NCT03719443 - First in Human Study to Assess Safety of VIS649 in Healthy Subjects | Crick

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

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Inclusion Criteria: 1. Subject voluntarily agrees to participate in this study and signs an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form prior to performing any of the Screening Visit procedures and be able to sign and date an appropriate Health Insurance Portability and Accountability Act (HIPAA) authorization form or subject privacy form, if appropriate. 2. Male and female subjects between 18 to 55 years of age, inclusive, at the Screening Visit. 3. For Japanese subjects: Subject is of Japanese descent as evidenced by verbal confirmation of familial heritage (a subject has all four Japanese grandparents born in Japan). 4. For non-Japanese subjects: Subjects must be of non-Asian descent, as evidenced by verbal confirmation that all four grandparents are non-Asian. 5. The following applies to female subjects: * Non-childbearing potential (surgically sterile \[hysterectomy or bilateral tubal ligation\]) for at least 6 months, or postmenopausal ≥ 1 year, or * Non-pregnant, non-lactating females of childbearing potential must report prior use (over the 28 days prior to dosing of study drug) of medically acceptable forms of birth control (hormonal contraception, abstinence, diaphragm with spermicide, condom with spermicide or intrauterine device, or partner with vasectomy), with agreement to continue to use a medically acceptable form of birth control (as described) through the end of their participation in the study. Alternatively, a reported history of abstinence beginning at least 28 days prior to study drug dosing, with agreement to continue abstinence through the end of their participation in the study are required. Females of childbearing potential must also have a negative serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine hCG pregnancy test at Baseline (Day -1). Female subjects must also agree not to donate eggs/bank eggs for the duration of their participation in the study. 6. For male, subject and/or his partner must use a highly effective form of contraception (i.e., double-barrier as described above, have had a vasectomy, or have a female partner of non childbearing potential) or agree to abstinence following study drug dosing, through the end of the subject's participation in the study. Male subjects must also agree to not donate sperm for the duration of their participation in the study, following study drug dosing. 7. Screening laboratory values must meet the following criteria: * White blood cells 3,000 12,000/mm3 * Platelets \>150,000/mm3 * Hemoglobin \>13 gm/dL for male and\>11 gm/dL for female * Estimated glomerular filtration rate \>80 mL/min/1.73 m2 * Serum creatinine \<1.25x Upper Limit of Normal (ULN) * Blood Urea Nitrogen (BUN) ≤25mg/dL * Aspartate aminotransferase (AST) ≤50 U/L * Alanine aminotransferase (ALT) ≤67 U/L * Alkaline phosphatase ≤150 U/L * Total Bilirubin ≤1.4 mg/dL unless patient has Gilbert Syndrome, in which case direct bilirubin must be within normal range * Glucose (fasting) \<115 mg/dL * Drug and alcohol screen Negative * Serum Immunoglobulin G (IgG) \>750 mg/dL (7.5 g/L) * Serum Immunoglobulin M (IgM) \>55 mg/dL (0.55 g/L) * Serum IgA \>80 mg/dL (0.8 g/L) 8. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, at the Screening Visit. 9. Healthy, determined by pre-study medical evaluation (medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluations), as judged by the Investigator. 10. Is willing and able to comply with study restrictions and to remain at the central processing unit (CPU) for the in-patient duration of the study and return for all follow-up outpatient visits. 11. QTcF or QTcB \< 450 msec at Screening (may be repeated once). Exclusion Criteria: 1. Is participating in another clinical study of any investigational drug, device, or intervention or has received any investigational medication during the last 30 days or five half-lives, whichever is longer, before Baseline (Day -1). 2. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the study. 3. Subject has a history or current evidence of a serious and/or unstable cardiovascular, respiratory, gastrointestinal, hematologic, autoimmune, blood dyscrasias or other medical disorder, including psychiatric disorders, cirrhosis or malignancy. History of minor skin cancers (not including melanoma) or surgically treated, limited cervical carcinomas (i.e., carcinoma in situ) are not exclusionary. 4. Subject has a history or presence of proteinuria, chronic kidney disease, disease requiring immunosuppressive therapy (including systemic steroids), or is considered to be immunosuppressed for any other reason. 5. Previous receipt of antibody or biologic therapy whether licensed or investigational (immunoglobulin products, monoclonal antibodies or antibody fragments) within 30 days prior to dosing or 5 half-lives within the dose of Investigational medicinal products (IMP), whichever is longer. 6. History of a previous severe allergic reaction with generalized urticaria; angioedema or anaphylaxis. 7. Blood pressure \>160/100 mmHg or \<90/50 mmHg (may be repeated once if abnormal), at the Screening visit and Day 1. 8. Known hypoglobulinemia disorder (i.e., common variable immunodeficiency), X linked agammaglobulinemia, selective IgA deficiency, selective IgM deficiency). 9. History of pre-existing latent infections (e.g., tuberculosis) or any infection requiring hospitalization or treatment with antivirals or antibiotics, or vaccination within 30 days prior to administration of study medication. 10. Concomitant use of marketed or investigational systemic immunosuppressive or immunomodulatory medications (e.g., corticosteroids, methotrexate, azathioprine, etc. and/or biologics) is prohibited and require a washout period prior to Screening (30 days or 5 half lives, whichever is longer). 11. Has received any prescription or non-prescription (over-the-counter \[OTC\]) except acetaminophen or ibuprofen, including hormonal contraceptives, topical medications, vitamins, dietary or herbal during the last 30 days or 5 half-lives, whichever is longer, preceding Baseline (Day -1). 12. Subjects who consume more than 21 units of alcohol per week (7 days) or those who have a history of alcohol or drug/chemical abuse; one unit of alcohol is equivalent to eight ounces of beer, 4 ounces of wine, or one ounce of spirits. 13. Subject is a user or former user of nicotine-containing products (including but not limited to cigarettes, cigars, and chewing or dipping tobacco) who stopped use or consumption (i.e., smoking, chewing, or pinching) of these nicotine-containing products less than 3 months before study drug administration or is using or has used topical or oral nicotine preparations for smoking cessation within the past 90 days before study drug administration. 14. Subjects who consume greater than 500 mg of caffeine or xanthine-containing products per day (e.g., coffee, tea, soft drinks, energy drinks, or chocolate). 15. Subjects who refuse to abstain from alcohol, xanthine-containing or caffeine-containing foods or beverages, or grapefruit foods or beverages, or Seville-orange containing foods (e.g., orange marmalade) or beverages, from 48 hours prior to check-in on Day-1 through the end of the study. 16. Subjects with a positive urine drug (inclusive of marijuana) or alcohol Screening test result at Screening and Day -1. 17. Subjects with a positive hepatitis B surface antigen test or evidence of chronic hepatitis C virus (HCV) infection at Screening (a negative HCV antibody assay at screening is sufficient to rule-out chronic HCV infection for this study). 18. Subjects with a known history of a positive Human Immunodeficiency Virus (HIV) or a positive test result at Screening. 19. Subjects who have donated \>500 mL or blood within 60 days prior to start of Screening. 20. The subject has donated any plasma within 7 days prior to Baseline (Day -1). 21. Is an employee of the clinical research team (any Visterra or research site employee), or has a family member who is an employee of these organizations.

Outcomes

Primary Outcomes

Overall Summary of Treatment Emergent Adverse Events

The number adverse events (AEs), serious adverse events (SAEs), and drug related events following administration of VIS649. Safety will be assessed via AE severity per CTCAE v4.0

Time frame: Baseline to day 112

Secondary Outcomes

Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants

The maximum serum concentration (Cmax) of VIS649 determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participant

The time to the maximum serum concentration (tmax) of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

The Pharmacokinetic Exposure Profiles of VIS649 in Serum. All Participants

Summary of the pharmacokinetic profiles of VIS649 exposure in serum for all participants. AUC0-112 presents the area under the concentration time curve from pre-dose (time 0) to the concentration on day 112. AUC0-last presents the area under the concentration time curve from pre-dose (time 0) to the last quantifiable concentration. AUC0-inf presents the area under the concentration time curve from pre-dose (time 0) extrapolated to infinite time.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

T 1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. All Participants

The terminal elimination half life (t1/2) of VIS649 from the concentration-time profile as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose.

The clearance rate (CL) of VIS649 using the exposure calculated to infinity of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants.

Time frame: Day 1 to day 112

Vd: The Volume of Distribution of VIS649 in Serum Samples. All Participants

The volume of distribution of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants.

Time frame: Day 1 to day 112

Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Time Profile. Japanese Participants

The maximum serum concentration (Cmax) of VIS649 determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. Japanese participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Japanese Participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

The Pharmacokinetic Exposure Profiles of VIS649 in Serum. Japanese Participants

AUC0-112 presents the area under the concentration time curve from pre-dose (time 0) to the concentration on day 112. AUC0-last presents the area under the concentration time curve from pre-dose (time 0) to the last quantifiable concentration. AUC0-inf presents the area under the concentration time curve from pre-dose (time 0) extrapolated to infinite time.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. Japanese Participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. Japanese Participants

Time frame: Day 1 to day 112.

Vd: The Volume of Distribution of VIS649 in Serum Samples. Japanese Participants

The volume of distribution of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods.

Time frame: Day 1 to day 112.

Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Non-Japanese Participants

The maximum serum concentration (Cmax) of VIS649 determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Non-Japanese Participants

The time to the maximum serum concentration (tmax) of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

The Pharmacokinetic Exposure Profiles of VIS649 in Serum. Non-Japanese Participants

Summary of the pharmacokinetic profiles of VIS649 exposure in serum for non-Japanese participants. AUC0-112 presents the area under the concentration time curve from pre-dose (time 0) to the concentration on day 112. AUC0-last presents the area under the concentration time curve from pre-dose (time 0) to the last quantifiable concentration. AUC0-inf presents the area under the concentration time curve from pre-dose (time 0) extrapolated to infinite time.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. Non-Japanese Participants

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. Non-Japanese Participants

Time frame: Day 1 to day 112.

Vd: The Volume of Distribution of VIS649 in Serum Samples. Non-Japanese Participants

The volume of distribution of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods.

Time frame: Day 1 to day 112.

Pharmacodynamic Effect of VIS649 on Total Immunoglobulin G Species. All Participants

The effect of VIS649 treatment on total IgG levels in serum, weekly observations from baseline to Week 24

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Total Immunoglobulin A Species. All Participants

The effect of VIS649 treatment on total IgA levels in serum, weekly observations from Baseline to Week 24

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Total Immunoglobulin M Species. All Participants

The effect of VIS649 treatment on total IgM levels in serum, weekly observations from Baseline to Week 24

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Circulating CD16 +CD56 (Natural Killer) Cells for All Participants in Cohorts 1-4

The effect of VIS649 treatment on the population of circulating CD16 +CD56 (Natural killer) cells in serum for all participants in cohorts 1-4.

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Circulating CD19 (B Cells) for All Participants in Cohorts 1-4

The effect of VIS649 treatment on the population of circulating CD19 (B Cells) in serum for all participants in cohorts 1-4.

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Circulating CD4 T Cells for All Participants in Cohorts 1-4

The effect of VIS649 treatment on the population of circulating CD4 T cells in serum for all participants in cohorts 1-4.

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Circulating CD3 T Cells for All Participants in Cohorts 1-4

The effect of VIS649 treatment on the population of circulating CD3 T cells in serum for all participants in cohorts 1-4.

Time frame: From baseline to Week 24

Pharmacodynamic Effect of VIS649 on Circulating CD8 T Cells for All Participants in Cohorts 1-4

The effect of VIS649 treatment on the population of circulating CD8 T cells in serum for all participants in cohorts 1-4.

Time frame: From baseline to Week 24

Summary of Anti -VIS649 Anti-drug Antibodies (ADA)

Summary of Anti -VIS649 anti-drug antibodies (ADA) by treatment group, all participants

Time frame: Baseline to Day 112

Summary of Anti -VIS649 Antibody (ADA) Titer by Treatment

Summary of Anti -VIS649 antibody (ADA) titer by treatment, all participants with ADA positive results

Time frame: Baseline to Day 112

Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants by Anti-VIS649 Status

The maximum serum concentration (Cmax) of VIS649 determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants by anti-VIS649 status (positive or negative).

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants by Anti-VIS649 Status

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

The Pharmacokinetic Exposure Profiles of VIS649 in Serum Samples, All Participants by Anti-VIS649 Antibody Status.

Summary of the pharmacokinetic profiles of VIS649 exposure in serum for all participants based on their anti-VIS649 antibody status (negative/positive). AUC0-112 presents the area under the concentration time curve from pre-dose (time 0) to the concentration on day 112. AUC0-last presents the area under the concentration time curve from pre-dose (time 0) to the last quantifiable concentration. AUC0-inf presents the area under the concentration time curve from pre-dose (time 0) extrapolated to infinite time.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. All Participants by Anti-VIS649 Antibody Status.

Time frame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.

CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. All Participants by Anti-VIS649 Antibody Status.

Time frame: 112 days

Vd: The Volume of Distribution of VIS649 in Serum Samples. All Participants by Anti-VIS649 Antibody Status (Positive or Negative)

The calculated volume of distribution of VIS649 as determined by an electrochemiluminescence (ECL) immunoassay and analyzed by standard non-compartmental pharmacokinetic methods. All participants by anti-VIS649 antibody status (positive or negative).

Time frame: 112 days

First in Human Study to Assess Safety of VIS649 in Healthy Subjects

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes