FDA grants breakthrough therapy designation to Promacta (EU trade name: Revolade)

Earlier this week, Ligand Pharmaceuticals Inc. ( LGND ) announced that the U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to Promacta (EU trade name: Revolade). Ligand and its partner GlaxoSmithKline ( GSK ) are looking to get Promacta approved for the treatment of cytopenias in patients suffering from severe aplastic anemia (SAA), who are unresponsive to immunosuppressive therapy.

The FDA granted breakthrough therapy designation to Promacta based on data from an open-label phase II National Institute of Health (NIH) study (n = 43) evaluating Promacta in treatment experienced SAA patients,  who showed insufficient response to immunosuppressive therapy.

The designation, which was enacted as part of the 2012 Food and Drug Administration Safety and Innovation Act, is granted to potential new treatments for serious or life-threatening diseases or conditions where the initial clinical data shows that the treatment has the potential to demonstrate substantial improvement on one or more clinically significant endpoints compared to existing treatments. The designation should help fasten the development and review process for the candidate.

We note that Promacta is already approved for the treatment of thrombocytopenia (reduced platelet count) in patients with chronic hepatitis C virus (HCV) infection to enable the initiation and maintenance of interferon-based therapy. Promacta is also approved for thrombocytopenia in patients with chronic idiopathic thrombocytopenia (ITP).

PROMACTA (eltrombopag) Tablets contain eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist for oral administration. Eltrombopag interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production. Each tablet contains eltrombopag olamine in the amount equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of eltrombopag free acid.

Eltrombopag olamine is a biphenyl hydrazone. The chemical name for eltrombopag olamine is 3′-{ (2Z)-2-[1 -(3,4-dimethylphenyl)-3-methyl-5-oxo- 1,5-dihydro-4H-pyrazol-4- ylidene]hydrazino}-2′-hydroxy-3-biphenylcarboxylic acid – 2-aminoethanol (1:2). It has the molecular formula C₂₅H₂₂N₄O₄•2(C₂H₇NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid. Eltrombopag olamine has the following structural formula:

Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water.

The inactive ingredients of PROMACTA are: Tablet Core: magnesium stearate, mannitol, microcrystalline cellulose, povidone, and sodium starch glycolate. Coating: hypromellose, polyethylene glycol 400, titanium dioxide, polysorbate 80 (12.5 mg tablet), FD&C Yellow No. 6 aluminum lake (25 mg tablet), FD&C Blue No. 2 aluminum lake (50 mg tablet), Iron Oxide Red and Iron Oxide Black (75 mg tablet), or Iron Oxide Yellow and Iron Oxide Black (100 mg tablet).