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

Study Overview
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Brief Summary
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This is a phase 1, randomized, placebo-controlled, double-blind, single ascending dose study of IV VIS649 in healthy subjects. VIS649 is a monoclonal immunoglobulin G2 (IgG2) antibody targeting the B-cell growth factor APRILL. The study will enroll up to 45 subjects and will be conducted in up to 5 sequential dosing cohorts at four different dose levels, enrolling 9 subjects per cohort. Subjects will be randomized to VIS649 or placebo in a ratio of 7:2 (7 active, 2 placebo). Safety, pharmacokinetic (PK) and pharmacodynamic (PD) data from the initial cohorts will be assessed.

Detailed Description
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On Day 1, a single dose of VIS649 or placebo will be administered IV. Pharmacokinetics sampling will start with a collection prior to the start of infusion and at multiple timepoints throughout the study. Pharmacodynamics sampling will occur at baseline and multiple timepoints throughout the study. Sentinel subjects will be utilized; the first two subjects in each cohort will be randomized to receive either VIS649 or placebo and will receive study drug at least 24 hours before the remaining subjects in the cohort are dosed. The safety profile of these subjects over the 24 hour post-administration period will be reviewed to determine whether it is appropriate to proceed with enrollment of the remaining subjects in the cohort as planned. This will occur for each dose escalation. The maximum duration of participation (Screening through End-of-study) for individual subjects will be approximately 20 weeks (5 months). The scheduled final visit will occur 16 weeks post-dosing (112 days).

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VIS649 Administered Intravenously in Healthy Subjects

Conditions
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Immunoglobulin A Nephropathy, IgAN - IgA Nephropathy, IgA Nephropathy

Intervention / Treatment
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* Biological: VIS649
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Male and female subjects between 18 to 55 years of age, inclusive, at the Screening Visit. 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). For non-Japanese subjects: Subjects must be of non-Asian descent, as evidenced by verbal confirmation that all four grandparents are non-Asian. 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. 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. 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) Body mass index (BMI) between 18 and 32 kg/m2, inclusive, at the Screening Visit. 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. 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. QTcF or QTcB < 450 msec at Screening (may be repeated once). Exclusion Criteria: 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). Subject is judged by the Investigator or the Medical Monitor to be inappropriate for the study. 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. 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. 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. History of a previous severe allergic reaction with generalized urticaria; angioedema or anaphylaxis. Blood pressure >160/100 mmHg or <90/50 mmHg (may be repeated once if abnormal), at the Screening visit and Day 1. Known hypoglobulinemia disorder (i.e., common variable immunodeficiency), X linked agammaglobulinemia, selective IgA deficiency, selective IgM deficiency). 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. 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). 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). 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. 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. 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). 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. Subjects with a positive urine drug (inclusive of marijuana) or alcohol Screening test result at Screening and Day -1. 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). Subjects with a known history of a positive Human Immunodeficiency Virus (HIV) or a positive test result at Screening. Subjects who have donated >500 mL or blood within 60 days prior to start of Screening. The subject has donated any plasma within 7 days prior to Baseline (Day -1). 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: phase 1, randomized, placebo-controlled, double-blind, single ascending dose study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VIS649<br>A single dose of VIS649 will be administered IV over approximately 1 hour on Day 1, at doses ranging from 0.5 mg/kg up to but not to exceed 20 mg/kg. No other doses will be administered during the study. | Biological: VIS649<br>* Single IV dose of study product on Day 1 of study<br>|
| Placebo Comparator: Placebo<br>Single IV dose of placebo will be administered via IV over approximately 1 hour on Day 1. No other doses will be administered during the study. | Biological: Placebo<br>* Singe IV dose of placebo administered via IV on Day 1 of study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events | The proportion of subjects with AEs and serious adverse events (SAEs) following administration of VIS649. Safety will be assessed via AE severity per CTCAE v4.0 | 112 days | 
| Frequency of 12-lead ECG treatment emergent abnormalities | QT interval change will be measured with Bazett (QTcB) or Fridericia (QTcF) heart rate correction formulas | 112 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The levels of anti-drug antibodies | Blood anti-drug antibodies (ADA) level assessments over time | 112 days | 
| The PK profile of VIS649 in serum/blood samples | characterize blood VIS649 concentration over time | 112 days | 
| The effect of VIS649 on pharmacodynamic (PD) parameters | Changes in serum immunoglobulin levels over time | 112 days | 
| The effect of VIS649 on pharmacodynamic (PD) parameters | Changes in plasma (or serum) APRIL levels | 112 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic glomerular disease, autoimmune glomerulonephritis