Alessandro Riva, MD
The European Commission (EC) has approved eltrombopag (Revolade) as a treatment for adult patients with severe aplastic anemia (SAA) who are refractory to immunosuppressive therapy or are heavily pretreated and not suitable for hematopoietic stem cell transplant, based on data from an open-label, single-arm phase II trial.
The EC decision allows for the medication to be marketed across 28 European Union member states. In the United States, eltrombopag (Promacta) was approved for patients with SAA in August 2014, following a breakthrough therapy designation from the FDA. In the pivotal phase II study, which was conducted by the National Institutes of Health, treatment with eltrombopag demonstrated a robust normalization of blood cell counts in patients with SAA.
"Today's approval from the European Commission is important news for adults in the EU with severe aplastic anemia, who now have an alternative to standard therapies that have not provided sufficient benefit," Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs, said in a statement. "Revolade helps address an unmet need in this community and underscores our commitment to patients affected by rare diseases."
In the phase II study, 43 patients with SAA who had a platelet count ≤30 x 109
/L and who experienced an insufficient response to immunosuppressive therapy received treatment with eltrombopag. Overall, 84% of patients in the study had received at least two prior immunosuppressive therapies. The median age of patients was 45 years.
Eltrombopag was administered at a starting dose of 50-mg daily, which was increased in 2-week increments to a maximum dose of 150 mg daily. Responding patients continued to receive the drug in an expansion trial. At baseline, the median platelet count was 20 x 109
/L, hemoglobin was 8.4 g/dL, absolute neutrophil count (ANC) was 0.58 x 109
/L, and absolute reticulocyte count was 24.3 x 109
/L. The primary endpoint of the study was hematologic response at 12 weeks, which was defined as a 20,000/µl increase in blood cell counts above baseline.
In the study, 40% of patients experienced a hematologic response, including tri- and bilineage responses. A total of 17 patients continued treatment in the extension phase, with 8 achieving a response across several parameters. Half of the patients in the extension cohort tapered off therapy while maintaining a response.
Patients remained platelet transfusion-free for a median of 200 days with eltrombopag. Additionally, patients were red blood cell transfusion-free for a median of 208 days. Five patients had blood counts near normal ranges at a median of 28.5 months.
The most common adverse reactions were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%). Of the 43 patients enrolled, 8 had a new cytogenetic abnormality reported, including five patients who had complex changes in chromosome 7, suggesting the need to monitor bone marrow aspirates for cytogenetic changes in patients on eltrombopag. However, no patients had evolved to acute myeloid leukemia at the time of the analysis.
Eltrombopag became the first oral platelet growth factor to receive FDA approval in 2008. This initial indication was for adult patients with chronic immune thrombocytopenic purpura (ITP) following an insufficient response to corticosteroids, immunoglobulins, or splenectomy. In August 2015, this indication was extended to children age 1 to 17 with the same condition.
Following a multibillion-dollar product exchange with GlaxoSmithKline that was completed in early March 2015, eltrombopag is now manufactured and developed by Novartis. In addition to its indications for ITP and SAA, eltrombopag is also approved in combination with interferon and ribavirin for patients with chronic hepatitis C–associated thrombocytopenia.