Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

Dear Editor:

In response to your article, Update on Immunomodulatory Drugs (IMiDs) in Hematologic and Solid Malignancies [1], I would like to point out a few inaccuracies and oversights in the discussion of apremilast.

This article incorrectly identified apremilast as an IMiDs® compound, Celgene's proprietary class of IMiDs® immunomodulatory drugs, which includes lenalidomide and pomalidomide. Apremilast is a specific inhibitor of phosphodiesterase-4 (PDE4) [2] and, therefore, acts by an entirely different mechanism of action from lenalidomide and pomalidomide. As a selective PDE4 inhibitor, apremilast increases intracellular cAMP levels, resulting in a decrease in the production of pro-inflammatory mediators, such as TNF-α, IL-23, and IFN-, and an increase in anti-inflammatory mediators, such as IL-10 [2]. Apremilast inhibits cytokine production by T cells and NK cells [2], in contrast to lenalidomide and pomalidomide, which enhance T- and NK-cell stimulation [1]. The molecular binding target of thalidomide, lenalidomide, and pomalidomide has recently been identified as cereblon, a component of the CUL4/DDB1 E3 ubiquitin ligase complex [3,4]. Furthermore, the key pharmacophore that mediates cereblon binding has been identified as the amino-glutarimide moiety [3], a chemical group not present in the apremilast structure [1]. Because of these clear and extensive differences, apremilast should not have been included in a review of the IMiDs® compounds.

I also wish to clarify some information on indications and available clinical data, specifically regarding safety and tolerability. To date, apremilast has demonstrated efficacy in the treatment of subjects with active psoriatic arthritis and moderate to severe plaque psoriasis in Phase II studies [5,6] and is currently in development for the treatment of psoriatic arthritis (Phase III), psoriasis (Phase III), ankylosing spondylitis (Phase III), rheumatoid arthritis (Phase II), and Behçets disease (Phase II). Phase II studies demonstrated that apremilast has a favorable risk:benefit profile and is generally well tolerated. The majority (∼ 90%) of treatment-emergent adverse events (TEAEs) were mild or moderate and did not result in treatment discontinuation. Although gastrointestinal AEs, such as nausea and diarrhea, were among the most commonly reported TEAEs, gastrointestinal toxicity has not been reported in clinical studies to date. Ongoing Phase III studies will provide additional information regarding the efficacy, safety, and tolerability of apremilast in the treatment of patients with psoriasis and psoriatic arthritis.

In summary, apremilast is a specific inhibitor of PDE4 with a chemical structure and mechanism of action that differs from the IMiDs® compounds reviewed in this article.

Declaration of interest

PH Schafer is an employee of Celgene Corp. Celgene assisted in the scientific and legal review of this letter.

Acknowledgements

The author acknowledges W Drown, from Peloton Advantage, for facilitating communication with the journal.