Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

Autor:	Guha M; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.) mausumee.guha@yahoo.com., Thibault S; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Pham S; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Bernales S; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Pai R; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Herrera FJ; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Johnson TR; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Vitsky A; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Fernando T; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.)., Finkelstein M; Pfizer Worldwide Research and Development, La Jolla, California (M.G., S.T., T.R.J., A.V., T.F., M.F.); 1cBio, Inc., Moraga, California (S.P.); Fundación Ciencia & Vida, Santiago, Chile (S.B.); Merck Research Laboratories, South San Francisco, California (R.P.); and Trancura Biosciences, Alameda, California (F.J.H.).
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Oct 18; Vol. 391 (2), pp. 335-345. Date of Electronic Publication: 2024 Oct 18.
DOI:	10.1124/jpet.124.002193
Abstrakt:	The development of transforming growth factor β receptor inhibitors (TGF β Ri) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGF β RI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGF β in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGF β Ri classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGF β Ri have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients. (Copyright © 2024 by The Author(s).)
Databáze:	MEDLINE
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