Evaluation of the Safety and Tolerability of Gemini in Subjects With Stage 3-4 Chronic Kidney Disease.

Design: Randomized, Placebo Controlled, Single Blind, Single-Ascending Dose Study in Patients with Stage 3-4 CKD.

This study is planned as a placebo controlled, single dose, escalating dose study to evaluate the safety and tolerability of intravenous Gemini in adult subjects with stage 3 or 4 chronic kidney disease. This study will enroll up to 40 subjects in up to 5 cohorts. Each cohort will consist of 8 unique subjects, 6 assigned to Gemini and 2 assigned to placebo. All subjects will provide written informed consent and be screened for eligibility before enrollment. All eligibility criteria must be met prior to dosing.

On Day 1, each study subject will receive a single IV dose (each total dose volume = 20 mL) via syringe pump for at least 10 minutes but not longer than 15 minutes and as per the institution's standard method. Time 0 starts once the entire dose is administered and the line has been flushed to ensure any residual drug is delivered.

A Safety Review Committee (SRC) will assess safety and tolerability including AEs, after at least 6 subjects in each cohort have completed Day 8 to determine the subsequent cohort dose. If a grade 3 or higher adverse event is not experienced, as determined by the SRC, or the criteria for stopping dosing has not been met at a given cohort dose level, dose escalation will proceed to the next cohort and dose level.

Dosing will continue until any cohort experiences a dose limiting toxicity (DLT), defined as a dose that causes any grade 3 or higher adverse event, or stopping criteria is met or the highest dose as determined in the Phase 1 study has been tolerated. If a dose is stopped due to a DLT or stopping criteria, cohorts scheduled at a higher dose will not be utilized. The SRC will meet to review safety and tolerability data and may determine if a lower dose can be given. This dose will be documented in the minutes and a dose recommendation memo which will be provided to the clinical sites.

Once the maximum tolerated dose is determined, the dose will be repeated (Cohort 4) for a total of 16 subjects dosed at the highest level tolerated. The repeated dose cohort will consist of 8 unique subjects, 6 assigned to Gemini and 2 assigned to placebo. If the maximum tolerated dose is reached within the first 2 cohorts, the dose will be repeated until a minimum of 32 subjects are enrolled.

If the highest dose determined in the Phase 1 study is tolerated, optional higher dosing of may be administered as determined by the SRC, or the same dose will be repeated.

All visits will be conducted as an outpatient or via telephone.

Inclusion criteria

• Male or female subjects ≥18 to ≤ 80 years of age at screening
• Willing and able to provide written informed consent
• eGFR of ≥ 15 and ≤ 60 per
• Female subjects must be of non-childbearing potential or using a medically acceptable contraceptive regimen
• Male subjects must be surgically sterile or using a medically acceptable contraceptive regimen
• Willing and able to tolerate IV infusions and multiple blood draws
• Willing to comply with the study schedule, restrictions, and requirements

Exclusion criteria

• CKD Secondary to or associated with any of the following:

• History of rapidly progressive glomerulonephritis (RPGN)
• Glomerulonephritis requiring any use of immunosuppression in the last 6 months
• Body mass index ≤ 19.0 kg/m2 or ≥ 40.0 kg/m2
• Currently taking a sodium/glucose cotransporter-2 inhibitor (SGLT2i) or non-steroidal mineralocorticoidantagonist (MRA) requiring dose adjustments within 12 weeks prior to Day 1 or if dose is anticipated to change
• Currently taking tumor necrosis factor (TNF) inhibitors, TNF blocker, interleukin-6 (IL-6) blockers or interleukin-1 (IL-1) blocking drugs
• Receiving steroids or any other immunosuppressive agent or anti-inflammatory drugs
• Currently taking an angiotensin-converting enzyme inhibitor (ACEi) and/or an angiotensin II receptor blocker (ARB) requiring dose adjustments
• Any use of direct renin inhibitors;
• Live vaccinations within 3 months prior to the start of the trial or expected during the trial
• Received a mRNA vaccine within 4 weeks
• Uncontrolled diabetes (HbA1c > 11.0%)
• Clinical laboratory results of ALT and/or AST that are > 2.5X upper limit of normal (ULN)
• Clinical Laboratory results of Total bilirubin that is > 1.5X the ULN
• Has a Urine Albumin-to-Creatinine Ratio (uACR) level > 3000 mg/g
• Age-related macular degeneration (AMD), diabetic macular edema or active diabetic proliferative retinopathy that was likely to require treatment during the trial
• Uncontrolled hypertension
• New York Heart Association Class IV congestive heart failure
• Any organ transplant recipient, or a planned transplant during the study
• Currently has known Hepatitis B or uncontrolled human immunodeficiency virus (HIV) or uncontrolled Hepatitis C virus (HCV) that may interfere with the study
• Myocardial infarction, acute coronary syndrome, or stroke within 6 months
• History of myelodysplastic syndrome
• History of deep vein thrombosis (DVT) that required active treatment in the last 6 months. Superficial thrombosis is not excluded
• History of hemosiderosis or hemochromatosis
• History of rheumatoid arthritis or systemic lupus erythematosus (SLE)
• History of drug use that may interfere with the study or study result
• Red cell transfusion within 12 weeks
• History of malignancy in the previous 5 years except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin or cervical carcinoma in situ
• Coronavirus disease 2019 (COVID-19) diagnosis within 1 month
• Evidence of active infection unless subject is appropriate for this study per the Investigator
• Life expectancy less than 6 months
• Intolerance to study medication
• Pregnancy or lactation
• Received treatment with any investigational product in any clinical study within 30 days prior to administration of study drug or five half-lives, whichever is longer
• In the opinion of the Investigator or identified Sub-I(s), any other disease processes or confounding variables that would inappropriately alter the outcome of the study