PF-04447943 + hydroxyurea

This combination consists of **PF-04447943**, a potent and selective **phosphodiesterase 9A (PDE9A) inhibitor** developed by Pfizer, and **hydroxyurea** (marketed as Siklos, among other names), a cytotoxic antimetabolite that inhibits the synthesis of DNA by acting as a ribonucleotide reductase inhibitor. PF-04447943 increases cellular and plasma cGMP levels by inhibiting its degradation, thereby reducing adhesion of blood cells and the risk of vaso-occlusion, which is a key pathophysiological process in sickle cell disease (SCD)[1][3][5]. Hydroxyurea increases fetal hemoglobin and reduces sickle hemoglobin polymerization, improving red cell deformability, and also contributes to increased cGMP via nitric oxide pathways[1][5]. The combination has been investigated in **phase 1b clinical studies** as a potential treatment to reduce vaso-occlusive crises and adhesion biomarker levels in stable SCD patients, where PF-04447943 was administered with or without concurrent hydroxyurea and demonstrated safety, tolerability, and biomarker changes consistent with reduced vaso-occlusion[1][3][5]. Hydroxyurea is also indicated for resistant chronic myeloid leukemia and locally advanced squamous cell carcinomas of the head and neck[7].

Brand names

Siklos