Primary Objectives: • To evaluate the safety and tolerability of ascending doses of KER 047 in participants with iron-refractory iron deficiency anemia (IRIDA)Secondary Objectives:• To evaluate the pharmacodynamic (PD) effects of KER 047 on iron…
ID
Source
Brief title
Condition
- Other condition
- Red blood cell disorders
- Blood and lymphatic system disorders congenital
Synonym
Health condition
iron-refractory iron deficiency anemia (IRIDA)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Endpoints:
• Safety and tolerability as determined by the incidence of treatment-emergent
adverse events (TEAEs), dose limiting toxicities (DLT's), treatment related
serious AEs, and discontinuations due to AEs; and change from baseline in
clinical laboratory values, vital signs, and electrocardiogram (ECG)
Pharmacodynamic Endpoints:
The following laboratory values will be assessed as change from baseline after
28 days of treatment in Part 1 and after 28 or 56 days of treatment in Part 2:
• Hepcidin concentration in plasma
• Serum iron
• Ferritin
• Total iron binding capacity (TIBC)
• Transferrin saturation (TSAT)
• Reticulocyte hemoglobin content (RET-He/CHr)
• Soluble transferrin receptor (sTfR) and sTfR/log ferritin index
• TSAT/hepcidin; ferritin/hepcidin
Pharmacokinetic Endpoints:
The following parameters for KER-047 and any metabolites of interest will be
assessed in Part 1 on Days 8, 15, 22, and 29, and in Part 2 on Days 8, 15, 22,
and 29 if treatment was 28 days or Days 8, 15, 22, 29, 36, 43, 50, and 57 if
treatment was 56 days:
• Trough plasma concentraion (Ctrough)
• Plasma accumulation (Rac)
Secondary outcome
Exploratory Endpoints:
• Proportion of participants who have a response, defined as a hemoglobin
increase of >= 1.5 g/dL (0.9 mmol/L) from baseline after 28 days of treatment in
Part 1 and 28 or 56 days of treatment in Part 2. Proportion of participants who
have a response, defined as a hemoglobin increase of >= 1.0 g/dL (0.6 mmol/L)
from baseline after 28 days of treatment in Part 1 and 28 or 56 days of
treatment in Part 2.
• Change from baseline in hemoglobin after 28 days of treatment in Part 1
and 28 or 56 days of treatment in Part 2
• Change from baseline in hemoglobin after 14 days of treatment in Part 1 and
28 or 56 days of treatment in Part 2.
• Change from baseline in red blood cell indices (mean corpuscular volume
[MCV], mean corposcular hemoglobin [MCH], mean corpuscular hemoglobin
concentration [MCHC]), and reticulocyte count after 28 days of treatment in
Part 1 and 28 or 56 days of treatment in Part 2.
• Change from baseline in health-related quality of life as measured by SF-36
after 28 days of treatment in Part 1 and 28 or 56 days of treatment in Part 2.
Background summary
Iron is required to synthesize hemoglobin for maturing red blood cells (RBCs).
Most iron is
recycled by hepatic and splenic macrophages after phagocytosis of senescent
RBCs, while a
small amount is absorbed daily by duodenal enterocytes. Hepcidin is the
iron-regulatory protein
hormone produced by hepatocytes, which negatively regulates serum iron by
inducing
internalization and degradation of the only known iron exporter protein,
ferroportin. Liver
sinusoidal endothelial cells sense iron-loaded transferrin and ferritin levels
in serum and regulate
hepcidin production through the bone morphogenetic protein (BMP) pathway,
especially BMP2
and BMP6. Increased hepcidin results in reduced iron absorption by the
duodenum, and reduced
release of iron from liver and iron-recycling macrophages.1
Anemias may be classified based on the presence of high or low hepcidin.
Iron-deficient and
iron-loading anemias have low hepcidin levels. In contrast, iron-refractory
iron deficiency
anemia (IRIDA), hepcidin-producing adenoma-associated anemia, and anemia of
inflammation
(also known as anemia of chronic disease) are characterized by high hepcidin
levels. Disorders
with anemia and iron overload secondary to chronic transfusions, such as β-
thalassemia major
are also associated with elevated hepcidin.
IRIDA is a rare, inherited form of iron deficiency anemia that results from
loss of function
mutations in the TMPRSS6 gene,2 which encodes for matriptase-2 (MT-2), a
transmembrane
serine protease that cleaves hemojuvelin from hepatocytes resulting in
inhibition of hepcidin.
Decreased activity of MT-2 results in elevated activin receptor-like kinase 2
(ALK2) signaling
and high hepcidin levels.3 Patients with IRIDA are usually diagnosed in
childhood, presenting
with mild to moderate anemia. Since most children with IRIDA exhibit normal
growth and
development, the anemia is usually detected in the process of routine
screening. Signs and
symptoms associated with iron deficiency, such as koilonychias or hair loss,
and anemia, such as
fatigue, weakness, and shortness of breath, are rare. Hematologic examination
shows a
reticulocytopenic, hypochromic, microcytic anemia, with disproportionately low
mean
corpuscular volume (MCV) with respect to the degree of anemia. Iron biomarkers
show low
transferrin saturation, and low serum iron that is only partially responsive to
oral and parenteral
iron, due to poor absorption and defective utilization.3
Currently, there are no therapies approved for the treatment of IRIDA, and
those that are used are
not without side effects. High-dose oral iron is difficult to tolerate due to
gastrointestinal (GI)
effects. Intravenous (IV) iron has restrictive and time-consuming
administration requirements
which results in underutilization. Blood transfusion may be used as a last
resort treatment for
severe symptomatic anemia, but is generally to be avoided due to
transfusion-associated risks.3,4
Therefore, there is an unmet need for more effective, safer, and more
convenient treatments for
IRIDA.
Studies conducted in a TMPRSS66 siRNA knockdown mouse model of IRIDA
demonstrated
that KER-047 treatment resulted in reduced hepcidin, increased serum iron, and
ameliorated
anemia. Thus, KER-047, via inhibited hepcidin expression and increased iron
mobilization, has
the potential to benefit patients with anemia related to high hepcidin, such as
IRIDA.
Study objective
Primary Objectives:
• To evaluate the safety and tolerability of ascending doses of KER 047 in
participants with iron-refractory iron deficiency anemia (IRIDA)
Secondary Objectives:
• To evaluate the pharmacodynamic (PD) effects of KER 047 on iron metabolism in
participants with IRIDA
• To evaluate plasma accumulation of KER 047 across the treatment period
Exploratory Objectives:
• To evaluate the effect of KER 047 on anemia in participants with IRIDA
• To evaluate the effect of KER 047 on health-related quality-of-life as
measured by the 36-Item Short Form Survey (SF 36)
To evaluate the safety and tolerability of ascending doses of KER--047 in
participants with IRIDA
Study design
Study Design:
This is a phase 2, two-part, open-label, intra-participant dose escalation and
dose expansion study to evaluate the effects of KER-047 in participants with
IRIDA. Participants may enroll in Part 1, in and/or Part 2 only, or in both
parts. Part 1 (dose escalation) is planned to be 3 ascending dose levels. An
optional additional level may be added at the recommendation of the Safety
Review Committee (SRC); see Dose Escalation description, below. Part 2 (Dose
Expansion) is planned to be an expansion with dose level selected based on
review of the data from Part 1.
Intervention
KER-047 is a powder for oral suspension and will be suspended in water to
produce an in-use suspension for oral dosing.
Study burden and risks
The burden and risk mainly consist of extra time spent compared to standard
treatment, the use of KER-047 and the risks of medical evaluation, including
venipuncture.
Potential Risks:
• Increased fracture risk. Increased risk of joint inflammation.
• Abdominal discomfort, weight loss, constipation, gastroenteritis, nausea and
vomiting, gastric ulceration
• Corneal erosions, eye pain
• Acute kidney injury, proteinuria, hematuria
• Macro- and micro-vasculitis
• Liver enzyme increase
• Lymphopenia, neutropenia
Please refer to 25 of the protocol, Table 2 for proposed mitigation and
monitoring of these risks
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US
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Age
Inclusion criteria
Participants are eligible for the study if all of the following criteria apply:
1. Male or female >= 18 years of age, at the time of signing informed consent.
2. Confirmed diagnosis of IRIDA based on the following:
- Documented homozygous or compound heterozygous TMPRSS6 gene variant(s) of
Class 3 or greater (variant of uncertain significance, likely pathogenic,
pathogenic) per the Association for Clinical Genomic Science.
3. Serum TSAT at screening less than 15%.
4. Participants receiving oral iron supplementation must be on a stable dose
for >=4 weeks prior to Day 1, with a maximum of 60 mg/day of oral elemental
iron. Intravenous (IV) iron is not permitted during the study.
5. Ability to understand the purpose and risks of the study and provide signed
and dated informed consent and authorization to use protected health
information in accordance with national and local study participant privacy
regulations.
6. Females of childbearing potential and sexually active males must agree to
use effective methods of contraception as outlined in the protocol.
7. In the opinion of the Investigator, the participant is able and willing to
comply with the requirements of the protocol (e.g., all study procedures,
return for follow-up visits).
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
Medical History
1. Body mass index >35 kg/m2
2. Any active infection requiring parenteral antibiotic therapy within 28 days
prior to Day 1 or oral antibiotics within 14 days of Day 1. Any infection with
>5 days of fever (> 38.5* C) within 28 days prior to Day 1.
3. Presence of uncontrolled heart disease or New York Heart Association Class 3
or 4 heart failure.
4. History or presence at screening of an uncontrolled chronic disease.
5. History of drug or alcohol abuse, as defined by the investigator, within the
past 2 years.
6. History of stroke, arterial embolism, or unresolved deep venous thrombosis
within 6 months prior to Day 1.
7. Major surgery within 28 days prior to Day 1. Participants who had surgery
more than 28 days prior to Day 1 must have recovered satisfactorily to
participate in the study, in the opinion of the Investigator.
8. Known positive for human immunodeficiency virus, active infectious hepatitis
B, or active infectious hepatitis C.
9. Any malignancy that has not been in remission and/or has required systemic
therapy including radiation, chemotherapy, hormonal therapy, or surgery within
the last year prior to Day 1.
10. History of solid organ or hematological transplantation.
11. Have had a fracture within 4 weeks of D1.
12. History of severe allergic or anaphylactic reactions or hypersensitivity to
recombinant proteins or excipients in the IMP.
Treatment History
13. Treatment with IV iron within 28 days prior to study entry.
14. Receiving treatment with proton pump inhibitors (PPIs). Participants
receiving PPIs who discontinue use at least 7 days prior to Day 1 are permitted
to enroll.
15. Receiving and plan to continue any disallowed medications.
16. Treatment with another investigational drug or device, or approved therapy
for investigational use <= 28 days prior to Day 1, or, if the half-life of the
previous product is known, within 5 times the half-life prior to Day 1,
whichever is longer.
Laboratory Exclusions
17. Hemoglobin level >=13.8 g/dL (8.56 mmol/L) (males) or >=12.1 g/dL (7.51
mmol/L) (females)
18. Serum ferritin < 50 or > 500 µg/L
19. Absolute lymphocyte count < 1.00 x 109/L
20. Absolute neutrophil count < 1.50 x 109/L
21. Estimated glomerular filtration rate by Chronic Kidney Disease-Epidemiology
Collaboration creatinine equation < 45 mL/min/1.73 m2
22. Alanine transaminase or aspartate transaminase > 2 x upper limit of normal
(ULN)
Miscellaneous
23. Pregnant or lactating females.
24. Any other condition not specifically noted above that, in the judgment of
the Investigator or Sponsor, would preclude the participant from participating
in the study.
25. Participants who are investigational site staff members directly involved
in the conduct of the trial and their immediate family members, site staff
members otherwise supervised by the Investigator, or participants who are Keros
or CRO employees directly involved in the conduct of the study. Immediate
family is defined as a spouse, parent, child, or sibling, whether biological or
legally adopted.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 2021-000348-22 |
| EudraCT | EUCTR2021-000348-22-NL |
| CCMO | NL77168.091.21 |