TARGETED ALK2 INHIBITION AS A THERAPEUTIC APPROACH TO REDUCING
HEPCIDIN AND ELEVATING SERUM IRON
Thomas Backus, Natalia Medeiros, Evan Lema, ffolliott M Fisher, Jasbir Seehra and Jennifer L Lachey
Keros Therapeutics, Lexington, MA
Hepcidin is an endocrine regulator of iron metabolism that, when elevated, can decrease
levels of iron available for erythropoiesis and, as a result, decrease red blood cell production.
Signaling though activin-like kinase-2 (ALK2), a TGFβ type 1 receptor, has been implicated in
regulation of hepcidin-mediated iron regulation and mobilization; however, to date, ALK2’s
specific degree of involvement has not been convincingly elucidated, mainly due to the
redundant effects of the type 1 receptors ALK3 and ALK5. Activation of type 1 receptors
including ALK2, ALK3, and ALK5 via ligand BMPs and co-receptor hemojuvelin (m-HJV), results
in downstream SMAD phosphorylation, increased hepcidin, and decreased serum iron while
suppression of the receptor signaling would have the opposite effects. To assess the specific
effect of ALK2 inhibition on hepcidin and iron mobilization, we utilized multiple modalities of
inhibition and tested inhibitors in both naive and diseased animals. KTI-2338, a small molecule
ALK2 kinase inhibitor, was characterized to inhibit ALK-2 signaling potently and selectively
in in-vitro assays. To further assess the specific contribution of ALK2 to hepcidin expression
and iron mobilization, we evaluated the effect of the novel neutralizing antibody KTI-A2.0MAb.
This fully human antibody is targeted against the extracellular domain of ALK2 with
no affinity for the other type-1 receptors.
In wild-type animals, targeting ALK2 signaling with either a small molecule or biologic
therapeutic leads to decreased serum hepcidin and increased serum
iron. To assess the efficacy of ALK2 inhibition in a disease state, we utilized an siRNA-based
model of Iron-Refractory Iron Deficiency Anemia (IRIDA). In IRIDA, patients exhibit a loss of
functional TMPRSS6, a gene that encodes the transmembrane type II serine protease
Matriptase-2 (MT-2). MT-2 suppresses hepcidin secretion by cleaving m-HJV, interrupting
ALK2 signaling and downstream SMAD activation. Failure to cleave m-HJV allows
continued activation of BMPRs, increased hepcidin and decreased serum iron. Phenocopying
what is observed in IRIDA patients, intravenous dosing of TMPRSS6 targeted siRNA results
suppressed TMPRSS6 expression and functional MT-2, increases in serum hepcidin, and
decreases in serum iron. Therapeutic dosing of either a small molecule or biologic ALK2
inhibitor in the siRNA based IRIDA model resulted in rescue of hemoglobin, hematocrit, serum
hepcidin, and serum iron in the disease state. Following treatment, hemoglobin, hematocrit,
and serum iron were increased and serum hepcidin was decreased in treated
groups compared to control cohorts receiving vehicle.
Herein, we have evaluated multiple modalities of ALK2 inhibition in both healthy
and disease states. We have characterized that inhibition of ALK2 signaling via either
modality in both naïve and anemic mice contributes to a decrease in serum hepcidin and
increase in serum iron levels. Though the use of a selective ALK2 targeted biologic does
not completely preclude involvement of other BMP receptors such as ALK3, these data
support our assertion that ALK2 signaling is an integral part of hepcidin-mediated
iron mobilization, and illustrate the potential therapeutic benefit of ALK2 inhibition (with a
small molecule inhibitor or a neutralizing monoclonal antibody) in anemia of high
hepcidin including IRIDA and anemia of inflammation.
POSTER 2
SCIENTIFIC PROGRAMME
SESSION I
BONE MARROW
RESPONSE TO VIRAL
INFECTIONS
SESSION II
HAEMATOLOGICAL
RESPONSE TO SARS
COV2 INFECTION
SESSION III
DYSERYTHROPOIESIS IN
CLONAL HAEMOPOIESIS
AND MDS
SESSION IV
ERYTHROPOIESIS
CONTROL
SESSION V
ERYTHROPOIESIS
CONTROL : PHASE 2
SESSION VI
IRON METABOLISM
AND ERYTHROPOIESIS
SESSION VII
INHERITED
DYSERYTHROPOIESIS
SESSION VIII
GENE THERAPY/EDITION
SESSION IX – DRUGS
AND INEFFECTIVE
ERYTHROPOIESIS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
FACULTY DISCLOSURES