Clinical trial NCT03719443: First in Human Study to Assess Safety of VIS649 in Healthy Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Immunoglobulin A Nephropathy
IgAN - IgA Nephropathy
IgA Nephropathy
Keywords: chronic glomerular disease
autoimmune glomerulonephritis
Lead sponsor: Visterra, Inc.
Sponsor class: INDUSTRY
First posted: 2018-10-25
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: phase 1, randomized, placebo-controlled, double-blind, single ascending dose study
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Summary of Treatment Emergent Adverse Events
timeFrame: Baseline to day 112
Secondary outcomes:
measure: Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participant
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: The Pharmacokinetic Exposure Profiles of VIS649 in Serum. All Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: T 1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. All Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose.
timeFrame: Day 1 to day 112
measure: Vd: The Volume of Distribution of VIS649 in Serum Samples. All Participants
timeFrame: Day 1 to day 112
measure: Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Time Profile. Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: The Pharmacokinetic Exposure Profiles of VIS649 in Serum. Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. Japanese Participants
timeFrame: Day 1 to day 112.
measure: Vd: The Volume of Distribution of VIS649 in Serum Samples. Japanese Participants
timeFrame: Day 1 to day 112.
measure: Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Non-Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. Non-Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: The Pharmacokinetic Exposure Profiles of VIS649 in Serum. Non-Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. Non-Japanese Participants
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. Non-Japanese Participants
timeFrame: Day 1 to day 112.
measure: Vd: The Volume of Distribution of VIS649 in Serum Samples. Non-Japanese Participants
timeFrame: Day 1 to day 112.
measure: Pharmacodynamic Effect of VIS649 on Total Immunoglobulin G Species. All Participants
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Total Immunoglobulin A Species. All Participants
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Total Immunoglobulin M Species. All Participants
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Circulating CD16 +CD56 (Natural Killer) Cells for All Participants in Cohorts 1-4
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Circulating CD19 (B Cells) for All Participants in Cohorts 1-4
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Circulating CD4 T Cells for All Participants in Cohorts 1-4
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Circulating CD3 T Cells for All Participants in Cohorts 1-4
timeFrame: From baseline to Week 24
measure: Pharmacodynamic Effect of VIS649 on Circulating CD8 T Cells for All Participants in Cohorts 1-4
timeFrame: From baseline to Week 24
measure: Summary of Anti -VIS649 Anti-drug Antibodies (ADA)
timeFrame: Baseline to Day 112
measure: Summary of Anti -VIS649 Antibody (ADA) Titer by Treatment
timeFrame: Baseline to Day 112
measure: Cmax: Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants by Anti-VIS649 Status
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: Tmax: Time to the Maximum Serum VIS649 Concentration Determined Directly From the Concentration-time Profile. All Participants by Anti-VIS649 Status
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: The Pharmacokinetic Exposure Profiles of VIS649 in Serum Samples, All Participants by Anti-VIS649 Antibody Status.
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: T1/2 The Terminal Elimination Half Life of VIS649 in Serum Samples. All Participants by Anti-VIS649 Antibody Status.
timeFrame: 0, 1, 2, 8, and 24-hours post-dose, Day 3, 7, 14, 28, 42, 56, 70, and 112.
measure: CL: The Clearance of VIS649 in Serum Samples Calculated Using Exposure Extrapolated to Infinity by Dose. All Participants by Anti-VIS649 Antibody Status.
timeFrame: 112 days
measure: Vd: The Volume of Distribution of VIS649 in Serum Samples. All Participants by Anti-VIS649 Antibody Status (Positive or Negative)
timeFrame: 112 days
Other outcomes:
Locations:
city: Glendale
country: United States
facility: California Clinical Trials Medical Group
state: California
Study officials:
affiliation: Parexel
name: Esther Yoon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mathur M, Barratt J, Suzuki Y, Engler F, Pasetti MF, Yarbrough J, Sloan S, Oldach D. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers. Kidney Int Rep. 2022 Feb 8;7(5):993-1003. doi: 10.1016/j.ekir.2022.01.1073. eCollection 2022 May.