A new view to treating hematologic diseases

Disc Medicine’s therapies are designed to regulate hepcidin expression and treat patients with hematologic diseases. Our core development programs target hepcidin biology.

Stage:

DISCOVERY PRECLINICAL CLINICAL
Anti-hemojuvelin antibody 1
DISCOVERY PRECLINICAL CLINICAL
Anti-hemojuvelin antibody 2
DISCOVERY PRECLINICAL CLINICAL
Matriptase-2 inhibitor
DISCOVERY PRECLINICAL CLINICAL

Anti-hemojuvelin antibody

  • Hemojuvelin is a direct regulator of hepcidin gene expression.
  • Reducing hemojuvelin activity decreases hepcidin levels and may have therapeutic utility in diseases such as myeloproliferative disorders and anemia of chronic disease.
  • Disc Medicine is currently conducting preclinical studies of anti-hemojuvelin antibodies as a potential treatment for these hematologic disorders.

Myeloproliferative Disorders

Myeloproliferative disorders are often caused by acquired mutations in the bone marrow that lead to increased immune cell production, reduced red cell production, and can result in fibrosis (scarring) of the bone marrow over time1. Hepcidin levels are increased by inflammatory signals, leading to sequestration of iron in immune cells and away from developing red cells that may exacerbate both anemia and inflammation in these myeloproliferative disorders. By restoring hepcidin regulation at lower levels we hope to improve red cell production and symptoms in patients.

1 Vainchenker and Kralovics, Blood 2017

Anemia of Chronic Disease

Elevated hepcidin levels leading to anemia can also be caused by impaired hepcidin clearance or inflammatory/autoimmune disorders, such as chronic kidney disease and rheumatoid arthritis1. In these disorders, elevated hepcidin levels lead to iron sequestration in the liver and in immune cells where it is not available to support red cell production, resulting in anemia and the consequences of anemia such as weakness and fatigue2,3. In preclinical studies, antagonizing hemojuvelin to reduce hepcidin has led to increased hemoglobin production and reduced inflammatory signals.

1 Haurani F, Ann Clin Lab Sci, 2006
2 Ganz and Nemeth, Semin Nephrol, 2016
3 Demirag et al, Intern Med 2009

IRIDA

Iron refractory iron deficiency anemia is a rare inherited disorder caused by mutations in matriptase-2 (TMPRSS6) that leads to chronic elevation of hepcidin, iron sequestration, and anemia that does not respond to iron supplementation1. Restoring hepcidin regulation addresses the underlying genetic cause of this disorder, and in preclinical studies of mice with similar mutations in TMPRSS6 a single dose of a hemojuvelin antagonist was sufficient to restore hemoglobin levels to normal2.

1 Falco et al, Haematologica 2013
2 Kovac et al, Haematologica 2016

Anti-hemojuvelin antibody

Overview

  • Hemojuvelin is a direct regulator of hepcidin gene expression.
  • Reducing hemojuvelin activity decreases hepcidin levels and may have therapeutic utility in diseases such as myeloproliferative disorders and anemia of chronic disease.
  • Disc Medicine is currently conducting preclinical studies of anti-hemojuvelin antibodies as a potential treatment for these hematologic disorders.

Myeloproliferative Disorders

Myeloproliferative Disorders

Myeloproliferative disorders are often caused by acquired mutations in the bone marrow that lead to increased immune cell production, reduced red cell production, and can result in fibrosis (scarring) of the bone marrow over time1. Hepcidin levels are increased by inflammatory signals, leading to sequestration of iron in immune cells and away from developing red cells that may exacerbate both anemia and inflammation in these myeloproliferative disorders. By restoring hepcidin regulation at lower levels we hope to improve red cell production and symptoms in patients.

1 Vainchenker and Kralovics, Blood 2017

Anemia of Chronic Disease

Anemia of Chronic Disease

Elevated hepcidin levels leading to anemia can also be caused by impaired hepcidin clearance or inflammatory/autoimmune disorders, such as chronic kidney disease and rheumatoid arthritis1. In these disorders, elevated hepcidin levels lead to iron sequestration in the liver and in immune cells where it is not available to support red cell production, resulting in anemia and the consequences of anemia such as weakness and fatigue2,3. In preclinical studies, antagonizing hemojuvelin to reduce hepcidin has led to increased hemoglobin production and reduced inflammatory signals.

1 Haurani F, Ann Clin Lab Sci, 2006
2 Ganz and Nemeth, Semin Nephrol, 2016
3 Demirag et al, Intern Med 2009

IRIDA

IRIDA

Iron refractory iron deficiency anemia is a rare inherited disorder caused by mutations in matriptase-2 (TMPRSS6) that leads to chronic elevation of hepcidin, iron sequestration, and anemia that does not respond to iron supplementation1. Restoring hepcidin regulation addresses the underlying genetic cause of this disorder, and in preclinical studies of mice with similar mutations in TMPRSS6 a single dose of a hemojuvelin antagonist was sufficient to restore hemoglobin levels to normal2.

1 Falco et al, Haematologica 2013
2 Kovac et al, Haematologica 2016

Matriptase-2 inhibitor

  • Matriptase-2 is a negative regulator of hepcidin synthesis.
  • Small molecule inhibitors of matriptase-2 increase hepcidin levels and have potential therapeutic utility in diseases such as beta thalassemia, myelodysplastic syndrome and hemochromatosis.
  • Disc Medicine is conducting preclinical studies of a matriptase-2 inhibitor as a potential treatment for rare hematologic disease.

Myelodysplastic Syndrome

Low-grade and early forms of myelodysplastic syndrome are characterized by ineffective erythropoiesis similar to thalassemia, but in these cases the mutations that lead to the disorder are acquired with age rather than inherited from birth. Like thalassemia, impaired red cell formation in myelodysplastic syndrome leads to hepcidin suppression, iron loading, anemia, fatigue, and risk of iron toxicity1,2. Patients with suppressed hepcidin levels tend to respond less well to erythropoiesis stimulating agents3. While in more aggressive forms of the disease there is an increased risk of leukemic transformation, for many patients MDS is a chronic disease with ineffective erythropoiesis and anemia as the major symptom.

1 Ambaglio et al, Haematologica, 2013
2 Bondu et al, Sci Transl Med 2019
3 Kosmider et al, Blood 2017

Beta Thalassemia

Thalassemia is an inborn genetic disorder caused by mutations in either alpha or beta-globin chains of hemoglobin. An imbalance of these two equally contributing components of hemoglobin leads to protein aggregation and release of free iron in the developing red blood cell that impairs the survival of these cells (ineffective erythropoiesis) and leads to hepcidin suppression and iron loading in tissues such as the heart and liver. Patients experience this as anemia, fatigue, and elevated risk of iron toxicity over time. Transfusion and iron chelation can improve anemia in the short term, but at the risk of increasing iron toxicity, and many patients who are not transfused have limited therapeutic options. Preclinical studies reducing matriptase-2 activity have resulted in restored hepcidin regulation, improved red cell survival and hemoglobin levels, and reduced iron accumulation1,2. Patients with less active forms of the matriptase-2 gene have less severe symptoms of beta thalassemia3.

1 Schmidt et al, Blood 2013
2 Guo et al, J Clin Invest. 2013
3 Cua et al, Am J Hematol. 2015

Hereditary Hemochromatosis

Hemochromatosis is an inherited iron loading disorder caused by genetic mutations that reduce hepcidin levels1. Over time, accumulation of iron can lead to iron loading in tissues such as the heart and liver resulting in risk of disorders including diabetes and liver cirrhosis. For many patients, regular bloodletting (phlebotomy) can maintain iron levels in the normal range, however certain patients such as those with cardiovascular disease or concurrent anemia may not be able to receive regular phlebotomy. Restoring hepcidin regulation in these patients will address the underlying genetic cause of the disorder.

1 Weiss, G. Nat. Rev. Gastroenterol. Hepatol, 2010

Matriptase-2 inhibitor

Overview

  • Matriptase-2 is a negative regulator of hepcidin synthesis.
  • Small molecule inhibitors of matriptase-2 increase hepcidin levels and have potential therapeutic utility in diseases such as beta thalassemia, myelodysplastic syndrome and hemochromatosis.
  • Disc Medicine is conducting preclinical studies of a matriptase-2 inhibitor as a potential treatment for rare hematologic disease.

Myelodysplastic Syndrome

Myelodysplastic Syndrome

Low-grade and early forms of myelodysplastic syndrome are characterized by ineffective erythropoiesis similar to thalassemia, but in these cases the mutations that lead to the disorder are acquired with age rather than inherited from birth. Like thalassemia, impaired red cell formation in myelodysplastic syndrome leads to hepcidin suppression, iron loading, anemia, fatigue, and risk of iron toxicity1,2. Patients with suppressed hepcidin levels tend to respond less well to erythropoiesis stimulating agents3. While in more aggressive forms of the disease there is an increased risk of leukemic transformation, for many patients MDS is a chronic disease with ineffective erythropoiesis and anemia as the major symptom.

1 Ambaglio et al, Haematologica, 2013
2 Bondu et al, Sci Transl Med 2019
3 Kosmider et al, Blood 2017

Beta Thalassemia

Beta Thalassemia

Thalassemia is an inborn genetic disorder caused by mutations in either alpha or beta-globin chains of hemoglobin. An imbalance of these two equally contributing components of hemoglobin leads to protein aggregation and release of free iron in the developing red blood cell that impairs the survival of these cells (ineffective erythropoiesis) and leads to hepcidin suppression and iron loading in tissues such as the heart and liver. Patients experience this as anemia, fatigue, and elevated risk of iron toxicity over time. Transfusion and iron chelation can improve anemia in the short term, but at the risk of increasing iron toxicity, and many patients who are not transfused have limited therapeutic options. Preclinical studies reducing matriptase-2 activity have resulted in restored hepcidin regulation, improved red cell survival and hemoglobin levels, and reduced iron accumulation1,2. Patients with less active forms of the matriptase-2 gene have less severe symptoms of beta thalassemia3.

1 Schmidt et al, Blood 2013
2 Guo et al, J Clin Invest. 2013
3 Cua et al, Am J Hematol. 2015

Hereditary Hemochromatosis

Hereditary Hemochromatosis

Hemochromatosis is an inherited iron loading disorder caused by genetic mutations that reduce hepcidin levels1. Over time, accumulation of iron can lead to iron loading in tissues such as the heart and liver resulting in risk of disorders including diabetes and liver cirrhosis. For many patients, regular bloodletting (phlebotomy) can maintain iron levels in the normal range, however certain patients such as those with cardiovascular disease or concurrent anemia may not be able to receive regular phlebotomy. Restoring hepcidin regulation in these patients will address the underlying genetic cause of the disorder.

1 Weiss, G. Nat. Rev. Gastroenterol. Hepatol, 2010