Rate of Cataracts Across the Eltrombopag Clinical Studies in Patients with Chronic Immune Thrombocytopenia

Systemic corticosteroids, a common first-line treatment for chronic immune thrombocytopenia (ITP), are known to be associated with an increased risk of cataracts. Feudjo-Tepie et al (2009) determined that the rate of cataracts was higher in patients treated with oral corticosteroids (14.0/1000 patient years [PYs] vs 6.0/1000 PY). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, is approved for the treatment of chronic ITP, a disease characterized by low platelet counts. Preclinical studies of eltrombopag in young rodents showed the potential for cataract development at doses ≥4 times the human clinical exposure. The potential for an association between treatment with eltrombopag and an increased risk for cataracts was assessed in 5 clinical trials in chronic ITP. Methods: Ocular data from 5 trials were analyzed: 2 placebo-controlled, 6-week studies, TRA100773A (phase 2) and TRA100773B (phase 3); a 6-month, placebo-controlled phase 3 study (RAISE); a phase 2 study with 3 intermittent treatment cycles of up to 6 weeks (REPEAT); and an ongoing extension study (EXTEND, data from June 2006-February 2010). Ocular monitoring included assessment of ocular health history and cataract risk factors such as chronic corticosteroid use, and a complete ophthalmologic exam, including assessment of the lens using the Age-Related Eye Disease Study (AREDS) lens opacity grading protocol (AREDS Research Group, 2001). Ocular exams were performed at baseline, frequently during treatment, and 6 months following discontinuation of treatment. A Clinical Events Committee (CEC) composed of 3 external ophthalmologists was assembled to provide external medical review of the ocular data across the eltrombopag program. The CEC adjudicated the presence or absence of cataracts from treatment-blinded data and, where possible, made attributions of potential relatedness to study medication. Results: At baseline, 47/392 patients (12%) had pre-existing cataracts or were aphakic/pseudophakic. Across the trials, chronic corticosteroid use was the most commonly reported cataract risk factor, reported in 62% of patients with risk factor assessment. After CEC adjudication, in the two 6-week trials, 2/49 placebo-treated patients (4%) and 6/112 eltrombopag-treated patients (5%) had an incident cataract or progression of cataracts. All 8 patients reported prior use of corticosteroids, and 7/8 reported at least 1 risk factor for cataracts at their first ocular exam. In RAISE, 6/61 placebo-treated patients (10%) and 11/135 eltrombopag-treated patients (8%) had incident cataract or progression of cataracts. All 17 patients reported prior use of corticosteroids, identified as a risk factor at the baseline ocular exam. In REPEAT, the CEC identified 2/66 patients with potential cataract findings; given the additional risk factors in both patients, the CEC concluded there was no evidence of a drug-related increased risk of cataracts in the study. In the ongoing eltrombopag extension study, 25/299 patients (8%) had incident cataract or progression of cataracts. Twenty patients reported at least 1 cataract risk factor, and 24 patients had documented use of corticosteroids. The CEC noted variability in the AREDS lens grading, in which there was apparent progression followed by apparent regression to a lower, less severe grade on the AREDS scale. Conclusion: The CEC adjudication of the ocular data from the placebo-controlled eltrombopag studies in chronic ITP showed that a similar proportion of patients in the placebo- and eltrombopag-treatment groups had incident cataract or progression of cataracts. In the extension study, with patients exposed to eltrombopag for over 3 years, the proportion of patients with cataracts is similar to that observed in the placebo-controlled studies (despite the significant difference in exposure to eltrombopag). The noted variability in the AREDS lens grading reflects the inherent challenges for the clinician in implementing this scale in a consistent manner. Based upon the ocular data reviewed to date by the CEC, there is no evidence of an increased risk of cataract or cataract progression in chronic ITP patients treated with eltrombopag. The possibility of a relationship between eltrombopag and cataracts has not been completely excluded and is still being monitored in clinical trials.

Cooper:GlaxoSmithKline: Honoraria. Wong:Biogen Idec: Honoraria, Research Funding; Sanofi: Research Funding; Bayer: Honoraria, Research Funding; GSK: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer Inc: Research Funding; Roche: Research Funding; Leo Pharma: Honoraria; Johnson & Johnson: Research Funding. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership.