CompletedPhase 1ACTRN12621001621808

A Study to Investigate the Safety of SIR2446M in Healthy Volunteers

A Randomized, Double-Blind and Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SIR2446M after Oral Administrations in Healthy Volunteers

Sponsor

Sironax Aus Pty Ltd

Enrollment

114 participants

Start Date

Dec 17, 2021

Study Type

Interventional

Conditions

Degenerative disease

Summary

SIR2446M is a Receptor-Interacting Protein 1 (RIP1) inhibitor that is under development as a new investigational drug for the treatment of degenerative and inflammatory diseases. SIR2446M will be supplied as API-in-capsule in this study. The primary objectives are to evaluate the safety and tolerability of SIR2446M after single escalating doses, and multiple escalating doses for 10 days, administered orally in healthy participants. In part 1 the secondary objectives are to characterize the PK profile and preliminary food effect of SIR2446M after single escalating oral doses in healthy participants; to compare the PK profile of SIR2446M in capsule and tablet after single dose; and to explore the metabolite identification of SIR2446M in urine after a single dose. In part 2 the secondary objectives are to characterize the PK profile of SIR2446M after escalating multiple oral doses in healthy participants; to characterize the PD profile of SIR2446M after escalating multiple oral doses in healthy participants; and to explore the metabolite identification of SIR2446M in plasma after multiple doses.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 55 Yearss

Inclusion Criteria10

Are capable of signing informed consent form (ICF) and complying with study procedures;
Male or female healthy participants between the ages of 18 and 55 years old, inclusive;
Women of childbearing potential (WOCBP) must be practicing a medically acceptable method of contraception with an annual failure rate of less than 1% during the study and 30 days after discontinuation of study treatment. Women are considered not childbearing potential if they are more than 1 year postmenopausal or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation).
All male patients with female partners of child-bearing potential must use two acceptable methods of contraception (one of which must be a barrier method), and must agree to abstain from sperm donation during and for 90 days after participation in the study.
Considered healthy by the Principal Investigator (PI) or delegate, based on a detailed medical history, full physical examination, clinical laboratory tests, 12-lead ECG and vital signs;
Nonsmoker/Social smoker, defined as not having smoked more than 2 nicotine/tobacco containing products per month in the last 3 months before screening. During the study, participant should be able to abstain from the use of nicotine/tobacco containing products;
Able to abstain from the consumption of alcohol and any alcohol-containing products from 48 hours before dosing to the end of the study;
Able to abstain from the consumption of coffee and any caffeine-containing products from 48 hours before dosing to the end of the study;
Body mass index (BMI) of 18 to 30 kg/m2 inclusive and body weight not less than 50 kg;
Willing and able to adhere to study restrictions and to be confined at the clinical research center.

Exclusion Criteria21

Clinically significant history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity;
Clinically significant hematological findings at screening;
Abnormal findings indicating hepatic impairment, such as AST, ALT, or alkaline phosphatase greater than or equal to 1.5 times upper limit of normal (ULN), total bilirubin greater than or equal to 2.0 times ULN, albumin less than or equal to 3 g/dL, serum amylase or lipase greater than or 1.5 times ULN at screening;
Abnormal findings indicating renal impairment, such as creatinine greater than or equal to
5 times ULN, estimated creatinine clearance of 80 mL/minute or less calculated by the Cockcroft-Gault formula at screening;
Clinically significant ECG findings such as QTc value greater than or equal to 450 ms for male or greater than or equal to 470 ms for female at screening/day -1; 6. Participants with a mean systolic blood pressure of three measurements greater than 140 mmHg, or a mean diastolic blood pressure of three measurements greater than 90 mmHg at screening. Blood pressure will be measured at sitting position at screening; 7. Known or suspected malignancy, except adequately treated basal cell carcinoma;
Positive blood screen for human immunodeficiency virus (HIV), or hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) or nasopharynx swab test for SARS-CoV-2 (or any other test for COVID);
A history of seizure. However, a history of febrile seizure is allowed;
Plan to become pregnant during the study and within 30 days after the study;
A hospital admission or major surgery within 60 days prior to screening;
Receipt of any other investigational drug product within 3 months or 5 half-lives (whichever is longer) prior to dosing;
DSM-V substance use disorders and alcohol abuse within 12 months prior to screening;
A positive result for alcohol or drugs of abuse at screening or admission. Repeat test will be allowed if false positive is considered by the PI or designee;
An unwillingness or inability to comply with food and beverage restrictions during study participation, consumption of grapefruit or grapefruit juice within 14 days before dosing and until completed follow up assessments;
Donation or blood collection of more than 1 unit (approximate 450 mL) of blood (or blood products) or acute loss of blood during the 30 days prior to screening;
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer or inhibitor) or 5 half-lives (whichever is longer) prior to dosing;
Use of vaccines (including COVID vaccine) within 7 days prior to dosing in SAD part and within 14 days prior to dosing in MAD part;
A history of suicide attempt in the past 12 months and/or seen by the Investigator as having a significant history of risk of suicide or homicide;
Participant has a known or suspected hypersensitivity toSIR2446M and any components of SIR2446M capsules or tablets;
Participant who has lactose intolerance history;
Participant has any other condition, which makes the participant unsuitable for study participation.

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Interventions

RIP1 mediates the downstream effects of multiple biological activities including inflammatory responses. Therefore RIP1 inhibitors may be advantageous over selective inhibitors for a specific cytokine to reduce inflammatory response. SIR2446M is a Receptor-Interacting Protein1 (RIP1) inhibitor that is under development as a new investigational drug for the treatment of inflammatory diseases such as Alzheimer's disease and Multiple Sclerosis. This is a two part, double-blind, randomised and placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of an oral capsule or oral tablet dose of SIR2446M in healthy volunteers. Part 1 will be a single ascending dose (SAD) design to assess single doses of the study drug with and without food. All participants except those in the food-effect group will receive either placebo or the study drug in capsule form. Part 2 will be a multiple ascending dose(MAD) design to assess multiple doses of the study drug. Participants in the MAD groups will receive either placebo or study drug in oral tablet form. Participants in the food effect group will receive the study drug in oral tablet form. In Part 1, 56 participants will receive either study drug or matched placebo at one of seven dose levels (3mg, 10mg, 30mg, 100mg, 200mg, 400mg, or 600mg). Participants will stay to complete safety assessments up to 72 hours post dose, and then return to the clinical site on Day 11 (±3 days) for follow up assessments. These groups will receive a single dose only. There will be a separate food-effect cohort of 8 participants receiving 100mg tablet, who will receiving study drug on D1 then stay to complete safety assessments up to 72 hours post dose. The participants will return on Day 7 (+1 day) for a second dosing period at the same dose level following a high-fat, high-calorie breakfast. This breakfast will be provided to the participants. They will check out once the +72 hour safety assessments have been completed, and return on Day 18 (±3 days) for follow up assessments. In Part 2, 50 participants will receive either the study drug or the matched placebo once a day for 10 days at one of five dose levels (5 mg, 30mg, 100mg, 200mg or 400mg). Participants will stay until Day 13 for safety assessments, and return on day 20 (±3 days) for their follow up assessments. In both parts of the study, trained nurses will be administering the study drugs to the participants.