Lenalidomide (Revlimid®) is an immunomodulatory drug (IMiD) currently approved for the treatment of 5q- myelodysplastic syndrome and multiple myeloma. The clinical efficacy of lenalidomide is thought to be related in part to enhanced T-cell co-stimulation and NK-cell activation via augmented IL-2 and IFN-γ production (Bartlett et al., 2004; Corral and Kaplan, 1999). Lenalidomide also inhibits TNF-α production in peripheral blood mononuclear cells (PBMCs) and whole blood, which may further contribute to its anti-tumor activity (Mueller et al., 1999). In addition to immunomodulatory effects, lenalidomide directly induces growth arrest and apoptosis in multiple myeloma cells, which is also recognized as a key mechanism of clinical efficacy (Mitsiades, 2002; Bartlett et al., 2004).
IMiD-class compounds, including thalidomide, lenalidomide, and pomalidomide, have been developed as racemic mixtures of S- and R-enantiomers. The isolated enantiomers of thalidomide are known to have distinct biological activities. For example, the well-documented sedative effects of thalidomide are correlated with the R-enantiomer (Eriksson et al., 2000), whereas S-thalidomide exhibits enhanced potency for TNF-α inhibition and IL-2 induction compared to R-thalidomide (Mueller et al., 1999; Moreira et al., 2003; Macor, 2007). Due to facile in vivo conversion, isolated S- enantiomers of IMiDs have not been developed clinically. To our knowledge, it has not been previously reported whether lenalidomide has enantiospecific immunomodulatory, anti-proliferative, or toxicological properties.
Given the therapeutic importance of lenalidomide, we explored a number of deuterium-substituted analogs of lenalidomide, either as racemic mixtures or as isolated S- and R-enantiomers, and studied them in several in vitro pharmacological assays. We found that in each case tested, deuterated racemic lenalidomide analogs were indistinguishable from non-deuterated lenalidomide across all the assays employed, including IL-2 induction in anti-CD3-stimulated PBMC, TNF-α inhibition in LPS-stimulated whole blood, and inhibition of proliferation of MM.1S human multiple myeloma cells.
In contrast to deuterated racemic lenalidomide, CTP-221, an optimized deuterated S-lenalidomide analog, exhibited enhanced potency compared to racemic lenalidomide for IL-2 induction (2.7-fold), TNF-α inhibition (3.7-fold) and anti-proliferative (2.4-fold) activities in vitro. Interestingly, these enhancements in potency are greater than the maximal 2-fold enhancement one could expect from assessing an isolated active enantiomer in comparison to its racemate. These greater-than-expected enhancements in potency were consistently observed across all the assays comparing CTP-221 to lenalidomide, suggesting that deuterium substitution had additional effect(s) that drive increased potency. Furthermore, CTP-221 was significantly more potent than similarly deuterated R-lenalidomide in these assays (between 9.0 and 19.8-fold), demonstrating that the clinically relevant pharmacological activities of lenalidomide are primarily contained within the S-enantiomer. Finally, we found that CTP-221 was consistently more potent (1.2–2.0-fold) than non-deuterated S-lenalidomide.
Taken together, these in vitro data demonstrate that deuterated racemic lenalidomide does not offer apparent advantages versus lenalidomide. However, the deuterated S-lenalidomide analog CTP-221 is significantly more potent than lenalidomide in key biological activities believed important for clinical efficacy. We plan to explore the toxicological properties of CTP-221 to assess its therapeutic window relative to lenalidomide.
Wu:Concert Pharmaceuticals, Inc.: Employment, Equity Ownership. Aslanian:Concert Pharmaceuticals, Inc.: Employment, Equity Ownership. Liu:Concert Pharmaceuticals, Inc.: Employment, Equity Ownership. Hogan:Concert Pharmaceuticals, Inc.: Employment, Equity Ownership. Tung:Concert Pharmaceuticals, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.