Tarix is developing two structurally related peptide drugs, TXA127 and PanCyte.
TXA127 is a pharmaceutical grade formulation of the naturally occurring peptide Angiotensin (1-7), (or A (1-7)). This peptide is part of the renin-angiotensin-system (RAS), and was thought for many years to be an inactive by-product of degradation of other molecules in the RAS. In the 1990s, A(1-7) began to be studied for its action on myocardial tissue, and a specific receptor for A(1-7) was identified. This mas receptor is expressed in a variety of tissues, including bone marrow, brain, heart, and lung. It is now clear that A(1-7) is part of a pathway which includes angiotensin converting enzyme 2 (ACE2) and the mas receptor. It is now clear that the actions of ACE2-A(1-7)-mas counteract the detrimental effects of the “classical” RAS axis, ACE-Angiotensin II-AT1 receptor:
A(1-7) is produced in-vivo by the action of the enzyme angiotensin converting enzyme 2 (ACE2), which removes the last amino acid from angiotensin II, producing the seven amino acid peptide, A(1-7).
PanCyte is a synthetic “cyclic” analogue of TXA127. It is formed by replacing the fourth and seventh amino acids in the naturally occurring sequence with amino acids which can bind to each other via a thio-ether bridge, thus creating a loop in the molecule. This new structure is highly resistant to the enzymes which degrade and inactivate the naturally occurring peptide, while surprisingly retaining the same activity. The result is a new chemical entity with an extended patent life and greater potency, with the same or similar spectrum of activity as A(1-7).
TXA127 Pre-Clinical Data
TXA127 stimulates the proliferation of early hematopoietic progenitor stem cells. Subsequently, this stimulatory effect increases the number of hematologic precursors and circulating granulocytes, lymphocytes, and platelets following both chemotherapy and radiation exposure.
Hematopoeitic Cascade:
TXA127 has been shown to:
Increase the number of hematologic precursors, including CFU-GEMM (early stem cell), CFU-MEG (platelets), CFU-GM (neutrophils), and BFU-E (red cells);
increase the number of circulating lymphocytes, neutrophils, platelets, and red blood cells;
be synergistic with growth factors which act “downstream”, including GCSF (eg., Neupogen), erythropoietin, and thrombopoietin.
Stimulation of these pluripotent precursors leads to increases in the number of specific committed precursors as seen in the following two diagrams:
TXA127 increases the number of circulating blood cells
The increase in bone marrow precursors leads to an increase in the number of white blood cells and platelets in the peripheral blood. Below is a model showing the increase in white blood cells following treatment with TXA127.
TXA127 is synergistic with Neupogen and Erythropoietin
A fixed dose of TXA127 (300µg/kg), when combined with varying doses of Neupogen (upper curve), significantly shifts the dose-response curve compared to single-agent Neupogen (lower curve) in an animal model of neutropenia induced by gemcitabine chemotherapy.
TXA127 in combination with less than10% of the normal Neupogen dose was as effective as full dose Neupogen by itself. Furthermore, TXA127 added to full dose Neopogen was 50% better than full dose Neupogen by itself.
Similar synergy is seen between TXA127 and erythropoietin, as demonstrated through two red cell precursors, the earlier erythroid burst-forming units (BFU-E) and the later erythroid colony forming units (CFU-E).
Pre-clinical development of PanCyte
The cyclic structure of PanCyte protects it from degradation by proteases, yielding a much longer half-life than TXA127. PanCyte appears to have a very high affinity for the mas receptor. As a result, it may be useful in a variety of diseases in which the pathophysiology is related to the ACE/angiotensin II/AT1 receptor. These diseases include pulmonary fibrosis, acute lung injury, pulmonary arterial hypertension, and fibrosis of the kidney and liver. The development of PanCyte will initially focus on pulmonary indications.
Technology
Tarix is developing two structurally related peptide drugs, TXA127 and PanCyte.
TXA127 is a pharmaceutical grade formulation of the naturally occurring peptide Angiotensin (1-7), (or A (1-7)). This peptide is part of the renin-angiotensin-system (RAS), and was thought for many years to be an inactive by-product of degradation of other molecules in the RAS. In the 1990s, A(1-7) began to be studied for its action on myocardial tissue, and a specific receptor for A(1-7) was identified. This mas receptor is expressed in a variety of tissues, including bone marrow, brain, heart, and lung. It is now clear that A(1-7) is part of a pathway which includes angiotensin converting enzyme 2 (ACE2) and the mas receptor. It is now clear that the actions of ACE2-A(1-7)-mas counteract the detrimental effects of the “classical” RAS axis, ACE-Angiotensin II-AT1 receptor:
A(1-7) is produced in-vivo by the action of the enzyme angiotensin converting enzyme 2 (ACE2), which removes the last amino acid from angiotensin II, producing the seven amino acid peptide, A(1-7).
PanCyte is a synthetic “cyclic” analogue of TXA127. It is formed by replacing the fourth and seventh amino acids in the naturally occurring sequence with amino acids which can bind to each other via a thio-ether bridge, thus creating a loop in the molecule. This new structure is highly resistant to the enzymes which degrade and inactivate the naturally occurring peptide, while surprisingly retaining the same activity. The result is a new chemical entity with an extended patent life and greater potency, with the same or similar spectrum of activity as A(1-7).
TXA127 Pre-Clinical Data
TXA127 stimulates the proliferation of early hematopoietic progenitor stem cells. Subsequently, this stimulatory effect increases the number of hematologic precursors and circulating granulocytes, lymphocytes, and platelets following both chemotherapy and radiation exposure.
Hematopoeitic Cascade:
TXA127 has been shown to:
Stimulation of these pluripotent precursors leads to increases in the number of specific committed precursors as seen in the following two diagrams:
TXA127 increases the number of circulating blood cells
The increase in bone marrow precursors leads to an increase in the number of white blood cells and platelets in the peripheral blood. Below is a model showing the increase in white blood cells following treatment with TXA127.
TXA127 is synergistic with Neupogen and Erythropoietin
A fixed dose of TXA127 (300µg/kg), when combined with varying doses of Neupogen (upper curve), significantly shifts the dose-response curve compared to single-agent Neupogen (lower curve) in an animal model of neutropenia induced by gemcitabine chemotherapy.
TXA127 in combination with less than10% of the normal Neupogen dose was as effective as full dose Neupogen by itself. Furthermore, TXA127 added to full dose Neopogen was 50% better than full dose Neupogen by itself.
Similar synergy is seen between TXA127 and erythropoietin, as demonstrated through two red cell precursors, the earlier erythroid burst-forming units (BFU-E) and the later erythroid colony forming units (CFU-E).
Pre-clinical development of PanCyte
The cyclic structure of PanCyte protects it from degradation by proteases, yielding a much longer half-life than TXA127. PanCyte appears to have a very high affinity for the mas receptor. As a result, it may be useful in a variety of diseases in which the pathophysiology is related to the ACE/angiotensin II/AT1 receptor. These diseases include pulmonary fibrosis, acute lung injury, pulmonary arterial hypertension, and fibrosis of the kidney and liver. The development of PanCyte will initially focus on pulmonary indications.