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Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.

Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM - Drug Des Devel Ther (2015)

Bottom Line: Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma.Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development.The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib.

View Article: PubMed Central - PubMed

Affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.

ABSTRACT
Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

No MeSH data available.


Related in: MedlinePlus

Preparing for the first-in-human dose (FHD) study.Note: Standard Good-Laboratory Practice (GLP) animal toxicology studies were performed as well as a pharmacokinetic/pharmacodynamic (PK/PD) model established prior to the FHD study.
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f3-dddt-9-4479: Preparing for the first-in-human dose (FHD) study.Note: Standard Good-Laboratory Practice (GLP) animal toxicology studies were performed as well as a pharmacokinetic/pharmacodynamic (PK/PD) model established prior to the FHD study.

Mentions: Despite the long list of ALK5 SMI inhibitors, few ALK5 inhibitors have been moved to clinical investigation, perhaps because of the observed severe cardiac toxicities in animals.41,60 Galunisertib overcame this barrier by addressing the following: (a) running preclinical toxicology studies with administration schedules that identified a sufficient margin of safety, (b) developing a predictive PK/PD model using animal pharmacology information, and (c) developing assays of PD markers in patients with cancer to confirm the therapeutic window as predicted by the PK/PD model (Figure 3).


Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.

Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM - Drug Des Devel Ther (2015)

Preparing for the first-in-human dose (FHD) study.Note: Standard Good-Laboratory Practice (GLP) animal toxicology studies were performed as well as a pharmacokinetic/pharmacodynamic (PK/PD) model established prior to the FHD study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539082&req=5

f3-dddt-9-4479: Preparing for the first-in-human dose (FHD) study.Note: Standard Good-Laboratory Practice (GLP) animal toxicology studies were performed as well as a pharmacokinetic/pharmacodynamic (PK/PD) model established prior to the FHD study.
Mentions: Despite the long list of ALK5 SMI inhibitors, few ALK5 inhibitors have been moved to clinical investigation, perhaps because of the observed severe cardiac toxicities in animals.41,60 Galunisertib overcame this barrier by addressing the following: (a) running preclinical toxicology studies with administration schedules that identified a sufficient margin of safety, (b) developing a predictive PK/PD model using animal pharmacology information, and (c) developing assays of PD markers in patients with cancer to confirm the therapeutic window as predicted by the PK/PD model (Figure 3).

Bottom Line: Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma.Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development.The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib.

View Article: PubMed Central - PubMed

Affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.

ABSTRACT
Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

No MeSH data available.


Related in: MedlinePlus