TGF-β Biology & Role in Diseases

At Keros, we are leveraging our protein engineering and drug development expertise to bring new treatment options to patients with rare diseases.

Our science focuses on the transforming growth factor-beta (TGF-β) superfamily—a broad and complex area of biology—comprised of more than 30 ligands, 12 receptors, numerous co-receptors and secreted regulatory molecules that play critical roles in tissue development and homeostasis. Accordingly, imbalanced signaling in the TGF-β pathway may cause or contribute to the progression and symptoms of these diseases. Through many years of research and clinical development experience, we have honed a deep understanding of TGF-β and have developed a pipeline of candidates aimed at treating diseases that are linked to imbalanced signaling of the TGF-β pathway.

Red blood cells to represent Hematology disease area

KER-050 is being developed for the treatment of ineffective hematopoiesis. Hematopoiesis is the process by which blood cells are produced in the bone marrow. When cells properly mature, they leave the bone marrow and enter circulation. Ineffective hematopoiesis—the failure of immature blood cells to properly develop into mature cells—may lead to low levels of circulating red blood cells (anemia), white blood cells (neutropenia) or platelets (thrombocytopenia).

Elevated signaling through the TGF-β pathway by activin A is associated with increased bone loss, metastasis and impaired bone marrow, resulting in the observed pathology in hematological diseases. KER-050, which is designed to bind to and inhibit activin A, has the potential to improve the bone marrow and restore normal hematopoiesis by targeting multiple cell lineages.

Myelodysplastic Syndromes (MDS) is a heterogenous group of bone marrow disorders characterized by ineffective hematopoiesis. There are 60,000 to 170,000 people living with MDS in the United States, and 15,000 to 20,000 new cases are reported each year. Anemia is the most frequent consequence of ineffective hematopoiesis in patients with MDS due to low red blood cell production, resulting in insufficient tissue oxygenation and debilitating symptoms such as fatigue and shortness of breath. Of the 90% of MDS patients who present with anemia, approximately 40% become transfusion dependent.

Another consequence of ineffective hematopoiesis is thrombocytopenia, or low platelet count, a condition which impairs blood clotting and may contribute to uncontrolled bleeding. Thrombocytopenia occurs in approximately 40% to 65% of MDS patients.

Presently, treatment options for MDS include transfusions as well as erythroid maturation agents (EMAs) and off-label usage of erythroid stimulating agents (ESAs), which are given to increase red blood cells. However, as bone marrow failure progresses and transfusion requirements increase, available treatments become increasingly ineffective. Moreover, repeated blood transfusions result in iron overload, further exacerbating damage to the bone marrow and increasing the risk of acute myeloid leukemia progression and cardiovascular disease. Additionally, the benefit from a platelet transfusion is typically short-lived and availability is limited. Platelet-stimulating agents for the treatment of thrombocytopenia, which are not currently indicated for MDS, carry the risk of thromboembolic events and bone marrow fibrosis.

Diseased Bone Marrow & Osteohemopoietic Niche diagram

As an investigational ligand trap designed to bind activins, KER-050 has the potential to inhibit the overactive TGF-β signaling in diseases such as MDS to remove blockages in blood cell and platelet production in the bone marrow and potentially treat anemia and thrombocytopenia.

Based on data from our completed Phase 1 clinical trial of KER-050 in healthy volunteers and from our preclinical studies, we believe KER-050 has the potential to treat both anemia and thrombocytopenia. Additionally, preclinical studies showed that treatment with a research version of KER-050 was able to reduce bone loss. Based on these data, we believe KER-050 could potentially regenerate a healthy bone marrow and slow down progression of the disease in patients.

We are evaluating KER-050 in a Phase 2 clinical trial for the treatment of anemia and thrombocytopenia in patients with very low-. or intermediate-risk MDS.

Myelofibrosis (MF) is a rare form of cancer—affecting 16,000 to 18,500 patients in the United States—in which bone marrow is not able to produce healthy blood cells. As a result, the spleen begins to produce cells to compensate for this ineffective hematopoiesis, which ultimately causes the spleen to enlarge. Many of these patients go on to develop anemia, which significantly impairs their quality of life, resulting in severe fatigue, weakness, exercise intolerance, chest pain (angina), dizziness, cognitive impairment and a diminished sense of well-being.

JAK inhibitors are used to help alleviate the symptoms of MF by reducing spleen size. However, JAK inhibitors can cause cytopenias that require periodic red blood cell and platelet transfusions. There are no currently approved treatments for MF-associated cytopenias.

Based on data from our completed Phase 1 clinical trial of KER-050 in healthy volunteers and from our preclinical studies, we believe KER-050 has the potential to correct cytopenias that arise as a consequence of either MF or treatment with JAK inhibitors.

We are conducting a Phase 2 clinical trial evaluating KER-050 as a monotherapy and in combination with ruxolitinib, a JAK inhibitor, in patients with MF-associated cytopenias.

KER-012 is being developed for the treatment of PAH and for the treatment of cardiovascular disorders. Based on results from our preclinical studies and clinical trials to date, we believe that KER-012 has the potential to increase the signaling of BMP pathways through inhibition of activin A and activin B, and consequently treat diseases such as PAH that are associated with reduced BMP signaling due to inactivating mutations in the BMP receptor.

In preclinical models of PAH, a research version of KER-012 (RKER-012) prevented vascular thickening and reduced vascular resistance and cardiac hypertrophy. In addition, treatment with RKER-012 reduced markers of inflammation, fibrosis and vascular smooth muscle hypertrophy without a dose-limiting increase in red blood cells observed with similar third-party molecules. Preclinical studies also provide supporting data suggesting that RKER-012 has a cardio-protective mechanism of action.

In a Phase 1 trial in healthy volunteers, KER-012 was generally well tolerated and elicited changes in multiple biomarkers that suggest maximum activin target engagement with no dose-limiting increases in red blood cell parameters. See the relevant Keros press releases here, here, and here.

KER-012 is our investigational product candidate being developed for treatment of pulmonary and cardiovascular disorders, including PAH.

PAH is a debilitating disorder characterized by high blood pressure in the arteries of the lungs which cause stress to the lungs and the heart. Over time, this pressure weakens the heart musculature, resulting in hypertrophy and eventual heart failure. The symptoms of PAH severely affect a patient’s quality of life. These include shortness of breath, fatigue, fainting, chest pain, palpitations and swelling of extremities and abdomen. We estimate that there are approximately 40,000 addressable patients in the United States living with this condition.

While there are several therapies available to help control symptoms and improve quality of life for those who suffer from PAH, none appear to halt or reverse the progression of the disease. All approved therapies for PAH are vasodilators, which are medications that open blood vessels and lower pressure in the pulmonary arteries, but do not address the underlying disease pathology. In the most severe cases of PAH, supplemental oxygen or a single lung, double lung or heart-lung transplant may also be required.

We believe there is significant unmet need for a treatment that primarily targets the underlying disease and can be used alone or in combination with other PAH therapies.

Neuromuscular - illustration of nerve and muscle

KER-065 is being developed for the treatment of obesity and for the treatment of neuromuscular disorders. Based on our preclinical data, we believe that KER-065 has the potential to increase skeletal muscle and to reduce fat mass through an increase in energy expenditure, improve insulin sensitivity and improve cardiac function. Additionally, in combination with incretins, KER-065 could potentially ameliorate muscle loss, further reduce fat mass and improve cardiac health directly. 

In preclinical studies, KER-065 showed high affinity for and potent inhibition of ligands involved in the regulation of muscle and bone homeostasis. In a diet induced obesity model of mice, a research version of KER-065 (RKER-065) demonstrated increases in skeletal muscle.  In preclinical models of Duchenne muscular dystrophy (DMD), RKER-065 increased lean mass, forelimb grip strength and trabecular bone compared to vehicle-treated DMD mice.

We commenced a Phase 1 clinical trial evaluating KER-065 in a healthy volunteer adult population. This trial has been designed to enable the evaluation of any treatment-related increases in skeletal muscle, decreases in fat and improvements in bone health.

Obesity is a complex and chronic disease defined as having a body mass index, or BMI, of greater than or equal to 30, and is caused by abnormal or excessive fat accumulation due to an imbalance in energy intake and consumption over a long period of time. There are many comorbidities associated with obesity, including type 2 diabetes, cardiovascular disease, hypertension, heart disease, sleep apnea and some cancers, as well as an increased risk of death. According to the World Health Organization, in 2016, more than 1.9 billon adults worldwide were overweight, with 650 million considered to be obese. The prevalence of obesity has tripled since 1975 and is projected to affect one billion people globally by 2030.

Based on our preclinical data, we believe that KER-065 has the potential to increase skeletal muscle in obese individuals and to reduce fat mass through an increase in energy expenditure, improve insulin sensitivity and improve cardiac function. Additionally, in combination with incretins, KER-065 could potentially ameliorate muscle loss, further reduce fat mass and improve cardiac health directly.

Neuromuscular disease is a broad term that encompasses many diseases that either directly (via intrinsic muscle pathology) or indirectly (via nerve pathology) impair the functioning of muscles. Symptoms of neuromuscular disease include increasing generalized weakness and fatigue, dysphagia, dyspnea on exertion and at rest, sleepiness, morning headache, difficulties with concentration and mood changes. Most neuromuscular diseases are characterized by progressive muscular impairment leading to loss of muscle function and can lead to loss of ambulation, being wheelchair-bound, swallowing difficulties, respiratory muscle weakness and death. Neuromuscular disorders can progress rapidly or slowly. Decline in muscle mass can also be associated with secondary osteoporosis and obesity.

DMD is the most common form of muscular dystrophy and results in muscle degeneration and premature death. DMD is characterized by a lack of dystrophin, which causes muscle cells to have increased susceptibility to damage and to progressively die. Additionally, the absence of dystrophin in muscle cells leads to significant cell damage and ultimately causes muscle cell death and the replacement of muscle with fibrotic and fatty tissue. In DMD patients, symptoms typically manifest in the first few years of life. Patients experience progressive muscle weakness and muscle wasting followed by paralysis, respiratory and/or cardiac failure, resulting in early mortality in the third or fourth decade of life. We estimate that approximately one in every 3,500 male births is affected by DMD worldwide.

Based on our preclinical data, we believe that KER-065 has the potential to treat multiple pathophysiologies of DMD by improving muscle and bone strength and reducing fat mass and cardiac fibrosis.