A First-in-Human Safety Trial of MTX-474

INTERVENTION: This is a randomised, double‐blind, placebo‐controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, and PK of single and multiple ascending doses of MTX‐474 administered by a qualified designee of the study doctor intravenously over 60 minutes in healthy adults. The SAD portion of the study will consist of 6 planned dosing cohorts each comprising 8 healthy participants. The starting dose will be 0.125mg/kg (Cohort 1) with subsequent planned doses of 0.25 mg/kg (Cohort 2), 0.5 mg/kg (Cohort 3), 1 mg/kg (Cohort 4), 2 mg/kg (Cohort 5), and 4 mg/kg (Cohort 6). Within each cohort, participants will be randomly assigned to receive MTX‐474 or matched placebo. The MAD portion of the study will consist of 4 planned dosing cohorts administered once weekly (QW) for 4 infusions. Each cohort will comprise 8 healthy participants (n=6 MTX‐474; n=2 placebo). The starting dose will be 0.5 mg/kg (Cohort 1) with subsequent planned doses of 1 mg/kg (Cohort 2), 2 mg/kg (Cohort 3), and 4 mg/kg (Cohort 4). Planned doses may be adjusted in response to the data. Additional cohorts may be added as long as no Dose‐Limiting Toxicity (DLT) emerges. A cumulative review of safety and tolerability of MTX‐474 will be conducted by the study Investigator, Medical Monitor, and Sponsor's Responsible Medical Officer (SRMO) to inform dose escalation decisions for the next dose cohort. The Investigator, Medical Monitor, and SRMO will also verify that none of the stopping criteria for safety parameters was met before proceeding. CONDITION: Inflammatory and Immune System ‐ Connective tissue diseases Systemic Sclerosis; ; Systemic Sclerosis PRIMARY OUTCOME: To assess the safety and tolerability of MTX‐474 in healthy adult participants. [Clinical laboratory samples (Clinical Biochemistry, Haematology, C‐Reactive Protein, Urinalysis) will be collected and assessed, along with Physical Examinations, and ECGs. SAD Cohorts:; Clinical Laboratory Tests: Blood samples will be collected during the Screening, Day ‐1, Day 2, Day 3, Day 5, Day 8, Day 15, Day 22, and End of Study visits; Urinalysis: Urine samples will be collected at Screening, Day ‐1, Day 8, Day 15, Day 22, and End of Study visits for analysis. ; ECGs: Triplicate ECGs will be performed at Screening, Day ‐1, Day 1 (pre‐dose, 1‐hour post‐dose, 6‐hours post‐dose), Day 2, Day 8, Day 22, and End of Study visits; Physical Examination: A full Physical Examination will be performed at screening and Day ‐1. visits. A symptom‐directed Physical Exam will be performed at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 15, Day 22, and End of Study visits, as warranted. ; ; MAD Cohorts:; Clinical Laboratory Tests: Blood samples will be collected during the Screening, Day ‐1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 14, Day 16, Day 21, Day 23, Day 24 Day 26, Day 29, and End of Study visits; Urinalysis: Urine samples will be collected at Screening, Day ‐1, Day 7, Day 14, Day 21, Day 29, and End of Study visits for analysis. ; ECGs: Triplicate ECGs will be performed at Screening, Day ‐1, Day 1, Day 2, Day 8, Day 9, Day 15, Day 16, Day 22, Day 23, Day 29, and End of Study visits. On dosing days (Day 1, 8, 15, and 22) ECGs will be performed pre‐dose, 1‐hour post‐dose, and 6‐hours post‐dose. ; Physical Examination: A full Physical Examination will be performed at screening and Day ‐1. visits. A symptom‐directed Physical Exam will be performed at Day 1, Day 2, Day 3, Day 5, Day 6, Day 8, Day 15, Day 22, and End of Study visits, as warranted. ] To characterize the immunogenicity of MTX‐474 via assessment of anti‐drug antibodies (ADA) in healthy adult participants [Serum sample results will be summarized for presence, titer, and impact of ADA during the SAD and MAD portions of the study. SAD: ADA samples will be collected pre‐dose on Day 1 (within 2 hr before dosing), at 504 hr (±1 day) (ie, Day 22) post‐dose, and Day 29 (±1 day) (EOS/ET). The post‐dose ADA sampling timepoints will be calculated relative to the end of infusion.; MAD: ADA samples will be collected at pre‐dose (within 2 hr before dosing) on Day 1 and Day 22, Day 29 (±1 day), and Day 50 (±1 day) (EOS/ET). The post‐dose ADA sampling timepoint will be calculated relative to the end of infusion.] To characterize the pharmacokinetics (PK) of MTX‐474 in healthy adult participants.[The serum PK parameters to be evaluated may include, but are not limited to: ; ; Cmax: Maximum observed plasma concentration ; ; AUC0‐t: Area under the plasma concentration‐time curve from time zero to time t ; ; AUC0‐8 : Area under the plasma concentration‐time curve from time zero extrapolated to infinity (single dose only) ; ; AUC0‐tau: Area under the plasma concentration‐time curve from time zero to the end of dosing interval, tau ; ; t½ : Terminal elimination half‐life ; ; RAUCtau: Accumulation ratio SAD: PK samples will be collected pre‐dose on Day 1 (within 2 hr before dosing) and 1 hr (±15 min), 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), 168 hr (±6 hr), 336 hr (±1 day), 504 hr (±1 day) post‐dose, and Day 29 (±1 day) (EOS/ET). The post‐dose PK sampling timepoints will be calculated relative to the end of infusion.; MAD: PK samples will be collected at pre‐dose (within 2 hr before dosing) on Day 1, Day 8, Day 15, and Day 22; 1 hr (±15 min), 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), and 168 hr (±6 hr) post‐dose on Days 1 and 22; and Day 50 (±1 day) (EOS/ET). The 168‐hr post‐dose measurement can be same as the subsequent dosing day pre‐dose measurement. The post‐dose PK sampling timepoints will be calculated relative to the end of infusion.] SECONDARY OUTCOME: To assess the target engagement of MTX‐474 in healthy adult participants. This will be assessed as a composite outcome. [Serum samples for analysis of free and bound levels of EphrinB2, whole blood samples for pEphB4 levels, and serum samples for pro‐inflammatory and fibrosis biomarker evaluation. SAD Cohort: Samples for target engagement will be collected pre‐dose on Day 1 (within 2 hr before dosing), and 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr), 168 hr (±6 hr), 336 hr (±1 day), 504 hr (±1 day) post‐dose, and Day 29 (±1 day) (EOS/ET). The post‐dose sampling timepoint will be calculated relative to the end of infusion. ; MAD Cohort: Samples for target engagement and biomarker assessment will be collected pre‐dose (within 2 hr before dosing on each day) on Day 1, Day 8, Day 15, and Day 22; 6 hr (±30 min), 24 hr (±2 hr), 48 hr (±4 hr), 96 hr (±6 hr), 120 hr (±6 hr) and 168 hr (±6 hr) post‐dose on Days 1 and 22; Day 16;and Day 50 (±1 day) (EOS/ET). In addition, samples for target engagement will be collected at pre‐dose on day 1 (within 2 hr before dosing) and 168 hr (±6 hr) post‐dose on Day 22. The 168‐hr post‐dose measurement can be same as the subsequent pre‐dose measurement. The post‐dose sampling timepoints for target engagement and biomarker assessment will be calculated relative to the end of infusion.] INCLUSION CRITERIA: ‐ All genders, ages 18 to 60 years, inclusive ‐ Consumption of not more than 5 cigarettes or other cotinine‐containing products (including tobacco, nicotine gum, patches, and e‐cigarettes) per week as long as they are willing to abstain nicotine use approximately 5 days prior to admission and during inpatient stays ‐ Willing to refrain from marijuana‐ or cannabinol‐containing products for 30 days before Screening and until the last study visit ‐ Willing to refrain from ingestion of alcohol from 7 days before Screening until the last study visit ‐ Agrees to not donate egg or sperm (if applicable) from the time of first infusion until 125 days after the final dose; additionally agrees to not donate blood from 56 days prior to the time of first infusion until 90 days after the last study visit, or platelets/plasma 14 days prior to the time of first infusion until 90 days after the last study visit. ‐ All participants assigne