The goal of this clinical trial is to learn if ASCT-83 is safe and well-tolerated and measure how ASCT-83 is absorbed, distributed, and eliminated from the body over time. The study will be conducted in healthy adults. The main questions this study will answer are: * Is ASCT-83 safe at clinical doses? * Does ASCT-83 have side effects at clinical doses? * How is ASCT-83 absorbed, distributed, and eliminated from the body? Researchers will compare ASCT-83 to a placebo (a look-alike substance that contains no drug). The study has two parts: participants in Part 1 will receive only one dose of ASCT-83 or placebo participants in Part 2 will receive one dose of ASCT-83 or placebo a day for 7 days. Participants will visit the clinic to take ASCT-83 or placebo, to receive health checkups and undergo health tests. Participants in Part 1 will spend 5 days/4 nights in the clinic, participants in Part 2 will spend 11 days/10 nights in the clinic. In addition, there will be up to 3 outpatient visits. The results of this study will help determine safe dose levels and support the design of future clinical trials.
Seventy-two healthy participants will be randomized to the following groups: * Part 1, Single Ascending Dose (SAD): Healthy adult participants (age 18-64, inclusive) will be enrolled in 6 dose cohorts: 0.5 mg, 1 mg, 2 mg, 4 mg, 7.5 mg, or 10 mg. Each cohort consists of 8 participants (6 ASCT-83, 2 placebo), totaling 48 participants. * Part 2, Multiple Ascending Dose (MAD): 3 dose cohorts of 8 participants each (6 ASCT-83, 2 placebo), totaling 24 participants. Dosing and regimens for Part 2 will be determined following review of SAD data by the Data Safety Monitoring Committee (DSMC). All doses (ASCT-83 or placebo) will be administered as two subcutaneous (SC) injections (arm or thigh), with the second injection occurring within 10 minutes of the first. The first two participants in every cohort - one administered ASCT-83 and one administered placebo - will be the sentinel participants. In every cohort, the two sentinel participants must be observed for 72 hours before the rest of the cohort is dosed. The maximum dose escalation increment between any two cohorts will be two-fold. The maximum daily dose will not exceed the maximum tolerated dose established in the SAD study. Additional cohorts may be recruited based on the emerging safety, tolerability, and PK data.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
72
ASCT-83 is a 23-amino acid, macrocyclic peptide with a molecular weight of approximately 3 kilodaltons under development for the treatment of neuropathic pain (NeP). ASCT-83 25 mg/mL sterile solution for injection consists of 25 mg of ASCT-83 drug substance dissolved in 1 mL of histidine buffer. The product also contains mannitol to adjust the osmolarity of the final product. The product is stored at -20°C prior to dilution to achieve the target dose.
Placebo solution contaninig the same histidine buffer and mannitol concentrations as ASCT-83, with polyoxyl 35 castor oil (0.1% w/v) added to match the appearance of the active solution.
Incidence, severity and dose relationships of Treatment-Emergent Adverse Events (TEAEs) and non-TEAEs, Adverse Events of Special Interest (AESIs), Serious Adverse Events (SAEs), premature treatment and study discontinuation due to Adverse Events (AEs)
The investigator will assess and record information pertaining to the AE, which includes but is not limited to the following: date of onset, event diagnosis (when known) and/or signs and symptoms, duration, severity, seriousness (i.e. serious adverse event or not serious), expected/unexpected, and relationship to the study therapy or procedure, action(s) taken, and outcome. Severity grading: 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 4 Life-threatening consequences; urgent intervention indicated. 5 Death related to AE.
Time frame: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.
Incidence and severity of changes in clinical safety parameters, including vital signs (including body weight), laboratory (including markers of inflammation), ECG results, and skin assessments (including injection site reactions).
Time frame: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.
Incidence of suicidality
Suicide risk will be assessed through a questionnaire (Columbia-Suicide Severity Rating Scale (C-SSRS)). A score ≥4 is considered suicidal ideation.
Time frame: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.
Incidence and type of abnormal skin assessments, including injection-site reactions.
The FDA Toxicity Grading Scale (TGS) for injection/vaccine sites will be used: Mild/Grade 1, Moderate/Grade 2, Severe/Grade 3, Life-threatening/Grade 4.
Time frame: Single dose part of the study: from enrollment to 30-32 days after the end of treatment. Multiple dose part of the study: from enrollment to 36-38 days after the end of treatment.
Area under the concentration-time curve from time zero to infinity (AUC0-inf) of ASCT-83
Plasma concentration of ASCT-83 will be measured following a single dose of ASCT-83 (SAD part of the study) or multiple doses of ASCT-83 (MAD part of the study) to characterize the total exposure to ASCT-83.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Area under the concentration-time curve from time zero to 24 h (AUC0-24h) of ASCT-83
Plasma concentration of ASCT-83 will be measured following a single dose of ASCT-83 (SAD part of the study) or multiple doses of ASCT-83 (MAD part of the study) to characterize exposure to ASCT-83 over the last 24 h dosing interval.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Peak plasma concentration (Cmax) of ASCT-83
Plasma concentration of ASCT-83 will be measured to characterize the peak concentration of ASCT-83 in the blood following either a single dose (SAD part of the study) or multiple doses (MAD part of the study) of ASCT-83.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Time to reach maximum plasma concentration (Tmax) of ASCT-83
Plasma concentrations of ASCT-83 will be measured to determine the time at which the highest concentration of ASCT-83 is reached after either a single dose (SAD part of the study) or multiple doses of ASCT-83 (MAD part of the study).
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
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Terminal elimination half-life (t½) of ASCT-83
Concentrations of ASCT-83 in plasma will be measured to determine the time required for the drug concentration to decrease to half of its initial amount. Plasma concentrations will be measured both in the single dose (SAD) and the multiple dose (MAD) part of the study.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Apparent clearance (CL/F) of ASCT-83
Plasma clearance of ASCT-83 will be measured after both a single dose (SAD part of the study) and multiple doses (MAD part of the study) of ASCT-83.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Apparent volume of distribution (Vz/F) of ASCT-83
The distribution of ASCT-83 in the body (whether it stays in the blood or it spreads to the rest of the body) will be measured after a single dose (SAD part of the study) or multiple doses (MAD part of the study) of ASCT-83.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 hours post-dose. MAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1; pre-dose on Days 3 to 7; 24, 36, 48, and 72 hours after the final dose on Day 7
Amount of ASCT-83 excreted in urine
Amount of ASCT-83 excreted in urine will be measured after a single dose of ASCT-83 (SAD part of the study).
Time frame: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.
Fraction of ASCT-83 excreted in urine unchanged
The proportion of ASCT-83 that is eliminated in urine in its original, active form will be measured after a single dose of ASCT-83 (SAD part of the study).
Time frame: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.
Renal clearance (CLR) of ASCT-83
The amount of ASCT-83 excreted in the urine during an interval of time will be measured after a single dose of ASCT-83 (SAD part of the study).
Time frame: Pre-dose, then at 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, 24-36 hours, 36-48 hours, 48-60 hours, 60-72 hours post-dose.
Incidence of anti-drug antibodies (ADA) and titers (in ADA positive participants).
Time frame: Prior to initiation of dosing on Day 1, and on Days 7, 14, 25, 37.