Keros Therapeutics, Inc. (“Keros”) (Nasdaq: KROS), a clinical-stage
biopharmaceutical company focused on the discovery, development and
commercialization of novel treatments for patients suffering from
hematological, pulmonary and cardiovascular disorders with high
unmet medical need, today announced that it presented additional
biomarker data from its completed Phase 1 clinical trial of KER-012
in healthy post-menopausal women at the American Thoracic Society
(“ATS”) 2023 International Conference, held from May 19 through May
24, 2023. In addition, Keros presented preclinical data showing the
potential of a research form of KER-012 (“RKER-012”) to improve
left ventricular function in a mouse model of left ventricular
pressure overload, as well as preclinical data evaluating
transforming growth factor-beta (“TGF-β”) signaling in two major
cell types involved in the dysregulated vascular remodeling in
pulmonary arterial hypertension (“PAH”), and KER-012’s effect on
this ligand-induced signaling.
“We are pleased to present clinical and preclinical
data from our KER-012 program at the ATS conference this year. The
preclinical presentations demonstrate observed ligand selectivity
of KER-012 and changes in inflammation and fibrosis in models of
PAH and cardiovascular diseases. From our completed Phase 1
clinical trial of KER-012 in healthy post-menopausal women, we
presented new data with observed sustained changes in serum
biomarkers of cardiac dysfunction, inflammation and fibrosis,” said
Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of
Keros. “We believe these data support the potential of KER-012 to
treat fibrosis and inflammation in patients with PAH and in
patients with cardiovascular disease.”
Clinical Presentation
- Administration of KER-012, a Modified Activin Receptor IIB
Ligand Trap, Led to Changes in Biomarkers of Cardiovascular Health
in a Ph1 Study Conducted in Healthy Post-Menopausal Women
This Phase 1 clinical trial was a randomized,
double-blind, placebo-controlled, two-part trial to assess the
safety, tolerability, pharmacokinetics and pharmacodynamics of
KER-012. Keros reported preliminary topline data from the Part 1
single ascending dose portion of the trial in May 2022, and
additional preliminary clinical data from the Part 2 multiple
ascending dose portion of the trial in September 2022.
The following data from the subjects enrolled in
the highest dose cohort (4.5 mg/kg) from Part 2 of this trial were
presented at ATS 2023:
- Serum proteins associated with inflammation and structural
remodeling pathways were altered following one dose of 4.5 mg/kg of
KER-012 versus placebo, which Keros believes is consistent with the
predicted mechanism of action of KER-012:
- Decreases in markers of fibrosis, as indicated by changes in
matrix metalloproteinases (MMP-7 and 10) and collagen fragments,
were observed;
- Reductions in pro-inflammatory cytokines (IL-6 and IL-11) were
observed; and
- Increases in anti-inflammatory cytokines (IL-4 and IL-35) and
markers of macrophage polarization (MARCO and sCD163) were also
observed.
- Sustained reductions in a biomarker of cardiac dysfunction
(serum N-terminal pro-brain natriuretic peptide) were observed in
subjects administered 4.5 mg/kg of KER-012 versus placebo.
Preclinical Presentations
- RKER-012, a Novel Modified ActRII Ligand Trap, Attenuated
Cardiac Remodeling and Fibrosis in a Transverse Aortic Constriction
Model of Heart Failure
Keros used a transverse aortic constriction (“TAC”)
model of left ventricle overload to evaluate whether RKER-012 could
prevent or treat cardiac remodeling and fibrosis in mice.
Mice either underwent sham or TAC surgery.
Following these procedures, sham mice received vehicle and TAC mice
received either vehicle (“TAC-vehicle”) or 10 mg/kg of RKER-012
(“TAC-RKER-012”) twice weekly, starting from the first day
(“TAC-RKER-012 Group 1”) or fourteenth day (“TAC-RKER-012 Group 2”)
after surgery. Eight weeks post-surgery, mice were assessed for
associated cardiac pathologies. Relative to sham mice, TAC-vehicle
mice had increased heart weight, left ventricular posterior wall
thickness, interventricular septal end diastole, left ventricular
fibrosis and elevated tissue remodeling markers, indicating that
the TAC surgery worked as intended.
TAC-RKER-012 Group 1 mice had significantly reduced
heart weight, left ventricular posterior wall thickness,
interventricular septal end diastole and left ventricular fibrosis
compared to TAC-vehicle mice. TAC-RKER-012 Group 2 mice had
significantly reduced left ventricular posterior wall thickness and
interventricular septal end diastole compared to TAC-vehicle mice,
while heart weight and left ventricular fibrosis trended towards a
decrease.
These data demonstrate that RKER-012 lessened the
severity of cardiac fibrosis and remodeling, leading to an
improvement in left ventricular function, which Keros believes
supports the potential of KER-012 to benefit heart failure patients
as a preventative or treatment option.
- RKER-012, a Novel Activin Receptor Type IIB (ActRIIB) Ligand
Trap, Inhibited Mediators of Dysregulated Vascular Remodeling in
Pulmonary Endothelial and Smooth Muscle Cells
This preclinical study evaluated TGF-β ligand
signaling in human pulmonary arterial endothelial cells (“HPAECs”)
and smooth muscle cells (“HPASMCs”), which are two major cell types
involved in the dysregulated vascular remodeling in PAH, and
KER-012’s effect on this ligand-induced signaling.
HPAECs and HPASMCs were treated with activin A,
GDF11, or bone morphogenetic protein 9 (“BMP9”) in the presence of
KER-012. KER-012 treatment reduced activin A and GDF11-induced SMAD
2/3 signaling in the HPAECs and HPASMCs, but did not inhibit
BMP9-induced pSMAD1 signaling.
Separately, pulmonary arterial cells cultured in
normoxia or hypoxia for 48 hours to mimic conditions in PAH were
evaluated with RKER-012. Keros observed increases in activin A
induced by hypoxia in HPAECs, but not in HPASMCs, which is
consistent with the role of endothelial dysfunction in PAH and
suggests that activin A may be released from endothelial cells
during vascular remodeling. RKER-012 was able to reduce SMAD2
activation in hypoxic endothelial cells back to normoxic levels by
binding endogenously upregulated activin A in an in vitro model
replicating hypoxia in PAH.
These data from this in vitro model suggest that
KER-012 can potentially correct imbalanced SMAD signaling in PAH,
partially by inhibiting activin A, a key pathogenic driver of
PAH.
About the Completed Phase 1 Clinical Trial
of KER-012 in Healthy Volunteers
In September 2022, Keros completed a randomized,
double-blind, placebo-controlled, two-part Phase 1 clinical trial
to evaluate single and multiple ascending doses of KER-012 in
healthy post-menopausal women. The primary objectives of this trial
were to evaluate the safety and tolerability of escalating doses of
KER-012 administered as single and multiple subcutaneous doses in
healthy post-menopausal women.
In Part 1 of this trial, 32 subjects received
either a single 0.75, 1.5, 3 or 5 mg/kg dose of KER-012 and eight
subjects received a single dose of placebo, each administered
subcutaneously with an eight-week safety follow-up. The subjects
were enrolled in sequential single-ascending dose escalation
cohorts of ten subjects each. In Part 2 of the trial, subjects
received three subcutaneous doses of either 0.75, 1.5 or 4.5 mg/kg
of KER-012 or placebo administered 28 days apart with a 16-week
safety follow-up. A total of 26 subjects were enrolled in three
sequential multiple-ascending dose escalation cohorts, with eight
subjects in the 0.75 mg/kg cohort and six subjects in each of the
1.5 mg/kg and 4.5 mg/kg cohorts receiving KER-012. Six subjects
enrolled in Part 2 of this trial received placebo doses.
About KER-012
KER-012 is designed to bind to and inhibit the
signaling of TGF-β ligands that suppress bone growth, including
activin A and activin B. Keros believes that KER-012 has the
potential to increase the signaling of bone morphogenic protein
(“BMP”) pathways through this inhibition of activin A and activin B
signaling, and consequently treat diseases such as PAH that are
associated with reduced BMP signaling due to inactivating mutations
in the BMP receptors. KER-012 is being developed for the treatment
of PAH and for the treatment of cardiovascular disorders.
About Keros Therapeutics, Inc.
Keros is a clinical-stage biopharmaceutical company
focused on the discovery, development and commercialization of
novel treatments for patients suffering from hematological,
pulmonary and cardiovascular disorders with high unmet medical
need. Keros is a leader in understanding the role of the TGF-β
family of proteins, which are master regulators of red blood cell
and platelet production as well as of the growth, repair and
maintenance of a number of tissues, including blood vessels and
heart tissue. Keros’ lead protein therapeutic product candidate,
KER-050, is being developed for the treatment of low blood cell
counts, or cytopenias, including anemia and thrombocytopenia, in
patients with myelodysplastic syndromes and in patients with
myelofibrosis. Keros’ lead small molecule product candidate,
KER-047, is being developed for the treatment of functional iron
deficiency. Keros’ third product candidate, KER-012, is being
developed for the treatment of PAH and for the treatment of
cardiovascular disorders.
Cautionary Note Regarding Forward-Looking
Statements
Statements contained in this press release
regarding matters that are not historical facts are
“forward-looking statements” within the meaning of the Private
Securities Litigation Reform Act of 1995, as amended. Words such as
"believes," "intends," “potential” and "suggest" or similar
expressions are intended to identify forward-looking statements.
Examples of these forward-looking statements include statements
concerning: Keros’ expectations regarding its growth, strategy,
progress and the design, objectives and timing of its clinical
trials for KER-012; the potential of KER-012 to treat fibrosis and
inflammation in patients with PAH and in patients with
cardiovascular disease; the potential of KER-012 to benefit heart
failure patients as a preventative or treatment option; and the
potential of KER-012 to correct imbalanced SMAD signaling in PAH.
Because such statements are subject to risks and uncertainties,
actual results may differ materially from those expressed or
implied by such forward-looking statements. These risks and
uncertainties include, among others: Keros’ limited operating
history and historical losses; Keros’ ability to raise additional
funding to complete the development and any commercialization of
its product candidates; Keros’ dependence on the success of its
product candidates, KER-050, KER-047 and KER-012; that Keros may be
delayed in initiating, enrolling or completing any clinical trials;
competition from third parties that are developing products for
similar uses; Keros’ ability to obtain, maintain and protect its
intellectual property; and Keros’ dependence on third parties in
connection with manufacturing, clinical trials and preclinical
studies.
These and other risks are described more fully in
Keros’ filings with the Securities and Exchange Commission (“SEC”),
including the “Risk Factors” section of the Company’s Quarterly
Report on Form 10-Q, filed with the SEC on May 4, 2023, and its
other documents subsequently filed with or furnished to the SEC.
All forward-looking statements contained in this press release
speak only as of the date on which they were made. Except to the
extent required by law, Keros undertakes no obligation to update
such statements to reflect events that occur or circumstances that
exist after the date on which they were made.
Investor Contact:
Justin
Frantzjfrantz@soleburytrout.com617-221-9100
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