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Promacta (Eltrombopag) Gets Additional Indication

TPO receptor agonist now approved for aplastic anemia

The FDA has approved a supplemental new drug application (sNDA) for the once-daily use of Promacta (eltrombopag, GlaxoSmithKline) in patients with severe aplastic anemia (SAA) who have shown an insufficient response to immunosuppressive therapy (IST).

SAA is a rare blood disorder in which the bone marrow fails to produce enough red blood cells (RBCs), white blood cells, and platelets. Eltrombopag, an oral thrombopoietin (TPO) receptor agonist, works by helping to induce the proliferation and differentiation of bone-marrow stem cells to increase the production of blood cells.

Promacta gained “breakthrough therapy” status from the FDA in January 2014 and priority review in April 2014. The new approval is based on results from a single-arm, open-label, phase II study conducted by the National Heart, Lung, and Blood Institute (NHLBI). In that trial, the treated population had a median age of 45 years (range: 17 to 77 years) and 56% were male. Most of the patients (84%) had received at least two prior immunosuppressive therapies.

Eltrombopag was administered at an initial dosage of 50 mg once daily for 2 weeks and was increased over 2-week periods up to a maximum dosage of 150 mg once daily. The study’s primary endpoint was the patient’s hematologic response, which was initially assessed after 12 weeks of treatment with eltrombopag. Treatment was discontinued after 16 weeks if no hematologic response was observed. Additional efficacy assessments included the median duration of response.

Forty percent of patients (n = 17) experienced a hematologic response in at least one lineage — platelets, red blood cells, or white blood cells — after week 12. In the extension phase, eight patients achieved a multi-lineage response; four of these patients subsequently tapered off treatment and maintained their response (median follow up: 8.1 months; range: 7.2 to 10.6 months).

Ninety-one percent of the patients were platelet transfusion-dependent at baseline; the platelet transfusion-free period in responders ranged from 8 to 1,096 days (median: 200 days). Eighty-six percent of patients were RBC-transfusion dependent at baseline; the RBC transfusion-free period in responders ranged from 15 to 1,082 days (median: 208 days).

The most common adverse reactions (≥ 20%) in 43 patients with SAA who received eltrombopag included nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%). The patients’ bone marrow aspirates were evaluated for cytogenetic abnormalities. Eight patients (19%) had a new cytogenetic abnormality, including five patients who had complex changes in chromosome 7. If new cytogenetic abnormalities are observed, clinicians should consider discontinuation of eltrombopag.

The treatment of SAA is focused on increasing the patient’s blood cell count; definitive care includes IST or hematopoietic stem-cell transplantation (HSCT). Of patients treated with IST, one-quarter to one-third will not respond, and 30% to 40% of responders will relapse, causing symptoms to return. Approximately 40% of SAA patients who don’t respond to initial IST die from infection or bleeding within 5 years after their diagnosis.

Currently, no established standard of care exists for SAA patients who have had an insufficient response to IST or who are ineligible for HSCT.

In addition to the new approval of eltrombopag for SAA in the U.S., the drug is indicated for the treatment of thrombocytopenia in: 1) patients with chronic immune (idiopathic) thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; and 2) patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy.

Source: GSK; August 26, 2014.

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