Clinical trial NCT06535841: A First-in-Human Safety Trial of MTX-474
Official title: MTX-474-S101: A Phase 1 Randomized, Double-Blind, Dose-Escalating Study to Assess the Safety, Tolerability, and Pharmacokinetics of MTX-474 in Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: MTX-474-S101
MTX-474
Healthy Volunteer
MAD
SAD
Adult
Healthy
Lead sponsor: Mediar Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-08-02
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: A randomized, 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 in healthy adults.

Detailed description: This is a randomized, 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 in healthy adults.

SAD Portion

The SAD portion of the study will consist of 6 planned dosing cohorts each comprising 8 healthy participants. The starting dose will be 0.125 mg/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). Planned doses may be adjusted in response to the data. Additional participants and/or additional dosing cohorts may be added as needed based on the data.

Within each cohort, participants will be randomly assigned to receive MTX-474 or matched placebo. The first 2 participants (sentinel participants) within each cohort will be randomized 1:1 to receive MTX-474 or placebo on Day 1. These participants will be monitored for 24 hours, and after review of the safety data from both participants and approval by the study Investigator, the additional 6 participants will be randomized to study drug (n=5 MTX-474; n=1 placebo).

Each participant will undergo assessments at specified timepoints on Days 1 through 29. End-of-Study (EOS) procedures will be completed on Day 29 or upon early termination (ET). An End-of-Follow-up (EOF) assessment of PK and ADA will be completed on Day 29.

MAD Portion

The MAD portion of the study will consist of 4 planned dosing cohorts. 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 participants and/or additional dosing cohorts may be added as needed based on the data.

On Day 1, participants will be randomized to receive either MTX-474 or matched placebo. The randomized participants will receive a dose of study drug on Days 1, 8, 15, and 22. Participants will be housed inpatient from Day -1 through Day 2, Days 7 through 9, 14 through 16, and 21 through 23. All other visits will be conducted in the outpatient setting. Each participant will undergo assessments at specified timepoints on Days 1 through 50. End-of-study procedures will be completed on Day 50, or upon ET. An EOF assessment of PK and ADA will be completed on Day 50.

Safety and tolerability of MTX-474 will be reviewed through Day 29 by the study Investigator and SRMO to inform dose escalation decisions for the next dose cohort.

Additional cohorts for the SAD and MAD portions of the study may be added as needed to potentially explore alternative doses.

Eligibility criteria: Inclusion Criteria:

* All genders, ages 18 to 60 years, inclusive
* Willing and able to complete all protocol-required study visits and procedures
* 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
* Agree to a highly effective method of contraception for 28 days prior to the first dose of study drug, and persist through 65 days after the last dose of study drug.

Exclusion Criteria:

* Any concurrent active medical condition determined clinically significant by the Investigator
* Body mass index (BMI) \>32 kg/m2 or body weight \>100kg
* Use of any systemic immunosuppressant medications, medications to treat diabetes, antipsychotics, anticoagulants, or other medications within 90 days of Screening
* Cancer or a history of cancer or lymphoproliferative disorder within 5 years of Screening other than adequately treated non-melanomatous skin cancers or cervical carcinoma in situ
* Current infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) as evidenced by a positive hepatitis B surface antigen or a positive HIV test at Screening
* Currently pregnant, lactating, or planning to conceive or contribute to pregnancy during the trial and up to 65 days (for women of childbearing potential) or 125 days (for males) after the participant's last dose of study drug, if applicable
* History of severe depression, psychosis, or suicidal ideation within 5 years of Screening
* History of anaphylaxis or other significant allergies in the opinion of the Investigator
* History of substance use disorder as specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within 1 year of Screening
* Positive screen for drugs of abuse or alcohol intake at Screening or admission to the CRU (Day -1)
* Any clinically significant disease or laboratory abnormality detected at Screening that might interfere with a participant's ability to complete the study, on-study evaluations, or participant safety
* Any surgical procedure, including planned procedures within 12 weeks of Screening
* Participation in another research study of an investigational agent within 30 days of Screening or 5 half-lives of the agent, whichever is longer.

Primary outcomes:
measure: Incidence of Treatment-Related Adverse Events in healthy volunteers
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
measure: MTX-474 PK by dose will be evaluated for Cmax, as feasible
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
measure: Serum sample results will be summarized for presence of Anti-Drug Antibodies during the SAD and MAD portions of the study
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
measure: MTX-474 PK by dose will be evaluated for AUC0-t, as feasible
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
measure: MTX-474 PK by dose will be evaluated for AUC0-tau (MAD only), as feasible
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
measure: MTX-474 PK by dose will be evaluated for AUC0-∞, as feasible
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
Secondary outcomes:
measure: Blood serum samples will be collected to assess the target engagement of MTX-474 in healthy adult participants
timeFrame: Through Day 29 (SAD Cohort) or Day 50 (MAD Cohort)
Other outcomes:
measure: To assess the effect of MTX-474 on PD biomarker PRO-C3 for fibrosis in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker PRO-C6 for fibrosis in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker C7M for fibrosis in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker PRO-C4 for fibrosis in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IFN-γ for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-1β for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-2 for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-4 for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-6 for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-10 for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-12p70 for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker IL-17A for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
measure: To assess the effect of MTX-474 on PD biomarker TNF-α for inflammation in healthy adult participants
timeFrame: Through Day 50 (MAD Cohort)
Locations:
city: Herston
country: Australia
facility: Nucleus Network
state: Queensland
Study officials:
affiliation: Mediar Therapeutics
name: Jeffrey Bornstein, MD
role: STUDY_DIRECTOR
affiliation: Nucleus Network Brisbane
name: Gloria Wong, PhD, MBBS
role: PRINCIPAL_INVESTIGATOR
References: