Keros Therapeutics, Inc. (“Keros” or the “Company”) (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 data from its ongoing Phase
2 clinical trial of KER-050 in patients with very low-, low-, or
intermediate-risk myelodysplastic syndromes (“MDS”), as well as
preclinical data showing the potential of a research form of
KER-050 (“RKER-050”) to restore erythropoiesis in an animal model
of myelofibrosis (“MF”), at the 28th Annual Congress of the
European Hematology Association (“EHA”), held in person and
virtually June 8 through 15, 2023. In addition, Keros announced
preclinical data evaluating activin receptor-like kinase-2 (“ALK2”)
inhibition, as well as its combination with RKER-050, as potential
treatment options for anemia of inflammation.
“We are pleased to present additional data from our ongoing
Phase 2 clinical trial of KER-050 in MDS patients at EHA this year,
which demonstrated durable hematological responses with longer-term
treatment in a broad, lower-risk MDS patient population, including
those with high transfusion burden,” said Jasbir S. Seehra, Ph.D.,
President and Chief Executive Officer of Keros. “Additionally, we
are excited to announce that we have recently expanded this trial
to include two cohorts of MDS patients with iron overload, which
will enable us to further explore the potential of KER-050 to
reduce iron overload and improve iron utilization in MDS patients.
Separately, we believe that we will have sufficient data from this
trial at the end of this year that will allow us to begin the
process of engaging with regulators on the design of a Phase 3
clinical trial.”
Clinical Presentation
- KER-050 treatment improved markers of erythropoietic activity
and hematopoiesis over six months which resulted in hematological
responses across a broad, lower-risk MDS population
This ongoing, open-label, two-part, Phase 2 clinical trial is
evaluating KER-050 in participants with very low-, low-, or
intermediate-risk MDS. In Part 1, the dose escalation portion of
the trial, enrollment was balanced approximately one-to-one between
patients that did not have ring sideroblasts (“non-RS”) and
patients that have ring sideroblasts (“RS positive”). Patients in
Part 1 received KER-050 subcutaneously every 28 days for up to four
cycles at the following dose levels: Cohort 1, 0.75 mg/kg; Cohort
2, 1.5 mg/kg; Cohort 3, 2.5 mg/kg; Cohort 4, 3.75 mg/kg; and Cohort
5, 5.0 mg/kg. In Part 2, the dose confirmation portion of the
trial, an identical dosing schedule was followed, and patients
initiated treatment at a starting dose of 3.75 mg/kg, the
recommended Part 2 dose (“RP2D”), with the opportunity to dose
escalate to 5.0 mg/kg or to down-titrate based on individual
titration rules. Following completion of Part 1, eligible patients
were given the opportunity to escalate up to the RP2D and receive
long-term treatment with KER-050 for up to an additional 20 cycles
(“Part 1 Extension”).
As of April 3, 2023 (the “data cut-off date”), 25 patients from
Part 1, including the Part 1 Extension, and 34 patients from Part
2, had received at least one dose of KER-050 at RP2D (collectively,
the “safety population”). Of these patients, 37 had completed at
least 24 weeks of treatment or discontinued as of the data cut-off
date (the “evaluated RP2D patients”). Data for hematological
response and markers of hematopoiesis were presented from
exploratory analyses of these evaluated RP2D patients.
Of the 59 patients in the safety population, 71.2% (n=42/59)
were RS positive while 28.8% (n=17/59) were non-RS. The safety
population included 12 non-transfused (“NT”), 16 low transfusion
burden (“LTB”) and 31 high transfusion burden (“HTB”) patients.
As of the data cut-off date, KER-050 was generally well
tolerated by the 59 patients in the safety population. No patients
had progressed to acute myeloid leukemia. There were two cases of
fatal treatment-emergent adverse events (“TEAEs”) in the trial
(cardiac failure and myocardial infarction), each of which were
determined to be unrelated to treatment. Four additional patients
experienced TEAEs that led to discontinuation of treatment. One
case was deemed treatment related (injection site reaction), and in
three patients, the events were determined to be unrelated to
treatment (dyspnea, chronic obstructive pulmonary disease and
cardiac failure congestive (in one patient), and nodular melanoma).
The most commonly reported TEAEs (in ≥15% of patients) were
COVID-19, diarrhea, dyspnea, fatigue, nausea and nosebleeds
(epistaxis).
As of the data cut-off date, 51.4% (n=19/37) of the evaluated
RP2D patients achieved an overall erythroid response over the first
24 weeks of treatment, which is defined as meeting one of the
following two endpoints:
- Modified IWG 2006 Hematological improvement-erythroid (“HI-E”),
which is defined as either:
- a ≥ 1.5 g/dL mean increase in hemoglobin over any eight-week
period on treatment compared with the eight-week period prior to
Cycle 1, Day 1 in LTB and NT patients; or
- a reduction by ≥ 4 RBC units transfused during any eight-week
period on treatment, compared with the eight-week period prior to
Cycle 1, Day 1 in HTB patients.
- Transfusion independence (“TI”) for at least eight weeks in
transfusion-dependent patients who required ≥ 2 RBC units
transfused at baseline.
Additional data from the evaluated RP2D patients, as of the data
cut-off date, include:
- 51.4% (n=19/37) of the evaluated RP2D patients achieved HI-E
over an eight-week period during the first 24 weeks of
treatment.
- 42.3% (n=11/26) of the transfused RP2D patients receiving ≥ 2
RBC units at baseline achieved TI for at least eight weeks over the
first 24 weeks of treatment. Of these 26 patients, 19 were RS
positive and seven were non-RS.
- 42.1% (n=8/19) of these RS positive patients achieved TI for at
least eight weeks over the first 24 weeks of treatment.
- 42.9% (n=3/7) of these non-RS patients achieved TI for at least
eight weeks over the first 24 weeks of treatment.
- Of the transfused RP2D patients, 40.9% (n=9/22) of those who
are HTB achieved TI for at least eight weeks during the first 24
weeks of treatment. Of these 22 patients, 17 were RS positive and
five were non-RS.
- 35.3% (n=6/17) of these RS positive HTB patients achieved TI
for at least eight weeks.
- 60.0% (n=3/5) of these non-RS HTB patients achieved TI for at
least eight weeks.
- Of the 19 patients who achieved HI-E or TI during the first 24
weeks of treatment (the “HI-E or TI Responders”), 10 of them
(52.6%) had ongoing response as of the data cutoff date.
- The median duration of response for the HI-E or TI Responders
was 42.4 weeks.
As of the data cut-off date, 44.1% (n=15/34) of the evaluated
RP2D patients who had at least eight weeks of post-baseline
platelet measurements exhibited sustained increases in platelet
counts from baseline over at least eight weeks. Additionally,
sustained increases in hemoglobin were observed over six months of
treatment with KER-050 in the LTB and NT HI-E responders.
Additional data from the exploratory analysis of biomarkers of
erythropoiesis and iron overload (“IO”) were also presented, with
data from the evaluated RP2D patients. Key observations from this
analysis, as of the data cut-off date, are as follows:
- Soluble transferrin receptor levels generally increased with
KER-050 treatment in HI-E or TI Responders, while ferritin levels
generally decreased.
- As of the data cut-off date, 18 patients had baseline ferritin
of >500 ng/mL. Of those 18 patients, eight (44.4%) had a maximum
mean decrease of ≥250 ng/mL over any 12-week period during the
first six months of treatment with KER-050, suggesting potential
for KER-050 to reduce IO in the most impacted patients.
Based on these additional data, this trial has been expanded to
include two cohorts of MDS patients with iron overload either with
or without iron chelation, which would allow Keros to further
evaluate the potential of KER-050 to reduce serum ferritin, an
indicator of iron overload, in that MDS patient population.
Preclinical Presentations
- A modified activin receptor type II ligand trap RKER-050
restored erythropoiesis in a mouse model of myelofibrosis
RKER-050 was tested in a mouse model of advanced MF. Male MF
mice with established anemia were administered either vehicle or 10
mg/kg of RKER-050 twice weekly for 12 weeks. Healthy male mice
received only vehicle.
The vehicle-treated MF mice continued to exhibit a significant
or trending decrease in RBC parameters, including RBCs, hemoglobin
and hematocrit, compared to healthy controls. Relative to
vehicle-treated MF mice, RKER-050-treated MF mice had a significant
recovery of those RBC parameters, demonstrating that RKER-050 fully
reversed anemia in this MF mouse model.
In the bone marrow, vehicle-treated MF mice showed a significant
reduction in erythroid progenitors compared to healthy controls.
Treatment with RKER-050 significantly increased certain erythroid
progenitors in MF mice compared to vehicle-treated MF mice,
suggesting bone marrow erythropoiesis was increased with RKER-050
treatment. Additionally, RKER-050-treated MF mice also had
increased erythroid progenitors in the spleen compared to
vehicle-treated MF mice, which may be due to the severe state of
the disease-impacted bone marrow microenvironment in this MF mouse
model.
Additionally, RKER-050 significantly reduced megakaryocyte
progenitors in the bone marrow compared to the elevated levels
observed in vehicle-treated MF mice, suggesting RKER-050 may
positively influence the megakaryocyte lineage. However, platelets
in the RKER-050-treated MF mice were not significantly increased
compared to vehicle-treated MF mice at this advanced stage of
disease.
These results suggest that RKER-050 can promote erythropoiesis
and reduce aberrant megakaryocyte progenitor proliferation in the
bone marrow in this MF mouse model. Keros believes that KER-050 has
the potential to treat patients with MF and other hematological
diseases where ineffective hematopoiesis occurs.
- Combining ALK2 inhibition with a modified activin receptor IIA
ligand trap provided additive benefits in resolving anemia in a
mouse model of anemia of inflammation
This preclinical study evaluated whether RKER-050 combined with
RKER-216, an investigational neutralizing antibody to ALK2, could
ameliorate anemia in a mouse model of induced chronic kidney
disease (“CKD”) representative of anemia of inflammation
(“AI”).
To induce a model of CKD, mice were fed a diet containing 0.2%
adenine and 40 ppm iron for five weeks. After AI was confirmed, CKD
mice were treated with 3 mg/kg of RKER-216 or vehicle twice a week
for four weeks. In a separate study, CKD mice received twice weekly
treatment of 3 mg/kg of RKER-216 or vehicle in combination with
once weekly treatment of 7.5 mg/kg of RKER-050 or vehicle for four
weeks.
- RKER-216-treated CKD mice exhibited a >95% decrease in serum
hepcidin, decreases in spleen iron retention and an increase in
transferrin saturation compared to vehicle-treated CKD mice.
RKER-216-treated CKD mice also showed improvements in hemoglobin
and RBC production compared to vehicle-treated CKD mice. Taken
together, these data suggest that the observed increase in iron
availability resulting from the administration of RKER-216 may be
sufficient for improving iron-restricted erythropoiesis in this AI
model.
- While RKER-216 monotherapy improved hemoglobin and RBC levels
in CKD mice relative to vehicle-treated CKD mice, combination
treatment with RKER-050 resulted in a greater magnitude of increase
in both hematological parameters. No significant differences in
serum hepcidin, spleen iron, or transferrin saturation were
observed between CKD mice receiving combination therapy or
monotherapy.
By targeting ALK2 inhibition to suppress hepcidin, RKER-216
increased iron availability for erythropoiesis and partially
rescued anemia in CKD mice. Separately, the combination of RKER-216
and RKER-050 maximized the hematologic recovery in this AI model,
which supports the potential benefits of this combination
therapy.
About the Ongoing Phase 2 Clinical Trial of KER-050 in
Patients with MDS (NCT04419649)
Keros is conducting an open label, two-part, multiple ascending
dose Phase 2 clinical trial to evaluate KER-050 in participants
with very low-, low-, or intermediate-risk MDS who either have or
have not previously received treatment with an erythroid
stimulating agent.
The primary objective of this trial is to assess the safety and
tolerability of KER-050 in participants with MDS that are RS
positive or non-RS. The primary objective of Part 2 of this trial
is confirmation of the safety and tolerability of the RP2D (3.75
mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to
evaluate the pharmacokinetics, pharmacodynamics and efficacy of
KER-050.
Conference Call and Webcast Information
The Company will host a conference call and webcast today, June
9, 2023, at 8:00 a.m. Eastern time, to discuss updates to and
additional data from its hematology franchise, including the
additional results from the ongoing Phase 2 clinical trial of
KER-050 presented at the 28th Annual Congress of EHA.
The conference call will be webcast live at
https://event.webcasts.com/starthere.jsp?ei=1615749&tp_key=a5c7667d07.
The live teleconference may be accessed by dialing (877) 405-1224
(domestic) or (201) 389-0848 (international). An archived version
of the call will be available in the Investors section of the Keros
website at https://ir.kerostx.com/ for 90 days following the
conclusion of the call.
About KER-050
Keros’ lead protein therapeutic product candidate, KER-050, is
an engineered ligand trap comprised of a modified ligand-binding
domain of the transforming growth factor-beta receptor known as
activin receptor type IIA that is fused to the portion of the human
antibody known as the Fc domain. KER-050 is being developed for the
treatment of low blood cell counts, or cytopenias, including anemia
and thrombocytopenia, in patients with myelodysplastic syndromes,
or MDS, and in patients with MF.
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 transforming growth
factor-beta 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 MDS and in patients with MF. 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
pulmonary arterial hypertension 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 "anticipates," "believes,"
"expects," "intends," “plans,” “potential,” "projects,” “would” and
"future" 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-050, including its
regulatory plans; the potential of KER-050 to reduce serum ferritin
in MDS patients with iron overload; the potential of KER-050 to
treat patients with MF and other hematological diseases where
ineffective hematopoiesis occurs; the potential of RKER-050 to
promote erythropoiesis and reduce aberrant megakaryocyte
proliferation in the bone marrow; and the potential benefits of
combining RKER-050 with RKER-216 to treat anemia resulting from
CKD. 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@kerostx.com 617-221-6042
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