A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SRN001 in Healthy Korean and Caucasian Adult Males

Official title

A Randomized, Double-blind, Placebo-controlled, Multiple Doses, Dose-escalation Phase 1 Clinical Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SRN001 in Healthy Korean and Caucasian Adult Males

Overview

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of SRN001 in healthy adult volunteers.

Detailed description

SRN001 is a novel small interfering RNA (siRNA) drug being developed to treat fibrosis using Self Assembled Micelle inhibitory ribonucleic acid (SAMiRNA™) technology. Amphiregulin (AREG) is a growth factor involved in fibroblast proliferation and myofibroblast transformation which is the hallmark of fibrosis in lung and kidney tissues. AREG is a downstream gene overexpressed by Transforming growth factor-β (TGF-β) during fibrosis, promoting fibroblast to myofibroblast transition (FMT). SRN001 is designed to downregulate generating amphiregulin by RNA interference (RNAi). The goal of this clinical trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of SRN001 in healthy Korean and Caucasian adult males.

Interventions

• Drug SRN001
  SRN001 is an investigational drug administered at doses of 45 mg, 90 mg, or 180 mg depending on cohort.
• Drug 0.9% sodium chloride (normal saline)
  0.9% sodium chloride solution administered as placebo control.

Primary outcome measures

• Incidence of Treatment-Emergent Adverse Events (TEAEs) [Time frame: From first dose through end of study (up to 114 days)]
• Number of participants with serious adverse events (SAEs) [Time frame: From first dose through end of study (up to 114 days)]
• Number of participants with clinically significant abnormal laboratory results [Time frame: From first dose through end of study (up to 114 days)]
• Maximum Observed Plasma Concentration (Cmax) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose)]
• Time to Maximum Plasma Concentration (Tmax) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]
• Area Under the Curve from time zero to last measurable concentration (AUClast) [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]
• Area Under the Plasma Concentration-Time Curve over the Dosing Interval (AUCtau) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]
• Terminal Half-Life (t½) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]
• Clearance (CL) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]
• Apparent Volume of Distribution (Vz) of SRN001 [Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing]

Eligibility criteria

Inclusion criteria

• Healthy Korean or Caucasian male volunteers aged 19 to 60 years at the time of screening.
• Those who weighed 50.0 kg or more at the time of screening and had a body mass index (BMI) between 18.5 kg/m2 and 29.9 kg/m2.

Body mass index (BMI, kg/m2) = weight (kg) / {height (m2)} 2

• Those whose screening results showed a serum amphiregulin concentration of 100 pg/mL or higher.
• Those who voluntarily agreed to participate in this clinical trial after receiving a thorough explanation and fully understanding the clinical trial. Those who decided to participate and gave written consent to comply with the precautions.

Exclusion criteria

• Those with or have a history of clinically significant diseases of the hepatobiliary system (severe liver failure, viral hepatitis, etc.), kidney (severe renal failure, etc.), nervous system, immune system, respiratory system, digestive system, endocrine system, hematological/oncological system, cardiovascular system (heart failure, torsades de pointes, etc.), urinary system, psychiatric system (mood disorder, obsessive-compulsive disorder, etc.), or sexual dysfunction.
• Those with a history of hypersensitivity to RNA drugs or other drugs (aspirin, antibiotics, etc.) or a history of clinically significant hypersensitivity reactions (atopy, asthma, etc.).
• Those with a positive serum test result (hepatitis B test, hepatitis C test, human immunodeficiency virus (HIV) test, syphilis test).
• Those with a history of drug abuse or a positive urine drug screening test for drugs of abuse.
• Those who were screened in a sitting position after resting for at least 3 minutes. Those who exhibited the following values in measured vital signs:

• Systolic blood pressure < 80 mmHg or ≥ 140 mmHg
• Diastolic blood pressure < 45 mmHg or ≥ 90 mmHg
• Pulse < 45 bpm or > 100 bpm
• Body temperature < 35.5 ℃ or > 37.7 ℃
• Those who exhibited the following values or clinically significant abnormal rhythm findings on the electrocardiogram (12-lead ECG) during the screening test:

-QTcF > 450 msec

• Those who exhibited one or more of the following results in clinical laboratory tests during the screening test, including additional tests:

• AST (SGOT) or ALT (SGPT) > 60 IU/L
• Estimated glomerular filtration rate (CKD-EPI equation) < 60 mL/min/1.73 m2
• Those who have taken any prescription drugs or herbal medicines within two weeks prior to the scheduled first administration of the investigational drug, or have taken any over-the-counter drugs, health functional foods including liver function supplements, or vitamin preparations within one week (however, at the investigator's discretion, subjects may be selected as subjects if other conditions are appropriate) or are expected to take such drugs.
• Those who have taken drug-metabolizing enzyme inducers such as barbiturates or drug metabolism inhibitors such as clarithromycin within one month prior to the scheduled first administration of the investigational drug.
• Those who have participated in another clinical trial (including bioequivalence trials) and received the investigational drug within six months prior to the scheduled first administration of the investigational drug.
• Those who have donated whole blood within two months prior to the scheduled first administration of the investigational drug, or have donated blood components within one month prior to the scheduled first administration of the investigational drug, or have received a blood transfusion.
• Smokers (however, subjects may be selected as subjects if they quit smoking three months prior to the scheduled first administration of the investigational drug) or those who are unable to quit smoking until the completion of the clinical trial.
• Those who have continuously consumed alcohol (21 units/week, 1 unit = 10 g of pure alcohol) or cannot abstain from alcohol from 3 days before the scheduled first dose of the investigational drug until the end of the clinical trial.
• Those who have continuously consumed excessive caffeine (more than 5 units/day, 1 unit = 80 mg of caffeine) or cannot abstain from consuming caffeinated foods and beverages (coffee, tea (black tea, green tea, etc.), carbonated beverages, coffee drinks, coffee milk, tonic drinks, energy drinks, etc.) from 3 days before the scheduled first dose of the investigational drug until the end of the clinical trial.
• Those who cannot abstain from consuming grapefruit (grapefruit), grapefruit juice, or grapefruit-containing foods from 3 days before the scheduled first dose of the investigational drug until the end of the clinical trial.
• Those who have unusual eating habits (e.g., consuming more than 1 L of grapefruit juice per day) or cannot consume the standardized diet provided by the clinical trial center during their hospitalization.
• Those who use their own condoms from 3 days before the scheduled first dose of the investigational drug until the end of the clinical trial. Women of childbearing potential (spouse or partner) who do not consent to a contraceptive method considered highly effective.

\[Contraceptive methods considered highly effective\]

• Those who do not agree to refrain from donating sperm from 3 days prior to the scheduled first dose of the investigational drug until the end of the clinical trial.
• Those whom the investigator determines to be unsuitable for clinical trial participation for reasons other than those listed above.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

South Korea · 1 center

• Seoul National University Hospital — Seoul

Publications

• Yoon PO, Park JW, Lee CM, Kim SH, Kim HN, Ko Y, Bae SJ, Yun S, Park JH, Kwon T, Kim WS, Lee J, Lu Q, Kang HR, Cho WK, Elias JA, Yang JS, Park HO, Lee K, Lee CG. Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis. J Biol Chem. 2016 Mar 18;291(12):6433-46. doi: 10.1074/jbc.M115.693671. Epub 2016 Jan 27. PMID 26817844

Identifiers

NCT: NCT07407543 · SRN001-CA-25001A

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗