Pomalidomide is strongly antiangiogenic and teratogenic in relevant animal models

In characterizing the activity of pomalidomide in chicken and zebrafish embryos, Mahony et al. (1) were unable to detect teratogenic or antiangiogenic effects, but did detect anti-inflammatory effects. Because of the absence of antiangiogenic or teratogenic effects in their models, the authors conclude that “Pomalidomide likely represents a more effective and potentially safer option for treatment of multiple myeloma, ENL [erythema, nodosom, leprosum, an inflammatory complication of leprosy], and other conditions” (1).

Unfortunately the authors do not confront the wealth of data in higher species, examining its activity. Published data by us and other groups show that pomalidomide (3-aminothalidomide/3-amino-pthalimido-gluterimide/ENMD-0995/CC-4047/Actimid) is powerfully antiangiogenic (2) and teratogenic in rats and rabbits (3) (Food and Drug Administration-approved label). In fact, pomalidomide inhibits VEGF-driven angiogenesis more potently than thalidomide (2).

Furthermore, blood levels of pomalidomide in patients at the typical 4-mg/d dose have a C_max of 75 ng/mL and an average daily concentration of 17 ng/mL, whereas the immunomodulatory effects observed by Mahony et al. (1) are seen when the drug is in the 35–200 μg/mL range. The fact that Mahony et al. required three orders-of-magnitude higher concentrations to detect the structure-activity effects they report suggests that their systems do not accurately model the safety, efficacy, or mechanism of thalidomide analogs in humans. In addition, loss-of-expression of the putative teratorgenic target of thalidomide (cereblon) is associated with pomalidomide resistance in multiple myeloma (4, 5). We conclude that the clinical relevance of the Mahony et al. report is low and its extrapolation to patient care is potentially risky.