A Phase 1 Study of PVT401 in Healthy Subjects

Official title

A Phase 1, First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PVT401 Following Randomized, Double-blind, Placebo-controlled Single and Multiple Ascending Doses in Healthy Subjects

Overview

The goal of this clinical trial is to learn what happens to PVT401 when it enters the human body and how it affects the immune system. It will also provide information about the safety of PVT401 after a single dose and after multiple doses. The main questions it aims to answer are: Will participants experience any side effects when taking PVT401? How long does it take PVT401 to leave the body after it is administered? Healthy volunteers will participate in either the single ascending dose (SAD) or multiple ascending dose (MAD) phase. In the SAD phase, participants will: stay in the clinic for two nights, get one dose of PVT401 or a placebo intravenously (through a vein) on Day 1, have blood drawn periodically throughout their stay and be monitored for side effects, and return to the clinic for 3 follow up visits over the four weeks after dosing. In the MAD phase, participants will: stay in the clinic for one night prior to each dose of PVT401 or placebo, and get dosed twice a week for 5 weeks. They will have blood drawn periodically throughout the treatment period and be monitored for side effects, and return to the clinic for 4 follow up visits over the six months after dosing.

Detailed description

SAD Phase: four cohorts are planned (n=6 per cohort; 2:1 randomization of PVT401 to placebo). This phase consists of five study visits: Screening, Treatment, and Follow-up (Day 8, Day 15, and Day 29). The Screening and Follow-up visits are outpatient; the Treatment visit includes a two-night inpatient stay from Day -1 to Day 2.

Participants will be admitted to the clinic on Day -1, the day prior to dosing. PK sampling will take place on Day 1, and the safety and tolerability of the study drug will be monitored for each participant in the clinic until Day 2 (24 hours post-dose) checkout.

The decision to advance to the subsequent SAD dose cohort will be made by a Safety Review Committee (SRC) following review of all available safety and tolerability data of participants through Day 8.

After completion of a minimum of four cohorts and with the approval of the SRC, the study will transition to the MAD phase.

MAD Phase: two cohorts are planned (n=6 per cohort; 2:1 randomization of PVT401 to placebo). This phase consists of 15 study visits: Screening: Visit 1, Treatment (Visits 2 - 11, dosing b.i.w. for 5 weeks), and Follow-up (Visits 12 - 15, up to 6 months post-dose).

All Treatment visits include a one-night inpatient stay prior to dosing; the Screening and Follow-up visits are outpatient.

The Screening visit can take place up to 42 days prior to Day 1. Participants will check in to the clinic on Day -1, the day prior to the first planned dose on Day 1. Dosing in each cohort will commence with two sentinel participants randomized such that one will receive PVT401 and the other will receive placebo (normal saline; 0.9% sodium chloride). The safety and tolerability of the study drug will be monitored for each sentinel participant through the first two doses (Week 1, Day 1 and Day 4) and will be reviewed by the Investigator prior to dosing the remainder of the participants in the cohort. Following completion of the Day 4 assessments for sentinel participants, all available safety/tolerability information will be reviewed by the Investigator prior to making the decision to dose the remaining participants in each cohort. Once safety and tolerability have been confirmed, the remaining four participants will be randomised (3:1 ratio of PVT401:placebo).

On Week 1, Day 1, all participants will remain for 8 hours after their first dose for observation and PK sampling prior to discharge. Participants will also remain for assessments and observation for a minimum of 8 hours post-dose at all other dosing visits.

The decision to advance to the next MAD dose cohort will be made by the SRC after completion of the five-week dosing cycle, following review of all available safety and tolerability data from the previous cohorts.

Interventions

• Drug PVT401
  Parvus pMHC nanomedicines are being developed for the treatment of autoimmune diseases. They consist of an iron oxide core surrounded by dextran that has been linked to multiple copies of a major histocompatibility complex Class II molecule and peptide. The peptide representing a disease-associated autoantigen and its paired MHC II molecule are specific to each autoimmune disease, and will be recognized by the T-cell antigen receptor. PVT401 is a nanomedicine that will be used to target effector
• Drug Normal Saline (0.9% NaCl)
  All cohorts will be administered either PVT401 or placebo in a ratio of 2:1 PVT401:placebo. Participants receiving placebo will be administered an equivalent volume of normal saline as either a single IV dose or as a multiple dose treatment regimen.

Primary outcome measures

• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: adverse and serious adverse events [Time frame: From enrollment through 4-weeks post last dose of study drug]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: vital signs (temperature) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: vital signs (heart rate) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: vital signs (blood pressure) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: clinical laboratory parameters (hematology panel) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants.: clinical laboratory parameters (serum chemistry panel) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: clinical laboratory parameters (coagulation panel) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: clinical laboratory parameters (urinalysis) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: clinical laboratory parameters (serum iron panel) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]
• To evaluate the safety and tolerability of a single and multiple IV doses of PVT401 in healthy participants: ECG (PR interval) [Time frame: From enrollment through 4 weeks after dosing (single dose cohorts) or 6 months after the final dose (multiple dose cohorts)]

Secondary outcome measures (5)

• To measure the PK of PVT401 in plasma following single and multiple IV doses in healthy volunteers. [Time frame: Single Dose Cohorts: multiple timepoints pre-dose to 24 hours post-dose Multiple Dose Cohorts: *First and Last Dose: multiple timepoints from pre-dose to 4 hours post-dose]
• To measure the PK of PVT401 in plasma following single and multiple IV doses in healthy volunteers. [Time frame: Single Dose Cohorts: multiple timepoints pre-dose to 24 hours post-dose Multiple Dose Cohorts: *First and Last Dose: multiple timepoints from pre-dose to 4 hours post-dose]
• To measure the PK of PVT401 in plasma following single and multiple IV doses in healthy volunteers. [Time frame: Single Dose Cohorts: multiple timepoints pre-dose to 24 hours post-dose Multiple Dose Cohorts: *First and Last Dose: multiple timepoints from pre-dose to 4 hours post-dose]
• To measure the PK of PVT401 in plasma following single and multiple IV doses in healthy volunteers. [Time frame: Single Dose Cohorts: multiple timepoints pre-dose to 24 hours post-dose Multiple Dose Cohorts: *First and Last Dose: multiple timepoints from pre-dose to 4 hours post-dose]
• To measure the PK of PVT401 in plasma following single and multiple IV doses in healthy volunteers. [Time frame: Single Dose Cohorts: multiple timepoints pre-dose to 24 hours post-dose Multiple Dose Cohorts: *First and Last Dose: multiple timepoints from pre-dose to 4 hours post-dose]

Eligibility criteria

Inclusion criteria

• Healthy male or female, aged between 18 and 65 years, inclusive at Screening.
• Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive.
• Carry the HLA DRB4\*0101 or DRB4\*0103 allele.
• Participant is medically healthy (in the opinion of the Investigator), as determined by pre-study medical history and without clinically significant (CS) abnormalities.
• Female participants must be of non-child-bearing potential, or, if of child-bearing potential, must have negative pregnancy test, agree not to become pregnant or donate ova, and must agree to use adequate contraception.
• Male participants must agree not to donate sperm and use adequate contraception.

Exclusion criteria

• Any active infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
• History of hypersensitivity reaction, anaphylaxis or other CS reactions or known allergy to the study drug or its ingredients including but not limited to dextran.
• History of any CS disorder which, in the opinion of the Investigator would make implementation of the protocol or interpretation of study results difficult, or that would put the participant at risk by participating in the study.
• History of surgery or hospitalisation within 4 weeks prior to Screening, or surgery planned during the study.
• Participant has donated blood or blood products or experienced significant blood loss within 2 months prior to the first dose of study drug.
• Use of any vaccinations within 4 weeks prior to the first dose of study drug.
• Laboratory results at Screening that indicate inadequate renal function, with estimated creatinine clearance of < 60 mL/min/1.73m2.
• Use of any prescription medication within 14 days prior to the first dose of study drug and/or over-the-counter medication/vitamins/supplements/herbal/ plant-derived medications within 7 days prior to the first dose of study drug.
• Concurrent enrolment in another clinical study, or participation in another clinical study within 30 days or 5 half-lives, whichever is longer, prior to Screening.
• Regular consumption of > 10 standard alcoholic drinks/week. Participant is unwilling to abstain from alcohol while confined to the study clinic.
• Positive alcohol breath test at Screening, upon admission to the clinic on Day -1.
• Positive urine drugs of abuse test at Screening, upon admission to the clinic on Day -1.
• Participant is a heavy smoker, define as more than 2 cigarettes per day or 10 per week.
• Participant is unwilling to abstain from smoking while confined to the study clinic.
• Participant is breastfeeding/lactating or pregnant, or planning to breastfeed or become pregnant during the study.
• Positive Hepatitis B surface antigen (HBsAg), Hepatitis C (HepC) virus antibody, or human immunodeficiency (HIV) antibody tests.
• Positive for tuberculosis (TB) disease or latent TB infection.
• Ingestion of poppy seed-containing foods or beverages within 48 hours prior to first dose of study drug.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Australia · 1 center

• Nucleus Network Pty Ltd — Melbourne

Identifiers

NCT: NCT07423000 · PVT401_C1_001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗