A Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses and multiple ascending doses of SION-451 in healthy participants

This is a Phase 1, randomised, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and Pharmacokinetics (PK) of single ascending doses (SAD) and multiple ascending doses (MAD) of SION 451 in healthy participants. Study drug (SION-451 and placebo) will be administered as an oral suspension. This study is comprised of 2 Parts: Part A (SAD) and Part B (MAD). Each study part will include a Screening Period, a Treatment Period, and an End of Study (EoS) visit. Participants to be included in this study will be healthy male and female adults 18 to 55 years of age, inclusive, with no clinically significant concomitant medical conditions and who are not taking any concomitant medications. All potential participants will be screened a maximum of 28 days (Day -28) prior to check-in (Day -1) to assess their eligibility to enter the study and dosing will be initiated on Day 1. Participants will generally be fasted prior to each dose of study drug. Participants in Parts A and B of the study, will be randomised 6:2 to active:placebo, and treatment assignments will be blinded. SAD (Part A) Participants in Part A of the study will be admitted to the Clinical Research Unit (CRU) on Day -1. On the following morning (Day 1), participants will receive a single dose of study drug (active or placebo depending on their randomised treatment assignment) in a fasted state (at least 10 hours pre-dose and 4 hours post-dose). Sentinel dosing will be employed for each Part A dose escalation cohort such that the first 2 participants will be enrolled and randomised to active drug or placebo; if no stopping rules are 1:1 met after 48 hours of monitoring, the remaining participants in the cohort will be randomised. Each cohort will enrol approximately 8 participants randomised 6:2 to active:placebo. Approximately 6 SAD cohorts are planned and dosing will begin at 75mg (Cohort 1) up to 750mg (Cohort 5). Dose escalation decisions will be made by the SRC composed of medically qualified representatives from Sionna, the CRO, and the investigative site (including the Principal Investigator) following review of all available safety data. The SRC will review key safety data (eg, AEs, safety laboratory results, physical examinations, vital signs, ECGs) after completion of each SAD cohort to approve proceeding to the next dose-escalation cohort; where available, PK results from prior cohorts may also be reviewed. No subsequent dose will exceed 2× the dose level of a preceding cohort that has been safe and well tolerated. The dose level for Cohort 6 will also be determined based on SRC review of safety and PK data from previous cohorts. All participants will remain in the CRU until 72 hours following their final dose of study drug (Day 1) for safety monitoring and collection of blood samples for PK analysis. All participants will return to the CRU an EOS visit 7 (+/-1 day) after the last dose of study drug. MAD (Part B) Part B dosing will not begin until the SRC has reviewed the available safety data from at least the first 3 SAD cohorts and determines it is safe to proceed. A unique group of participants will be enrolled in Part B of the study and will be admitted to the CRU on Day -1. On Days 1 through 9, participants will receive a single dose level of study drug (active or placebo based on their randomised treatment assignment) administered twice or three times daily. On Day 10, MAD cohort participants will only receive a morning dose. Participants will fast for at least 10 hours pre-dose and 4 hours post-dose for the first dose on Day 1 and for the last dose given on the morning of Day 10; for all other doses, participants will fast for at least 2 hours pre-dose and 2 hours post-dose. Each cohort will enrol approximately 8 participants randomised 6:2 to active:placebo. The SRC may recommend lower or intermediate dose levels be explored, provided the selected dose or a higher dose has been declared safe and well tolerated in Part A. In addition, the SRC may recommend adjustment of the dose frequency from twice or three times daily based on the available safety and PK data. Approximately 6 MAD cohorts are planned and dosing will begin at 75mg (Cohort 1) up to 750mg (Cohort 5). The dose level for Cohort 6 will be determined based on SRC review of safety and PK data from previous cohorts. Participants will remain at the CRU for at least 72 hours following administration of their last dose (Day 13) for safety monitoring and collection of blood samples for PK analysis. All participants will return to the unit for an EoS visit 7 (±1) days after the last dose of study drug. Clinical facility staff will administer the study drug only to participants included in the study following the procedures set out in the study protocol . Administration of study drugs will be recorded in the appropriate drug accountability records and the electronic case report form (eCRF). Administration of study drug will be verified by a second staff member. Each Participant will be given only the study drug preparation carrying his/her study number.