HIV-1-infection
Conditions
Keywords
HIV, Latent HIV-1 infection, HIV therapy, antibody-based therapy
Brief summary
This is a Phase 1, open-label single-center study to determine the safety of MGD014 in participants with human immunodeficiency virus (HIV) infection on stable suppressive antiretroviral therapy (ART).
Detailed description
Eligible participants will be maintained on ART and receive either one infusion (Part 1) or multiple infusions of MGD014 (Part 2). Part 1 is a single ascending dose study with a 1+3 design for the first 2 dose cohorts, and a 3+3 design with staggered accrual for the 6 higher dose cohorts, with an aim of determining the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ascending doses up to either the Optimal Biologic Dose (OBD) or the maximum administered dose (MAD). Part 2 is a multi-dose expansion cohort with MGD014 administered at the OBD, as determined in Part 1. In Part 2, additional assessments on the effects of MGD014 on HIV latent infection parameters will be evaluated.
Interventions
BIOLOGICALMGD014
HIV-1 x CD3 bispecific DART molecule
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
MacroGenics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label dose-escalation study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Ability and willingness of participant to provide written informed consent. * HIV-1 infection, documented by any FDA-approved rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load. * On a potent, stable, continuous ART regimen for ≥ 24 months prior to Screening. * Plasma HIV-1 RNA \< 50 copies/mL at two time points in the previous 12 months prior to screening (one time point can be screening) and never ≥ 50 copies/mL on 2 consecutive time points in the last 24 months. * Adequate organ function based on acceptable laboratory parameters.
Exclusion criteria
* Women of childbearing potential defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or menopause. * History or other evidence of severe illness, immunodeficiency other than HIV, or any other condition that would make the potential participant unsuitable for study. * History or other evidence of any condition or process for which signs or symptoms could be confused with reactions to MGD014. * History of any HIV immunotherapy or HIV vaccine except for MGD014 within 12 months prior to screening. * History of clinically significant cardiovascular disease, severe allergic reactions, malignancy (except non-melanoma skin cancer) within 5 years, seizure disorder within 2 years, organ/tissue transplant, autoimmune disease, unstable asthma, bleeding disorder. * Evidence of active viral, or antifungal treatment within 7 days prior to the initiation of study drug * Active, asymptomatic, or suspected COVID-19/SARS-CoV-2 infection. * Active, untreated syphilis. * Use of blood products, cytokine therapy, growth-stimulating factors, cytotoxic chemotherapy or investigational therapy within 90 days. * Current use of the antivirals maraviroc and/or enfuvirtide. * Any vaccination with exception of flu vaccine within 30 days of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emerging Adverse Events | up to 77 days | Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Plasma Concentration | Study Day 0 | Cmax is the maximum (or peak) serum concentration of a drug in the body after the drug has been administered |
| Tmax: Time to Maximum Concentration | Study Day 0 | Tmax is the time it takes a drug to reach the maximum concentration |
| Ctrough: Trough Level Concentration | Study Day 14 | a trough level or trough concentration (Ctrough) is the concentration reached by a drug immediately before the next dose is administered, |
| Clearance | Study Day 0 to 42 | Total body clearance of the drug from plasma of MGD014 |
| AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | Study Day 0 to 42 | AUCinf, area under the concentration-time curve from the time of dose extrapolated to time infinity and reflects total drug exposure |
| Terminal Half Life of MGD014 | Study Day 0 to Study Day 42 | The half-life is the amount of time required for 50% of the drug to be removed from the body |
| Number of Participants That Developed Antidrug Antibodies to MGD014 | Study Day 1, 14, 28 and 42 (single infusion) and Study Day 1, 14, 28 and 77 (multiple infusions) | Number of participants with antidrug antibodies to MGD014 |
| Number of Participants With Increased Cytokine Levels | Study Day 1, 2 and 7 (single infusion) and Study Day 1, 3, 14 and 28 (multiple infusions) | Number of participants with increased cytokine levels from baseline after MGD014 administration. This safety measure compares serum cytokine levels obtained prior to dosing with levels obtained after dosing. Increased cytokines can be a measure of T-cell activation in response to MGD014 binding. Cytokines analyzed included interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)2, IL-5, IL-6, and IL-10. |
| Vz: Terminal Phase Volume of Distribution of MGD014 | Study Day 1, 2, 7, 14, 21, 28, and 42 (single infusion) and Study Day 1, 3, 14, 28, 42, and 77 (multiple infusions) | The ratio of the total quantity of drug in the body to drug plasma concentration during the elimination |
Countries
United States
Participant flow
Pre-assignment details
Three participants who were treated in Period 1 (single dose) in the 10, 100, or 300 mcg/kg dose cohorts were also treated in Period 2 (multiple dose) in the 300 mcg/kg dose cohort.
Participants by arm
| Arm | Count |
|---|---|
| MGD014 0.1 mcg/kg Single infusion of MGD014 | 1 |
| MGD014 0.3 mcg/kg Single infusion of MGD014 | 1 |
| MGD014 1.0 mcg/kg Single infusion of MGD014 | 4 |
| MGD014 3.0 mcg/kg Single infusion of MGD014 | 3 |
| MGD014 10.0 mcg/kg Single infusion of MGD014 | 3 |
| MGD014 30 mcg/kg Single infusion of MGD014 | 3 |
| MGD014 100 mcg/kg Single infusion of MGD014 | 3 |
| MGD014 300 mcg/kg Single infusion of MGD014 | 3 |
| Total | 21 |
Baseline characteristics
| Characteristic | MGD014 0.1 mcg/kg | Total | MGD014 300 mcg/kg | MGD014 100 mcg/kg | MGD014 30 mcg/kg | MGD014 10.0 mcg/kg | MGD014 3.0 mcg/kg | MGD014 1.0 mcg/kg | MGD014 0.3 mcg/kg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Period 1: Single Dose | 40.0 years | 44.4 years STANDARD_DEVIATION 11 | 42.3 years STANDARD_DEVIATION 17.1 | 33.7 years STANDARD_DEVIATION 5.86 | 41.0 years STANDARD_DEVIATION 10.82 | 56.7 years STANDARD_DEVIATION 7.09 | 37.9 years STANDARD_DEVIATION 5.51 | 49.8 years STANDARD_DEVIATION 9.18 | 53.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 19 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 7 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 13 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 1 participants | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 4 participants | 1 participants |
| Sex: Female, Male Single dose Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Single dose Male | 1 Participants | 21 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 4 / 4 | 3 / 3 | 2 / 3 | 2 / 3 | 2 / 3 | 3 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Number of Participants With Treatment-Emerging Adverse Events
Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit.
Time frame: up to 77 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Number of Participants With Treatment-Emerging Adverse Events | 1 Participants |
| MGD014 0.3 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 1 Participants |
| MGD014 1.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 4 Participants |
| MGD014 3.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 3 Participants |
| MGD014 10.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 2 Participants |
| MGD014 30.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 2 Participants |
| MGD014 100.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 2 Participants |
| MGD014 300.0 mcg/kg | Number of Participants With Treatment-Emerging Adverse Events | 3 Participants |
| MGD014 300.0 mcg/kg Multiple Doses | Number of Participants With Treatment-Emerging Adverse Events | 2 Participants |
Secondary
AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014
AUCinf, area under the concentration-time curve from the time of dose extrapolated to time infinity and reflects total drug exposure
Time frame: Study Day 0 to 42
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 134 mcg/L*hr |
| MGD014 0.3 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 313 mcg/L*hr |
| MGD014 1.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 2610 mcg/L*hr |
| MGD014 3.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 6360 mcg/L*hr |
| MGD014 10.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 22300 mcg/L*hr |
| MGD014 30.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 50900 mcg/L*hr |
| MGD014 100.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 170000 mcg/L*hr |
| MGD014 300.0 mcg/kg | AUC Inf: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity of MGD014 | 497000 mcg/L*hr |
Secondary
Clearance
Total body clearance of the drug from plasma of MGD014
Time frame: Study Day 0 to 42
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Clearance | 0.04 L/hr |
| MGD014 0.3 mcg/kg | Clearance | 0.07 L/hr |
| MGD014 1.0 mcg/kg | Clearance | 0.03 L/hr |
| MGD014 3.0 mcg/kg | Clearance | 0.05 L/hr |
| MGD014 10.0 mcg/kg | Clearance | 0.04 L/hr |
| MGD014 30.0 mcg/kg | Clearance | 0.04 L/hr |
| MGD014 100.0 mcg/kg | Clearance | 0.05 L/hr |
| MGD014 300.0 mcg/kg | Clearance | 0.05 L/hr |
Secondary
Cmax: Maximum Plasma Concentration
Cmax is the maximum (or peak) serum concentration of a drug in the body after the drug has been administered
Time frame: Study Day 0
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Cmax: Maximum Plasma Concentration | 2.9 mcg/L |
| MGD014 0.3 mcg/kg | Cmax: Maximum Plasma Concentration | 5.8 mcg/L |
| MGD014 1.0 mcg/kg | Cmax: Maximum Plasma Concentration | 24.5 mcg/L |
| MGD014 3.0 mcg/kg | Cmax: Maximum Plasma Concentration | 67.7 mcg/L |
| MGD014 10.0 mcg/kg | Cmax: Maximum Plasma Concentration | 181 mcg/L |
| MGD014 30.0 mcg/kg | Cmax: Maximum Plasma Concentration | 469 mcg/L |
| MGD014 100.0 mcg/kg | Cmax: Maximum Plasma Concentration | 1640 mcg/L |
| MGD014 300.0 mcg/kg | Cmax: Maximum Plasma Concentration | 5288.4 mcg/L |
Secondary
Ctrough: Trough Level Concentration
a trough level or trough concentration (Ctrough) is the concentration reached by a drug immediately before the next dose is administered,
Time frame: Study Day 14
Population: Mean trough concentration for the 300 mcg/kg dose is from the first MGD014 infusion (taken at Day 14) for participants (n=3) in Part 2 only. Trough concentration is not applicable for single-dose cohorts.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 300.0 mcg/kg | Ctrough: Trough Level Concentration | 320 mcg/L |
Secondary
Number of Participants That Developed Antidrug Antibodies to MGD014
Number of participants with antidrug antibodies to MGD014
Time frame: Study Day 1, 14, 28 and 42 (single infusion) and Study Day 1, 14, 28 and 77 (multiple infusions)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 0.3 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 1.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 3.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 10.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 30.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 100.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 0 Participants |
| MGD014 300.0 mcg/kg | Number of Participants That Developed Antidrug Antibodies to MGD014 | 2 Participants |
Secondary
Number of Participants With Increased Cytokine Levels
Number of participants with increased cytokine levels from baseline after MGD014 administration. This safety measure compares serum cytokine levels obtained prior to dosing with levels obtained after dosing. Increased cytokines can be a measure of T-cell activation in response to MGD014 binding. Cytokines analyzed included interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)2, IL-5, IL-6, and IL-10.
Time frame: Study Day 1, 2 and 7 (single infusion) and Study Day 1, 3, 14 and 28 (multiple infusions)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 0.3 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 1.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 1 Participants |
| MGD014 3.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 10.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 30.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 100.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
| MGD014 300.0 mcg/kg | Number of Participants With Increased Cytokine Levels | 0 Participants |
Secondary
Terminal Half Life of MGD014
The half-life is the amount of time required for 50% of the drug to be removed from the body
Time frame: Study Day 0 to Study Day 42
Population: Average terminal half-life did not include participants in Part 2 (n=3) due to a shortened PK schedule that did not support estimation of half-life
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Terminal Half Life of MGD014 | 32.0 hours |
| MGD014 0.3 mcg/kg | Terminal Half Life of MGD014 | 38.6 hours |
| MGD014 1.0 mcg/kg | Terminal Half Life of MGD014 | 244 hours |
| MGD014 3.0 mcg/kg | Terminal Half Life of MGD014 | 300 hours |
| MGD014 10.0 mcg/kg | Terminal Half Life of MGD014 | 295 hours |
| MGD014 30.0 mcg/kg | Terminal Half Life of MGD014 | 282 hours |
| MGD014 100.0 mcg/kg | Terminal Half Life of MGD014 | 285 hours |
| MGD014 300.0 mcg/kg | Terminal Half Life of MGD014 | 295 hours |
Secondary
Tmax: Time to Maximum Concentration
Tmax is the time it takes a drug to reach the maximum concentration
Time frame: Study Day 0
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Tmax: Time to Maximum Concentration | 3.0 hours |
| MGD014 0.3 mcg/kg | Tmax: Time to Maximum Concentration | 1.9 hours |
| MGD014 1.0 mcg/kg | Tmax: Time to Maximum Concentration | 2.4 hours |
| MGD014 3.0 mcg/kg | Tmax: Time to Maximum Concentration | 2.0 hours |
| MGD014 10.0 mcg/kg | Tmax: Time to Maximum Concentration | 2.7 hours |
| MGD014 30.0 mcg/kg | Tmax: Time to Maximum Concentration | 1.9 hours |
| MGD014 100.0 mcg/kg | Tmax: Time to Maximum Concentration | 2.6 hours |
| MGD014 300.0 mcg/kg | Tmax: Time to Maximum Concentration | 2.5 hours |
Secondary
Vz: Terminal Phase Volume of Distribution of MGD014
The ratio of the total quantity of drug in the body to drug plasma concentration during the elimination
Time frame: Study Day 1, 2, 7, 14, 21, 28, and 42 (single infusion) and Study Day 1, 3, 14, 28, 42, and 77 (multiple infusions)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MGD014 0.1 Micrograms/Kilogram (mcg/kg) | Vz: Terminal Phase Volume of Distribution of MGD014 | 2.1 liters |
| MGD014 0.3 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 4.1 liters |
| MGD014 1.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 8.7 liters |
| MGD014 3.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 19.7 liters |
| MGD014 10.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 17.5 liters |
| MGD014 30.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 17.4 liters |
| MGD014 100.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 21.6 liters |
| MGD014 300.0 mcg/kg | Vz: Terminal Phase Volume of Distribution of MGD014 | 15.8 liters |