counts ≥50,000/μL and <200,000/μL while minimizing the use of concomitant ITP medications. For the purpose of this analysis, response is defined as a platelet count ≥50,000/μL. Results: Among the 299 patients enrolled in EXTEND between June 2006 and February 2010, 67 (22%), 73 (24%), 47 (16%), and 112 (37%) patients had received 1, 2, 3, and ≥4 prior therapies (excluding eltrombopag). The most commonly used prior therapies were corticosteroids (81%), IVIg (45%), splenectomy (38%), and rituximab (23%). Of the 299 patients enrolled, 70% achieved response in >50% of study assessments and 46% achieved response in >75% of assessments. Among 210 patients treated ≥12 months, 79% achieved response in >50% of assessments and 56% in >75% of assessments. Among 138 patients treated for ≥24 months, 82% achieved response in >50% and 59% in >75% of assessments. Response in >50% and >75% of assessments by the number of prior therapies was similar between the groups (Figure 1). The proportion of patients who achieved a response in >50% of assessments was similar between splenectomized and non-splenectomized patients (65% and 73%, respectively). Conclusion: The majority of patients treated with eltrombopag for ≥12 months achieved a platelet count of ≥50,000/μL in >50% of study assessments. This response was observed even among patients previously treated with 4 or more ITP therapies, suggesting that eltrombopag may be a viable treatment option even for more refractory chronic ITP patients. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

scholarly journals Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3512-3512
Author(s):  
Rachael F. Grace ◽  
D. Mark Layton ◽  
Frédéric Galactéros ◽  
Wilma Barcellini ◽  
Eduard J. van Beers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
The Core ◽  
Equity Ownership ◽  
Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses &gt;25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals PETIT and PETIT 2: Treatment with Eltrombopag in 171 Children with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1450-1450 ◽  
Author(s):  
James B. Bussel ◽  
John D. Grainger ◽  
Purificacion Garcia de Miguel ◽  
Jenny M. Despotovic ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Thrombopoietin Receptor ◽  
Count Response ◽  
Equity Ownership

Abstract Background: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist, is approved for treating thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) with insufficient response to prior therapy. Pooled data from 2 similarly designed, randomized, double-blind, placebo (PBO)-controlled studies investigating safety and efficacy of EPAG in pediatric ITP are presented here. Methods: Subjects aged 1 to <18 years with a confirmed diagnosis of persistent or chronic ITP and a platelet count <30 Gi/L at day 1 were randomized 2:1 to EPAG or PBO and stratified by age: 12–17 years (Cohort 1), 6–11 years (Cohort 2), and 1–5 years (Cohort 3). Subjects could continue baseline ITP medications. After the PBO-controlled randomized phase, subjects were permitted to complete 17 or 24 weeks of treatment with open-label (OL) EPAG. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. Results: A total of 174 subjects were enrolled in both studies; 171 received ≥1 dose of EPAG. 159 subjects were randomized (intent-to-treat population), and 157 received ≥1 dose of randomized study treatment (safety population). In the randomized period, 3 EPAG and 1 PBO subject discontinued study treatment, of which 2 EPAG and 1 PBO discontinued due to adverse events (AEs). In the OL-EPAG period, an additional 14 EPAG subjects discontinued study treatment, 6 due to AEs. Males comprised 47% of the EPAG and PBO groups and 20% and 24% were East Asians, respectively. Most subjects (93%) were diagnosed with ITP for ≥12 months, and 13% were receiving ITP medications at baseline. The majority of subjects (81%) received ≥2 prior ITP therapies. Most subjects (59%) had a baseline platelet count <15 Gi/L. All 9 (6%) splenectomized subjects were randomized to the EPAG group. Randomized Period A higher proportion of EPAG versus PBO subjects (62% vs 24%; P < 0.001) achieved a response with platelet counts ≥50 Gi/L at least once between weeks 1–6 (Cohort 1, 64% vs 11%; Cohort 2, 64% vs 27%; Cohort 3, 54% vs 36%, respectively). At each week, a higher proportion of EPAG subjects had a response versus PBO (Fig. 1). A lower proportion of EPAG subjects (13%) received rescue treatment compared with PBO subjects (31%; P = 0.009). The odds of having World Health Organization (WHO) bleeding grades 1–4 (0.19; P = 0.011) and clinically significant (WHO grades 2–4) bleeding (0.29; P = 0.007) were lower for EPAG versus PBO subjects. EPAG-Only Period Sustained reduction or discontinuation of baseline ITP medications, primarily corticosteroids, was achieved by 50% of subjects; 81% of subjects had a platelet count response at least once; 52% (n = 80/154) had a platelet count response for ≥50% of assessments; and 38% (n = 58/154) responded for ≥75% of assessments. For >13 of 24 weeks, 47% of subjects achieved responses (Fig. 2). The median average daily dose for EPAG-exposed patients in Cohorts 1, 2, and 3 were 64.0 mg (0.93 mg/kg), 57.6 mg (1.50 mg/kg), and 37.0 mg (2.02 mg/kg), respectively. AEs Similar proportions of subjects in the EPAG and PBO groups reported an AE during the randomization period. The most common AEs (≥10% of subjects) were headache, upper respiratory tract infection, and nasopharyngitis in the EPAG group, and headache, epistaxis, and vomiting in the PBO group. Serious AEs (SAEs) were reported in 8% of EPAG subjects versus 12% of PBO subjects. No SAEs were reported by >1 subject in either treatment group except epistaxis, which was reported by 2 subjects in the PBO group. No SAEs were common to both treatment groups. In the randomized period, an ALT elevation of ³3 x ULN occurred in 5 (4.7%) subjects in the EPAG group and no subjects in the PBO group. In the OL period, there were an additional 7 subjects with ALT ³3 x ULN. All elevations resolved either while still on treatment or after discontinuation of study treatment. Overall, the hepatobiliary laboratory findings were mostly mild, reversible, and not accompanied by impaired liver function. Fewer EPAG than PBO subjects reported bleeding AEs (17% vs 36%, respectively). No thromboembolic events were reported. Cataract events were experienced by 2 subjects who received EPAG; both had used corticosteroids and 1 had pre-existing cataracts. Conclusions: EPAG was safe and raised platelet counts in 62% of pediatric patients with persistent and chronic ITP during the randomized phase. Treatment with EPAG was well tolerated in both studies as evidenced by the low incidence of treatment discontinuations due to AEs. Disclosures Bussel: Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Honoraria; Novartis: Honoraria; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Equity Ownership, Honoraria, Research Funding; Genzyme: Research Funding; Eisai, Inc.: Research Funding; Cangene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding. Off Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Grainger:GlaxoSmithKline: Honoraria; Baxter: Honoraria, Research Funding; Amgen: Honoraria. Pongtanakul:GlaxoSmithKline: Research Funding. Komvilaisak:GlaxoSmithKline: I am an investigator on this study. Other. Sosothikul:CSL Behring: Research Funding; GlaxoSmithKline: Research Funding. Drelichman:GlaxoSmithKline: I am investigator on this study. Other. David:GlaxoSmithKline: Research Funding. Marcello:GlaxoSmithKline: Employment. Iyengar:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Chagin:GlaxoSmithKline: Employment. Theodore:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3530-3530
Author(s):  
Michael D. Tarantino ◽  
James B. Bussel ◽  
Amy Geddis ◽  
Michael F. Guerrera ◽  
Alan K. Ikeda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Open Label ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Background Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim is a peptibody that stimulates platelet production via activation of the thrombopoietin (TPO) receptor. Romiplostim increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 trial. Patients who completed this study or an ongoing phase 3 trial were given the option of rolling over into an open-label long-term extension study. Objectives To evaluate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods Patients received weekly subcutaneous injections of romiplostim; the starting dose was the last dose in the prior study. Patients who had received placebo started at 1 μg/kg. Dose adjustments targeted platelet counts in the range of 50–200 x 109/L. The maximum allowed romiplostim dose was 10 µg/kg. Assessments of adverse events, concomitant medications, and local platelet counts were performed weekly. The primary endpoint was incidence of adverse events. The protocol did not require bone marrow biopsies to be performed, but when performed, specimens were submitted to a central lab for analysis. Patients who were on a stable dose had the option to receive romiplostim at home; patients and their caregivers then recorded dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results Twenty-two patients (N = 12 from the phase 1/2 study and N = 10 from the phase 3 study) were treated with romiplostim for up to 172 weeks (3.3 years). Baseline demographics included a median age of 12.0 years (range 3–16), 50% male, and 18.2% with prior splenectomy. Median romiplostim treatment duration was 89.0 weeks (range 3–172); median total number of doses was 64 (range 3–171); median average weekly romiplostim dose was 4.0 µg/kg (range 1–10), including ramp up to stable dose; and median maximum dose was 8.0 µg/kg (range 1–10). Of the 4 patients who discontinued the study, 3 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 18 continued on study. After the first week of this extension study, which for some patients was the first week of romiplostim, median platelet counts remained above 50 x 109/L throughout the study, and were in the target range of 50–200 x 109/L for all visits but weeks 76 and 156 (Figure). The median romiplostim dose (Q1, Q3) was 6.0 (2.0, 8.0) µg/kg at week 1 and 3.5 (0.0, 7.0) µg/kg at week 168 (Figure). Four patients discontinued romiplostim. Eight patients received rescue medications (defined as medications used for platelet counts < 10 x 109/L, bleeding/wet purpura, or investigator decision) which included immunoglobulins (3 patients), tranexamic acid (3 patients), platelet transfusion (1 patient), aminocaproic acid (1 patient), and prednisone (1 patient). Four patients had serious adverse events (asthma, hemangioma, hypotension, infection, thrombocytopenia, and transfusion reaction) and 1 had life-threatening adverse events (infection and thrombocytopenia). None of the serious adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Twelve patients had bleeding adverse events; 2 of which were deemed treatment-related (gingival bleeding and petechiae). Bleeding adverse events included epistaxis (4 patients); petechiae (3 patients); gingival bleeding (2 patients); hemorrhage (2 patients); and bleeding from the anus, injection site, lip, and mouth (1 patient each). No bone marrow biopsies were performed as part of this study. Conclusion In this open-label extension study, long term treatment with romiplostim maintained platelet counts in pediatric patients with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with ITP. Disclosures: Tarantino: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Octapharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Romiplostim is approved for the treatment of adults with chronic ITP. Romiplostim is not approved for the treatment of pediatric patients with chronic ITP. Bussel:Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: 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: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Long-Term Efficacy and Safety of Romiplostim for the Treatment of Patients with Chronic Immune Thrombocytopenia (ITP): 5-Year Update From An Open-Label Extension Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 681-681 ◽  
Author(s):  
James B. Bussel ◽  
David J Kuter ◽  
Adrian Newland ◽  
Joost TM de Wolf ◽  
Jeffrey Wasser ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Target Range ◽  
Weekly Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 681 Chronic ITP is characterized by increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies may produce only short-term responses and may have issues with toxicity. Romiplostim is a novel peptibody that increases platelet production by a mechanism similar to thrombopoietin; and is approved for the treatment of chronic ITP. We report data from adult patients with chronic ITP treated with romiplostim in an open-label extension study. Collection of safety and efficacy data from long-term treatment of these patients is ongoing. Eligible patients had completed a prior romiplostim study. Romiplostim was administered once weekly by subcutaneous injection, with dose adjustments to maintain platelet counts in the target range (50 to 200 × 109/L). Patients who achieved a stable dose of romiplostim for 3 consecutive weeks were eligible to administer romiplostim at home (by self-injection or by a caregiver); these patients returned to the clinic every 4 weeks for study evaluations. As of May 2009, 291 adult patients had been treated with romiplostim; most were female (63%) and their median time since diagnosis was 4.9 years (range, 1 to 46 years). Thirty-three percent had previously undergone a splenectomy. Patients were treated with romiplostim for a median of 48 weeks (range, 1 to 244 weeks). Two hundred and nineteen patients (75%) were continuing the study at the data cut-off. Home administration of romiplostim was able to be started by 75% of patients; 8/218 patients (4%) discontinued home administration and resumed study-site injection. The median of the average weekly dose across the overall study population was 4 mcg/kg (interquartile range: 2 to 7 mcg/kg). The weekly dose among individual patients remained stable: after week 12, 79% (228/288) of patients were administered a dose of romiplostim within 2 mcg/kg of their most frequent dose at least 90% of the time. Almost all patients (94%) experienced a platelet count ≥50 × 109/L during the study, and more than 50% of patients had platelet counts ≥50 × 109/L on 95% of all study visits. After the first week, median platelet counts remained within the target range (50 to 200 × 109/L) for the duration of the study. Of patients receiving concurrent ITP medication at baseline, 78% (29/37) were able to discontinue or reduce their dose by >25%. Adverse events were reported in 92% of patients overall; the most common were headache (32%); nasopharyngitis (30%); and contusion and fatigue (each 28%). The frequency of adverse events did not increase with time on study (Table). The patient incidence of bleeding events of moderate or greater severity (≥Grade 2) and of clinical significance (≥Grade 3) did not increase over time (Table). Thrombotic events were experienced by 17 (6%) patients and did not increase in frequency over time (Table). Bone marrow reticulin was present or increased in 9 patients with no evidence of progression to collagen fibrosis or chronic idiopathic myelofibrosis. Two patients developed neutralizing antibodies to romiplostim that were absent on retesting after drug withdrawal, with no cross-reactive antibodies to thrombopoietin. Thirteen patients died; 2 deaths were considered by the investigator as possibly related to treatment (unstable angina, myocardial infarction). In conclusion, romiplostim-treated patients were able to maintain platelet counts within the target range, with minimal dose adjustments for up to almost 5 years. Romiplostim was well-tolerated and adverse events did not increase with longer duration of treatment.Table.Summary of patient incidence of adverse events by study periodStudy periodAdverse eventsAny n (%)Serious n (%)Treatment related n (%)Bleeding n (%)Bleeding ≥Grade 2 n (%)Bleeding ≥Grade 3 n (%)Thrombotic events n (%) <24 wks N = 291245 (84)41 (14)68 (23)93 (32)36 (12)12 (4)7 (2) 24 to <48 wks N = 271215 (79)32 (12)31 (11)66 (24)23 (9)5 (2)5 (2) 48 to <72 wks N = 151113 (75)14 (9)18 (12)41 (27)12 (8)2 (1)3 (2) 72 to <96 wks N = 12498 (79)11 (9)4 (11)38 (31)6 (5)1 (1)2 (2) 96 to <120 wks N = 11283 (74)19 (17)8 (7)31 (28)9 (8)1 (1)4 (4) 120 to <144 wks N = 10176 (75)8 (8)7 (7)21 (21)7 (7)1 (1)1 (1) 144 to <168 wks N = 8151 (63)6 (7)2 (3)15 (19)4 (5)00 68 to <192 wks N = 4726 (55)3 (6)2 (4)9 (19)4 (9)1 (2)1 (2) 192 to <216 wks N = 2619 (73)2 (8)010 (39)2 (8)00 216 to <240 wks N = 2417 (71)2 (8)07 (29)2 (8)1 (4)0 >240 wks N = 61 (17)000000 Disclosures: Bussel: Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Kuter:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Newland:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pangenetics: Consultancy; Schering Plough: Consultancy; Baxter: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Wasser:Amgen Inc.: Speakers Bureau. Chang:Amgen Inc.: Employment, Equity Ownership. Nie:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Study to Determine the Safety and Efficacy of Romiplostim in Children with Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 680-680 ◽  
Author(s):  
George R. Buchanan ◽  
Lisa Bomgaars ◽  
James B. Bussel ◽  
Diane J. Nugent ◽  
David J. Gnarra ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Treatment Period ◽  
Research Funding ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 680 Introduction: ITP is an autoimmune disorder characterized by thrombocytopenia due to accelerated destruction as well as suboptimal platelet production. Childhood ITP is most commonly an acute illness; however, chronic ITP (duration > 6 months) develops in 20%–30% of ITP cases. Romiplostim, a peptibody protein designed to increase platelet production, is approved for treating chronic ITP in adults. The objective of this study was to evaluate the safety and efficacy of romiplostim in the treatment of thrombocytopenia in children with chronic ITP. Patients and Methods: ITP patients aged 12 months to <18 years with persistent severe thrombocytopenia for at least six months before enrollment (mean of 2 platelet counts ≥ 30 × 109/L at baseline) were included in this study. Patients were randomized (3:1) to receive romiplostim or placebo and stratified by age: 12 months - <3 years (N=4), 3 - <12 years (N=8), and 12 - <18 years (N=8). Treatment for a 12 week period was followed by a 4 week pharmacokinetic (PK) assessment period for responding patients (those who achieved a platelet count of >20 × 109/L above baseline for 2 consecutive weeks without rescue therapy at any point during the treatment period). Treatment was initiated at 1 μg/kg once weekly by subcutaneous injection. The dose was adjusted in 2 μg/kg increments every two weeks, to a maximum dose of 10 μg/kg/week based on weekly platelet counts. The incidence of adverse events (AEs) during the 12-week treatment period and the number of patients achieving platelet counts >50 × 109/L for 2 consecutive weeks during the treatment period, or achieving an increase in platelet count >20 × 109/L above baseline for 2 consecutive weeks during the treatment period was recorded. Results: A total of 22 (romiplostim, 17; placebo, 5) patients were randomized; 16 (73%) were boys and 6 (27%) were girls. Eight patients had undergone splenectomy. The mean age was 9.5 (SD: 5.1) years, with 4 subjects aged 12 months - <3 years, 10 aged 3 - <12 years, and 8 aged 12 - <18 years. The median baseline platelet count was 13 × 109/L (range 2 to 29 × 109/L) and the median duration of ITP was 2.4 years (range 0.6 to 14 years). All patients completed the study. Sixteen of 17 patients in the romiplostim arm (94%) and 5/5 in the placebo arm (100%) had at least 1 AE during the treatment period. The most common AEs were (romiplostim, placebo, respectively) headache (35%, 40%), epistaxis (35%, 20%), cough (12%, 40%), and vomiting (12%, 40%). Serious AEs were experienced by 1 patient in the romiplostim arm (moderate influenza and sepsis) and none in the placebo arm. AEs considered to be treatment related were reported for 3 (18%) and 1 (20%) subjects in the romiplostim and placebo arms, respectively; none of the treatment-related AEs were serious or of ≥3 grade severity. No patients died during the study and none tested positive for neutralizing antibodies to romiplostim or thrombopoietin. The same group of patients in the romiplostim-treated arm (15/17, 88.2%, 95% CI: 63.6%, 98.5%) achieved both efficacy endpoints during the treatment period. The median platelet count in the romiplostim-treated arm after 6 weeks of treatment was ≥50 × 109/L. The median weekly platelet count in the placebo arm remained stable at approximately 10 × 109/L. None of the placebo-treated patients achieved either platelet count endpoint. Rescue medication was administered to 2/17 (12%) of romiplostim- and 2/5 (40%) of placebo-treated patients during the 12 week treatment period. Twelve (71%) and 2 (40%) subjects in the romiplostim and placebo arms, respectively, experienced bleeding events. The majority of bleeding events (15/17) in the romiplostim arm occurred in the first 6 weeks of treatment. Most bleeding events (14/17) in the romiplostim arm and all bleeding events in the placebo arm occurred when the platelet count was < 30 × 109/L. A total of 14 patients treated with romiplostim entered the PK assessment period. The romiplostim serum concentration results were not different among the 3 age cohorts. The mean weekly dose of romiplostim in the treatment period was 3.4 (SD: 1.6) μg/kg. Conclusion: Treatment with romiplostim appeared to be well tolerated in pediatric ITP patients, with no new safety concerns observed in this study as compared to adults with chronic ITP. Romiplostim was effective in treating thrombocytopenia in children with chronic ITP. Disclosures: Buchanan: Amgen Inc.: Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, in treatment of thrombocytopenia in pediatric ITP patients. . Bomgaars:Novartis: Research Funding. Bussel:Eisai, Inc: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; Scienta: Speakers Bureau. Nie:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Update On The Safety and Efficacy Of EXTENDed Treatment With Eltrombopag (EPAG) In Adults With Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2315-2315 ◽  
Author(s):  
James B. Bussel ◽  
Mansoor N. Saleh ◽  
Raymond S.M. Wong ◽  
Paul Burgess ◽  
Kalpana Bakshi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Treatment Duration ◽  
Research Funding ◽  
Rescue Therapy ◽  
Average Dose ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership

Abstract Background EPAG, an oral thrombopoietin receptor agonist approved for cITP, increased platelets (plts) and reduced bleeding in 6 wk and 6 m placebo-controlled trials in previously treated cITP patients. EXTEND is an ongoing, open-label extension study, begun in Jun 2006, to assess the safety and efficacy of long-term treatment with EPAG in cITP patients who completed a previous EPAG study. Long-term safety and efficacy data up to Feb 2013 are presented. Methods EPAG was started at 50 mg and titrated to 25-75 mg/d or less often, based on plt counts. Patients who received ≥2 y of EPAG and transitioned off due to commercial availability of EPAG were considered to have completed EXTEND, whether or not they continued treatment with commercial EPAG. Results Of 302 patients enrolled, 43% (129) completed, 48% (146) withdrew, and 9% (27) remain on study. The most common reasons for withdrawal were adverse events (AEs; 15%), patient decision (13%), lack of efficacy (11%), and stable plts ≥6 m following interruption of EPAG (3%). The Table shows baseline patient characteristics and treatment duration. Doses of 75, 25, and 25 mg QOD were required by 62%, 51%, and 20% of patients, respectively, at some time during the study; 5% remained on 50 mg throughout the study (overall median duration of exposure, 122 wk; average dose, 50.8 mg/d). Overall, 85% (258/302) of patients achieved plts ≥50,000/µL in the absence of rescue therapy, and 61% achieved plts ≥50,000/µL for ≥50% of on-treatment assessments. Median plts increased to ≥50,000/µL by Wk 2, remaining consistently ≥50,000/µL throughout the treatment period. Nine of 10 patients who withdrew due to stable plts for ≥6 m following interruption of EPAG maintained plts ≥100,000/µL for ≥6 m without any ITP therapy. Incidence of bleeding symptoms (WHO grades 1-4) decreased from baseline to 1 y and thereafter (Figure). Of 101 patients receiving concomitant ITP treatment at baseline, 40 had a sustained reduction or permanently stopped ≥1 concomitant ITP treatment without ever receiving rescue therapy. The most frequently discontinued/reduced ITP medications were corticosteroids (35/40; 88%) and danazol and azathioprine (4/40 each; 10%). In 92% (277) of patients, AEs occurred. Serious AEs (SAEs) occurred in 31% (94) of patients, and 22 patients had 33 SAEs considered possibly drug related. Drug-related SAEs occurring in ≥2 patients were cataracts (7), alanine aminotransferase (ALT) (4) or aspartate aminotransferase (2) increased, deep vein thrombosis (DVT; 4), bilirubin increased (3), myocardial infarction (MI; 2), and pulmonary embolism (PE; 2). AEs leading to withdrawal occurred in 44 patients (15%), 29 (10%) of whom experienced SAEs. The most frequent AEs leading to withdrawal were increased ALT (7), increased bilirubin (5), cataracts (4), and DVT (4). In 19 patients (6%), 26 thromboembolic events (TEEs) were reported (incidence rate, 2.53/100 patient y; 95% CI, 1.52-3.95). Observed TEEs were DVT (11), central nervous system ischemic events (7), MI (5), and PE (3). No association with elevated plt counts was observed, as only 3/19 patients experienced the TEE at or shortly after achieving their maximum plt count. Hepatobiliary laboratory abnormalities (HBLAs) were reported in 37 patients (12%), and 8 were withdrawn because of HBLAs. No HBLAs were associated with signs of liver impairment; most resolved on treatment or after discontinuation. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 115 patients treated with EPAG for ≤5.5 y found no clinically relevant increase in reticulin deposition. Two patients (2%) had maximum reticulin marrow fibrosis (MF) grade of ≥2 after >24 m on treatment; neither experienced any AE or hematologic parameter abnormality potentially related to impaired BM function. Conclusions Sustained plt increases and reduced bleeding symptoms were observed in EPAG-treated cITP patients throughout the study. Sustained increases in plt counts were maintained in a few patients after discontinuing EPAG. Concomitant ITP medications were reduced without requiring rescue medications. Eltrombopag was well tolerated with exposures ≤6.5 y. Rates of TEEs and HBLAs did not increase with longer treatment duration, and BM biopsies showed no clinically significant increase in MF grade. No new safety signals were observed. Long-term safety and efficacy continue to be assessed in this ongoing study. Disclosures: Bussel: Symphogen: Membership on an entity’s Board of Directors or advisory committees; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: 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: Research Funding; Eisai Inc.: Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wong:GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Chan:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

Long-Term Treatment of Chronic Immune Thrombocytopenic Purpura with Oral Eltrombopag: Results From the EXTEND Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 682-682 ◽  
Author(s):  
Mansoor N. Saleh ◽  
James B. Bussel ◽  
Gregory Cheng ◽  
Balkis Meddeb ◽  
Bhabita Mayer ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Thrombocytopenic Purpura ◽  
Once Daily ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Equity Ownership

Abstract Abstract 682 INTRODUCTION: Eltrombopag (PROMACTA; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, thrombopoietin receptor agonist approved in the US for the treatment of chronic immune thrombocytopenic purpura (ITP). Eltrombopag is also being evaluated for the treatment of thrombocytopenia due to other causes (eg, hepatitis C, MDS). Chronic ITP is characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to chronically low platelet counts. Eltrombopag has been shown to significantly increase platelet counts and reduce clinically relevant bleeding symptoms in 3 placebo-controlled ITP trials evaluating a total of 429 patients. EXTEND is an ongoing open-label, phase 3 extension study to assess the long-term safety and efficacy of eltrombopag in chronic ITP. METHODS: Patients with previously treated, chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted to maintain platelet counts between ≥50,000/μL and <200,000/μL, with doses between 75 mg and 25 mg once daily (or less often if necessary). Patients who achieved platelet counts ≥50,000/μL were considered responders. Bleeding events were prospectively evaluated using the World Health Organization (WHO) Bleeding Scale: grade 0 = no bleeding, grade 1 = mild bleeding, grade 2 = moderate bleeding, grade 3 = gross bleeding, and grade 4 = debilitating blood loss. Bone marrow (BM) biopsy was required after 1 year on treatment. RESULTS: At the time of this analysis, 299 patients (median age 50 years; 66% female) had received eltrombopag (240, 126, 48, and 17 patients exposed for ≥6, 12, 18, and 24 months, respectively). The median duration of eltrombopag treatment was 204 days and ranged from 2–861 days. At baseline, 33% were receiving concomitant ITP medication and 38% had been splenectomized. The majority of patients (70%) had baseline platelet counts <30,000/μL, followed by 17% and 13% with baseline platelet counts from μ30,000/μL to <50,000/μL, and μ50,000/μL, respectively; all had baseline platelet counts <50,000/μL at the time of entry into their previous study. Overall, 86% of patients (257/299) achieved a platelet count μ50,000/μL. Splenectomized and non-splenectomized patients responded equally well (89% and 82%, respectively). Patients responded to eltrombopag regardless of baseline use of concomitant ITP medications (no baseline ITP medications and baseline ITP medications: 86% each). Median platelet counts increased to μ50,000/μL by week 2, and remained μ50,000/μL throughout the observation period of the study (Figure 1). Patients on treatment for μ6 months or μ12 months achieved platelet counts of μ50,000/μL and 2x baseline for 69% (18/26 weeks) and 71% (37/52 weeks) of the time on treatment, respectively. At baseline, 56% of patients reported bleeding symptoms (WHO grades 1–4) compared to 27%, 21%, 40%, and 25% at 6, 12, 18, and 24 months, respectively. Adverse events (AEs) were reported in 248 patients (83%) while on therapy, the majority being mild to moderate. The most common AEs reported were headache (23%), upper respiratory tract infection (17%), nasopharyngitis (17%), fatigue (13%), arthralgia (12%), and diarrhea (11%). Five deaths were reported: 2 occurred on therapy and 3 occurred more than 30 days posttherapy; none considered related to study medication. A total of 24 patients (8%) met any of the hepatobiliary laboratory abnormality screening criteria (ALT ≥3x ULN, AST ≥3x ULN, total bilirubin >1.5x ULN, or alkaline phosphatase >1.5x ULN). Thirteen patients (4%) experienced 16 thromboembolic events (TEEs); 11/13 (85%) experienced the event at a platelet count lower than the maximum platelet count achieved during eltrombopag treatment. Platelet counts proximal to the TEEs ranged from 14,000–407,000/μL. Eighty-six BM biopsies were performed. No clinically relevant effects of eltrombopag on BM were detected. CONCLUSION: Oral eltrombopag treatment for up to 2 years effectively raised platelet counts, decreased bleeding symptoms, and was generally well-tolerated in chronic ITP. Disclosures: Saleh: GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Mayer:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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