EXTEND Study Update: Safety and Efficacy of Eltrombopag In Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2010

Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP) in the US and other countries. In 6-week and 6-month placebo-controlled trials, eltrombopag safely increased platelet counts and reduced bleeding symptoms in patients with previously treated chronic ITP. The safety and efficacy of eltrombopag treatment are being evaluated in EXTEND, an ongoing open-label, extension study in ITP patients who completed a previous eltrombopag study.

Enrolled patients had previously received eltrombopag or placebo in one of the following studies: two 6-week studies (773A and B), RAISE (6-month), or REPEAT (intermittent treatment). In EXTEND, specific goals include: 1) identification of a dose of eltrombopag that increases platelet counts (≥100,000/μ L) to support reduction of concomitant ITP medications (if taken); 2) identification of minimally effective doses of eltrombopag and concomitant ITP medication to maintain platelet counts ≥50,000/μ L; and 3) evaluation of the safety and efficacy of eltrombopag. Patients who completed at least 2 years of therapy and transitioned off study due to commercial availability of eltrombopag were considered to have completed the study.

Of 299 patients enrolled, 8% (23) completed the study, 41% (122) withdrew, and 52% (154) remain on study. The main reasons for withdrawal were adverse events (AEs, 11%), patient decision (11%), and lack of efficacy (10%). At baseline, platelet counts were ≤15, >15–<30, 30–50, and >50,000/μ L in 43%, 27%, 17%, and 13% of patients, respectively; 38% of patients were splenectomized; 33% were receiving concomitant ITP medication at baseline, and 53% had received ≥3 previous ITP therapies. 249, 210, 138, and 24 patients had been taking eltrombopag for ≥26, 52, 104, and 156 weeks, respectively, with a median duration of exposure of 100 weeks at the time of data analysis. The proportion of patients achieving a platelet count ≥50,000/μ L was similar regardless of the following baseline characteristics: splenectomy (84%) vs no splenectomy (89%); use of ITP medication (88%) vs no use of ITP medication (87%); and baseline platelet count <30,000/μ L (83%) vs 30–50,000/μ L (98%) vs >50,000/μ L (95%). Overall, 87% (261/299) of patients achieved a platelet count ≥50,000/μ L on treatment; 37 of these had a baseline platelet count of ≥50,000/μ L. Median platelet counts increased to ≥50,000/μ L by week 2 and remained consistently ≥50,000/μ L through week 164. The incidence of any bleeding symptoms (WHO grades 1–4) declined from 56% at baseline to 16% and 20% at weeks 52 and 104, respectively. Clinically significant bleeding (WHO grades 2–4) was reduced from 16% (47/299) at baseline to 3% (2/77) and 7% (3/41) at weeks 52 and 104, respectively. AEs and SAEs occurred in 88% (262) and 26% (79) of patients, respectively. The most frequent AEs were headache (26%), nasopharyngitis (23%), and upper respiratory tract infection (21%). AEs led to withdrawal of 13% (38) of patients, 9% (27) of which were due to SAEs.

Twenty-one thromboembolic events (TEE) have been reported in 5% (16) of patients; the incidence rate is 3.17/100 patient years (95% CI [1.81, 5.15]). The most common TEEs were DVT (8) and MI (4). No association has been observed with elevated platelet counts, as only 3/16 patients experienced the TEE closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities were reported in 29 patients (10%). All were reversible; the majority while on therapy. Of 299 patients enrolled, 6 (2%) have been withdrawn due to a hepatobiliary AE. After examining bone marrow biopsies from >150 patients treated with eltrombopag for >1 year, no clinically relevant increase in reticulin fiber deposition has been observed.

Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μ L and reducing bleeding symptoms. Eltrombopag has an overall positive risk/benefit assessment and was well tolerated during treatment of patients with chronic ITP even with exposures of more than 3 years. Bone marrow biopsies will continue to be assessed. Hepatobiliary laboratory abnormalities and thromboembolic events are risks that need to be monitored.

Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Bussel:GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.