TP-0184 LOWERS HEPCIDIN LEVELS AND IS A POTENTIAL THERAPEUTIC FOR ANEMIA OF CHRONIC DISEASE
(Abstract release date: 05/21/15)
EHA Library. Warner S. 06/13/15; 103178; S501
Disclosure(s): Tolero Pharmaceuticals, Inc.
Dr. Steven Warner
Contributions
Contributions
Abstract
Abstract: S501
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room Stolz 2
Background
The liver peptide hormone, hepcidin, is known as a master regulator of bioavailable iron and red blood cell formation. Hepcidin expression is in part regulated by pro-inflammatory cytokines that ultimately signal through the activin-like kinase receptor 2 (ALK2) and SMAD transcription factors leading to the expression of hepcidin. In chronic inflammatory conditions, such as chronic kidney disease, rheumatoid arthritis, colitis, and in some forms of cancer, hepcidin levels remain high, lowering bioavailable iron leading to anemia. Hepcidin functions by binding to and inhibiting ferroportin, an iron pump that functions in macrophage-based iron recycling and intestinal iron uptake. Several studies demonstrated that lowering hepcidin could provide a novel approach for targeting this complicated clinical challenge. Current clinical strategies for these patients focus on red blood cell transfusions and the use of erythropoetin-based therapies. Neither of these approaches target the underlying mechanism behind the anemia associated with chronic inflammation and cancer.
Aims
The aim of this work is to develop a small molecule inhibitor of ALK2 for the treatment of hepcidin-driven anemia of chronic diseases.
Methods
Two animal models were primarily employed for these studies. First, turpentine oil (TO) was used to induce an acute inflammatory response in C57BL/6 mice with associated hepcidin-driven anemia. The animals were orally administered TP-0184 1 hour prior to TO treatment and then 8 hours later. Plasma and livers were collected 16 hours after TO treatment. Second, a TC-1 lung cancer syngeneic model was used in C57BL/6 mice. The TC-1 cells were injected intraperitoneally and allowed to establish for about 1 week. The mice were then administered TP-0184 repeatedly for 3-5 days, after which, plasma and livers were collected. Liver hepcidin levels were determined by RT-qPCR and plasma hepcidin levels by mass spectrometry. Iron levels were measured by ELISA.
Results
TP-0184 is a small molecule inhibitor of the kinase activity of ALK2 with an IC50 value of 5 nM. It has minimal activity against JAK2 (IC50 = 8540 nM), compared to other analogs within the same series. TP-0184 is effective at targeting hepcidin expression in a HepG2 cell culture model with an EC50 lower than 100 nM. It achieves this activity in HepG2 cells with no observable toxicities and in a pathway-specific manner. Furthermore, TP-0184 has been evaluated in multiple animal models of inflammation and anemia. TO was used to induce an acute inflammatory response in mice resulting in a 14-fold increase in liver hepcidin levels. Two oral doses of TP-0184 at 100 mg/kg, separated by 8 hours, was able to almost completely reverse the induction of hepcidin that was stimulated by the TO treatment. In this same TO model, TP-0184 was evaluated at doses as low as 25 mg/kg to further explore the lower limits of its efficacy and to establish a therapeutic window. Similarly, TP-0184 was tested in an anemia of cancer model utilizing TC-1 lung cancer cells. Tumor-bearing animals experienced a 3-fold increase in liver hepcidin expression, which was again completely reversed by dosing with TP-0184 at 25 mg/kg. In addition to the activity observed in these models, TP-0184 demonstrates favorable pharmacokinetic properties and good drug-like characteristics making it a viable candidate molecule to move into advanced preclinical testing, IND-enabling studies and formal clinical development.
Summary
TP-0184 is a potent and selective inhibitor of ALK2 with good activity in preclinical models of anemia associated with inflammation. We anticipate a clinical development strategy that focuses on anemia of chronic disease where an erythropoetin-sparing approach might offer significant clinical benefit both to patients and to health management institutions.
Keyword(s): Anemia, EPO, Erythropoieisis, Hepcidin
Session topic: Iron clinical and biology
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room Stolz 2
Background
The liver peptide hormone, hepcidin, is known as a master regulator of bioavailable iron and red blood cell formation. Hepcidin expression is in part regulated by pro-inflammatory cytokines that ultimately signal through the activin-like kinase receptor 2 (ALK2) and SMAD transcription factors leading to the expression of hepcidin. In chronic inflammatory conditions, such as chronic kidney disease, rheumatoid arthritis, colitis, and in some forms of cancer, hepcidin levels remain high, lowering bioavailable iron leading to anemia. Hepcidin functions by binding to and inhibiting ferroportin, an iron pump that functions in macrophage-based iron recycling and intestinal iron uptake. Several studies demonstrated that lowering hepcidin could provide a novel approach for targeting this complicated clinical challenge. Current clinical strategies for these patients focus on red blood cell transfusions and the use of erythropoetin-based therapies. Neither of these approaches target the underlying mechanism behind the anemia associated with chronic inflammation and cancer.
Aims
The aim of this work is to develop a small molecule inhibitor of ALK2 for the treatment of hepcidin-driven anemia of chronic diseases.
Methods
Two animal models were primarily employed for these studies. First, turpentine oil (TO) was used to induce an acute inflammatory response in C57BL/6 mice with associated hepcidin-driven anemia. The animals were orally administered TP-0184 1 hour prior to TO treatment and then 8 hours later. Plasma and livers were collected 16 hours after TO treatment. Second, a TC-1 lung cancer syngeneic model was used in C57BL/6 mice. The TC-1 cells were injected intraperitoneally and allowed to establish for about 1 week. The mice were then administered TP-0184 repeatedly for 3-5 days, after which, plasma and livers were collected. Liver hepcidin levels were determined by RT-qPCR and plasma hepcidin levels by mass spectrometry. Iron levels were measured by ELISA.
Results
TP-0184 is a small molecule inhibitor of the kinase activity of ALK2 with an IC50 value of 5 nM. It has minimal activity against JAK2 (IC50 = 8540 nM), compared to other analogs within the same series. TP-0184 is effective at targeting hepcidin expression in a HepG2 cell culture model with an EC50 lower than 100 nM. It achieves this activity in HepG2 cells with no observable toxicities and in a pathway-specific manner. Furthermore, TP-0184 has been evaluated in multiple animal models of inflammation and anemia. TO was used to induce an acute inflammatory response in mice resulting in a 14-fold increase in liver hepcidin levels. Two oral doses of TP-0184 at 100 mg/kg, separated by 8 hours, was able to almost completely reverse the induction of hepcidin that was stimulated by the TO treatment. In this same TO model, TP-0184 was evaluated at doses as low as 25 mg/kg to further explore the lower limits of its efficacy and to establish a therapeutic window. Similarly, TP-0184 was tested in an anemia of cancer model utilizing TC-1 lung cancer cells. Tumor-bearing animals experienced a 3-fold increase in liver hepcidin expression, which was again completely reversed by dosing with TP-0184 at 25 mg/kg. In addition to the activity observed in these models, TP-0184 demonstrates favorable pharmacokinetic properties and good drug-like characteristics making it a viable candidate molecule to move into advanced preclinical testing, IND-enabling studies and formal clinical development.
Summary
TP-0184 is a potent and selective inhibitor of ALK2 with good activity in preclinical models of anemia associated with inflammation. We anticipate a clinical development strategy that focuses on anemia of chronic disease where an erythropoetin-sparing approach might offer significant clinical benefit both to patients and to health management institutions.
Keyword(s): Anemia, EPO, Erythropoieisis, Hepcidin
Session topic: Iron clinical and biology
Abstract: S501
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room Stolz 2
Background
The liver peptide hormone, hepcidin, is known as a master regulator of bioavailable iron and red blood cell formation. Hepcidin expression is in part regulated by pro-inflammatory cytokines that ultimately signal through the activin-like kinase receptor 2 (ALK2) and SMAD transcription factors leading to the expression of hepcidin. In chronic inflammatory conditions, such as chronic kidney disease, rheumatoid arthritis, colitis, and in some forms of cancer, hepcidin levels remain high, lowering bioavailable iron leading to anemia. Hepcidin functions by binding to and inhibiting ferroportin, an iron pump that functions in macrophage-based iron recycling and intestinal iron uptake. Several studies demonstrated that lowering hepcidin could provide a novel approach for targeting this complicated clinical challenge. Current clinical strategies for these patients focus on red blood cell transfusions and the use of erythropoetin-based therapies. Neither of these approaches target the underlying mechanism behind the anemia associated with chronic inflammation and cancer.
Aims
The aim of this work is to develop a small molecule inhibitor of ALK2 for the treatment of hepcidin-driven anemia of chronic diseases.
Methods
Two animal models were primarily employed for these studies. First, turpentine oil (TO) was used to induce an acute inflammatory response in C57BL/6 mice with associated hepcidin-driven anemia. The animals were orally administered TP-0184 1 hour prior to TO treatment and then 8 hours later. Plasma and livers were collected 16 hours after TO treatment. Second, a TC-1 lung cancer syngeneic model was used in C57BL/6 mice. The TC-1 cells were injected intraperitoneally and allowed to establish for about 1 week. The mice were then administered TP-0184 repeatedly for 3-5 days, after which, plasma and livers were collected. Liver hepcidin levels were determined by RT-qPCR and plasma hepcidin levels by mass spectrometry. Iron levels were measured by ELISA.
Results
TP-0184 is a small molecule inhibitor of the kinase activity of ALK2 with an IC50 value of 5 nM. It has minimal activity against JAK2 (IC50 = 8540 nM), compared to other analogs within the same series. TP-0184 is effective at targeting hepcidin expression in a HepG2 cell culture model with an EC50 lower than 100 nM. It achieves this activity in HepG2 cells with no observable toxicities and in a pathway-specific manner. Furthermore, TP-0184 has been evaluated in multiple animal models of inflammation and anemia. TO was used to induce an acute inflammatory response in mice resulting in a 14-fold increase in liver hepcidin levels. Two oral doses of TP-0184 at 100 mg/kg, separated by 8 hours, was able to almost completely reverse the induction of hepcidin that was stimulated by the TO treatment. In this same TO model, TP-0184 was evaluated at doses as low as 25 mg/kg to further explore the lower limits of its efficacy and to establish a therapeutic window. Similarly, TP-0184 was tested in an anemia of cancer model utilizing TC-1 lung cancer cells. Tumor-bearing animals experienced a 3-fold increase in liver hepcidin expression, which was again completely reversed by dosing with TP-0184 at 25 mg/kg. In addition to the activity observed in these models, TP-0184 demonstrates favorable pharmacokinetic properties and good drug-like characteristics making it a viable candidate molecule to move into advanced preclinical testing, IND-enabling studies and formal clinical development.
Summary
TP-0184 is a potent and selective inhibitor of ALK2 with good activity in preclinical models of anemia associated with inflammation. We anticipate a clinical development strategy that focuses on anemia of chronic disease where an erythropoetin-sparing approach might offer significant clinical benefit both to patients and to health management institutions.
Keyword(s): Anemia, EPO, Erythropoieisis, Hepcidin
Session topic: Iron clinical and biology
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 15:45 to 13.06.2015 16:00
Location: Room Stolz 2
Background
The liver peptide hormone, hepcidin, is known as a master regulator of bioavailable iron and red blood cell formation. Hepcidin expression is in part regulated by pro-inflammatory cytokines that ultimately signal through the activin-like kinase receptor 2 (ALK2) and SMAD transcription factors leading to the expression of hepcidin. In chronic inflammatory conditions, such as chronic kidney disease, rheumatoid arthritis, colitis, and in some forms of cancer, hepcidin levels remain high, lowering bioavailable iron leading to anemia. Hepcidin functions by binding to and inhibiting ferroportin, an iron pump that functions in macrophage-based iron recycling and intestinal iron uptake. Several studies demonstrated that lowering hepcidin could provide a novel approach for targeting this complicated clinical challenge. Current clinical strategies for these patients focus on red blood cell transfusions and the use of erythropoetin-based therapies. Neither of these approaches target the underlying mechanism behind the anemia associated with chronic inflammation and cancer.
Aims
The aim of this work is to develop a small molecule inhibitor of ALK2 for the treatment of hepcidin-driven anemia of chronic diseases.
Methods
Two animal models were primarily employed for these studies. First, turpentine oil (TO) was used to induce an acute inflammatory response in C57BL/6 mice with associated hepcidin-driven anemia. The animals were orally administered TP-0184 1 hour prior to TO treatment and then 8 hours later. Plasma and livers were collected 16 hours after TO treatment. Second, a TC-1 lung cancer syngeneic model was used in C57BL/6 mice. The TC-1 cells were injected intraperitoneally and allowed to establish for about 1 week. The mice were then administered TP-0184 repeatedly for 3-5 days, after which, plasma and livers were collected. Liver hepcidin levels were determined by RT-qPCR and plasma hepcidin levels by mass spectrometry. Iron levels were measured by ELISA.
Results
TP-0184 is a small molecule inhibitor of the kinase activity of ALK2 with an IC50 value of 5 nM. It has minimal activity against JAK2 (IC50 = 8540 nM), compared to other analogs within the same series. TP-0184 is effective at targeting hepcidin expression in a HepG2 cell culture model with an EC50 lower than 100 nM. It achieves this activity in HepG2 cells with no observable toxicities and in a pathway-specific manner. Furthermore, TP-0184 has been evaluated in multiple animal models of inflammation and anemia. TO was used to induce an acute inflammatory response in mice resulting in a 14-fold increase in liver hepcidin levels. Two oral doses of TP-0184 at 100 mg/kg, separated by 8 hours, was able to almost completely reverse the induction of hepcidin that was stimulated by the TO treatment. In this same TO model, TP-0184 was evaluated at doses as low as 25 mg/kg to further explore the lower limits of its efficacy and to establish a therapeutic window. Similarly, TP-0184 was tested in an anemia of cancer model utilizing TC-1 lung cancer cells. Tumor-bearing animals experienced a 3-fold increase in liver hepcidin expression, which was again completely reversed by dosing with TP-0184 at 25 mg/kg. In addition to the activity observed in these models, TP-0184 demonstrates favorable pharmacokinetic properties and good drug-like characteristics making it a viable candidate molecule to move into advanced preclinical testing, IND-enabling studies and formal clinical development.
Summary
TP-0184 is a potent and selective inhibitor of ALK2 with good activity in preclinical models of anemia associated with inflammation. We anticipate a clinical development strategy that focuses on anemia of chronic disease where an erythropoetin-sparing approach might offer significant clinical benefit both to patients and to health management institutions.
Keyword(s): Anemia, EPO, Erythropoieisis, Hepcidin
Session topic: Iron clinical and biology
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