Study to Evaluate Efficacy and Safety of BGE-117 in Moderately to Severely Anemic Older Individuals After Major Hip Surgery

The purpose of this study is to explore the safety and tolerability of BGE-117 and gain information on the effectiveness of different doses when given to patients 65 years or older with moderate to severe anemia following major hip surgery. BGE-117 is given once daily in a capsule by mouth for up to 12 weeks. Patients are also given oral iron supplements. Anemia following surgery has been associated with decreases in patient functioning. This study will measure improvement of anemia, as well as various patient functioning.

BGE-117 is being investigated to determine whether it is an effective treatment for moderate to severe anemia in older individuals (65 years of age or older) after major hip surgery. Currently, there are limited treatment options for postoperative anemia, in this patient population, available in the USA, Australia, or New Zealand. The increased risk of morbidity, mortality, and poor quality of life in the population of older individuals with postoperative anemia highlights the unmet medical need for a therapeutic agent that can alleviate physical and functional deficits in these patients. Study BGE-117-203 will be the first clinical study conducted in older patients with postoperative anemia. The study will collect important safety, efficacy, and dosing information across this population of patients to provide key data for designing further clinical studies in the development programs for BGE-117.

The study will enroll 2 populations of patients requiring hip surgery:

* older individuals who are scheduled for elective unilateral or bilateral hip surgery (total or partial hip replacement or revision of a previous replacement)
* older individuals with an acute hip fracture requiring surgical repair or replacement (usually performed within 48 hours after the fracture event)

These individuals must also meet the inclusion criterion for a hemoglobin level of ≤ 10 g/dL and ≥ 7.0 g/dL from postoperative Day 1 to postoperative Day 7.

The total planned enrollment for the study is approximately 192 subjects. The first 96 subjects who are enrolled will be randomized in a 1:2:1 ratio to 1 of 3 treatment groups:

* BGE-117 8 mg PO once daily with oral iron supplement 3 times per week (n = 24)
* BGE-117 4 mg PO once daily with oral iron supplement 3 times per week (n = 48)
* Matching placebo once daily with oral iron supplement 3 times per week (n = 24)

A Safety Review Meeting will be conducted when approximately 48 subjects have completed 4 weeks of treatment. Enrollment will remain ongoing for up to 96 subjects pending the Safety Review Meeting. If no safety concerns are identified that would preclude the inclusion of additional subjects, the subsequent 96 subjects who would be dosed up to 16 mg will be allowed to proceed without interruption. Additional safety reviews will be completed after 96 subjects and 144 subjects have completed 4 weeks of treatment.

The subsequent 96 subjects enrolled will be randomized in a 1:2:1 ratio to 1 of 3 treatment groups:

* BGE-117 8 mg PO once daily with oral iron supplement 3 times per week (n = 24)
* BGE-117 16 mg PO once daily with oral iron supplement 3 times per week (n = 48)
* Matching placebo once daily with oral iron supplement 3 times per week (n = 24)

At study completion, the goal is to have approximately 48 subjects in each of the 4 treatment groups (placebo, BGE-117 4 mg, BGE-117 8 mg, and BGE-117 16 mg) with each treatment group having a similar number of subjects with acute hip fracture or elective hip surgery.

The Treatment Period is 12 weeks, and all enrolled subjects will be followed for a total of 6 months after surgery (14 weeks after cessation of IP) to monitor hemoglobin progression and functional outcome as well as to continue to monitor for any potential AEs.

There will be no dose increases, however, dose decreases will be allowed if the rate of increase in hemoglobin exceeds the protocol defined limits. The goal is to maintain an approximate rate of hemoglobin increase of ≤ 1.5 g/dL every 2 weeks, and a maximum hemoglobin level of 12.0 g/dL. Dosing will be considered completed and no additional IP will be administered after the maximum hemoglobin value is confirmed.

Subjects will be randomized within 24 hours of meeting the hemoglobin entry criteria. The baseline hemoglobin value for the primary endpoint analysis will be the last (most recent) hemoglobin level obtained via central laboratory before administration of the first dose of blinded IP on Day 1. Treatment will start as soon as the subject has been randomized and is able to take oral medications. Subjects enrolled in the study will continue once daily treatment for a total of 12 weeks. Supplemental iron, provided by the Sponsor, will be administered orally as ferrous sulfate 325 mg 3 times per week (e.g., every Monday, Wednesday, and Friday).

Subjects may be discharged from the hospital as soon as it is medically appropriate, but they will continue to be seen at the study site at the following visits: Visit 2 (Day 1), Visit 4 (Day 15), Visit 8 (Day 43), and Visit 14 (Day 85). Home visits (including visits to rehabilitation facilities, assisted living facilities, and nursing home facilities) will be conducted at Visits 3, 5, 6, 7, 9, 10, 11, 12, and 13 to assess vital signs and collect a central blood sample for CBC and reticulocytes. There will be a home study visit approximately 14 days after administration of the last dose of IP (Visit 15). Additional home visits will be completed approximately 4 months after surgery on Day 127 (Visit 16), and approximately 5 months after surgery on Day 155 (Visit 17). A final Follow up Visit at the study site will be completed approximately 6 months after surgery on Day 183 (Visit 18).

All enrolled subjects must be able to personally give informed consent. Consent by guardian or proxy will not be permitted. Screening will include a full physical examination and baseline laboratory evaluation. Consent and screening procedures may be done preoperatively or postoperatively based on type of surgery. If a subject consents and meets eligibility criteria preoperatively, they must also meet eligibility criteria postoperatively to remain eligible for enrollment.

If a subject does not consent preoperatively (e.g., hip fracture), they can consent postoperatively. If enrolled, subjects will receive their first dose of IP at the study site. They will be instructed to take IP orally once daily, approximately 1 hour before breakfast for up to 83 additional days. Study medication will be administered in addition to oral iron supplements and standard of care as deemed appropriate by the subject's treating physicians. Oral iron in the form of ferrous sulfate 325 mg (supplied by the Sponsor) will be administered 3 times per week after an overnight fast at the same time-of-day as IP. Subjects will be monitored throughout the study for AEs and all relevant efficacy outcomes. Blood samples will be obtained periodically for safety laboratory tests, biomarkers of BGE 117 activity, inflammation, lipid, and iron status, and plasma pharmacokinetics (PK). Subjects will be followed until 6 months after their surgery.

Eligibility Criteria:
Inclusion Criteria:

1. Alert and able to voluntarily provide written, signed, and dated informed consent
2. ≥ 65 years of age at the time of completing informed consent
3. Major hip surgery, that has occurred within the previous 7 days or is scheduled to occur within the next 7 days, defined as:

   * Unilateral or bilateral total or partial hip arthroplasty or revision OR
   * Hip fracture repair surgery scheduled or performed within 48 hours after hospital admission (either fracture repair or total or partial hip replacement)
4. Postoperative anemia defined as a hemoglobin level ≤ 10.0 g/dL and ≥ 7.0 g/dL from postoperative Day 1 to postoperative Day 7
5. For hip fracture subjects only: score between 1 and 5 on the Clinical Frailty Scale (CFS) at baseline before fracture
6. Estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/m2 as measured by the Modification of Diet in Renal Disease (MDRD) method
7. Current or planned perioperative use of mechanical or chemical antithrombotic prophylaxis in accordance with local standard of care

Exclusion Criteria:

1. Any current unstable medical condition that the investigator considers would put the subject at unacceptable risk, affect study compliance, or prevent the understanding of the study's objectives or investigational procedures or possible consequences; for example, increased risk of falls that is judged to be clinically significant, clinically significant autonomic dysfunction, active infections requiring antimicrobial treatment
2. History of thromboembolic disease in the previous 6 months
3. Other medically significant injuries (e.g., head injuries, internal bleeding, or other as judged by the study investigator) that occur concurrently with hip fractures that complicate endpoint assessments, subject safety, and/or study conduct
4. History of seizures within the previous 2 years
5. History of coagulation disorder (e.g., Factor V Leiden, idiopathic thrombocytopenic purpura) or use of concomitant medications that increase the risk of thromboembolic events (TEEs) as judged by the study investigator
6. Class III or IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system
7. QTcF \> 500 msec or QTcF \> 530 msec in subjects with bundle branch block. A triplicate electrocardiogram (ECG) should be performed if the initial ECG indicates prolonged QTc interval using the automated or manually calculated QTcF value.
8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 3 × the upper limit of normal (ULN) (Historical standard-of-care laboratory results may be used to confirm eligibility if collected within 14 days before informed consent)
9. Bilirubin level \> 1.5 × ULN (isolated bilirubin level \> 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is \< 35%) (Historical standard of care laboratory results may be used to confirm eligibility if collected within 14 days before informed consent)
10. Recent or planned administration of an erythropoietin stimulating agent (ESA) or a HIF-PHI within 12 weeks of informed consent
11. History of malignant hypertension or current uncontrolled hypertension (average systolic blood pressure ≥ 160 mmHg and/or average diastolic blood pressure ≥ 100 mmHg based on 3 readings). Blood pressure should be measured after 5 minutes of unattended rest, with 2 repeated readings 1 to 2 minutes apart
12. History of diabetic retinopathy
13. History or diagnosis of any of the following:

    1. Anemia due to pernicious anemia, thalassemia, sickle cell anemia, sickle trait, or myelodysplastic syndromes
    2. Bone-marrow hypoplasia or pure red cell aplasia
    3. Androgen deprivation therapy within the previous 12 months or radiation treatment for prostate cancer
    4. Myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack, or prothrombotic arrhythmia or condition (e.g., untreated/uncontrolled atrial fibrillation) within 6 months before informed consent or during the Screening Period
    5. Active malignancy and/or receiving anti cancer treatment within 12 weeks of informed consent (squamous cell or basal cell carcinoma of the skin are excluded from this criterion). Subjects who have planned initiation of cancer therapies during the study period (such as, but not limited to, chemotherapy, radiotherapy) are excluded.
14. Planned intravenous (IV) iron therapy scheduled to start after informed consent and to continue during the expected time of participation in the study
15. Presence of acute kidney injury (AKI) based upon the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines:

    1. Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 hours, or
    2. Increase in serum creatinine to ≥ 1.5 times the value at baseline, which is known or presumed to have occurred within the previous 7 days
16. Chronic bleeding condition such as active gastrointestinal (GI) bleeding
17. Inability or unwillingness to adhere to protocol specified visits, procedures, and contraception requirements
18. Receipt of an investigational drug or device within 30 days before informed consent
19. Previously screened for or enrolled in the BGE-117-203 study
20. Known allergy to or intolerance of BGE-117, or other components of the IP (BGE-117 or matching placebo)
21. Known allergy to ferrous sulfate preparations