The purpose of this first-in-human (FIH) study is to assess the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of subcutaneous (SC) VIS171 in healthy participants (single ascending dose [SAD] - Part A) as well as in…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objectives and Endpoints - Part A (Single Ascending Dose)
Objectives Endpoints
Primary:
· To evaluate the safety and tolerability of VIS171.
Primary endpoint:
· Incidence and severity of TEAEs.
Objectives and Endpoints - Part B (Multiple Ascending Dose)
Objectives Endpoints
Primary:
· To Endpoint evaluate the safety and tolerability of VIS171.
Primary:
· Incidence and severity of TEAEs.
Secondary outcome
Secondary part A:
· To determine the PD effect of VIS171.
· To assess the PK of VIS171.
Secondary Endpoint:
· Mean fold change from baseline in immune cell types, including the following:
· Absolute number (cells/µL) and frequency (%) of Treg.
· Absolute number (cells/µL) and frequency (%) of helper T cells, cytotoxic T
cells, and natural killer cells.
· Pharmacokinetic parameters:
· Cmax, tmax, AUClast, and AUC*.
Secondary part B:
· To determine the PD effect of VIS171.
· To assess the PK of VIS171.
· To evaluate the
immunogenicity of VIS171.
Secondary Endpoint:
· Mean fold change from baseline in immune cell types, including the following:
· Absolute number (cells/µL) and frequency (%) of Treg.
· Absolute number (cells/µL) and frequency (%) of helper T cells, cytotoxic T
cells, and natural killer cells.
· Pharmacokinetic parameters:
· Cmax, tmax, and AUCtau.
· Characterization of ADA to VIS171 over time.
Background summary
Rationale: VIS171 is under development for the treatment of autoimmune diseases
with an underlying mechanism attributed to T cell dysregulation. VIS171 is a
fusion protein containing modified human interleukin-2 (IL-2) and a human
antibody fragment crystallizable (Fc) domain. Nonclinical studies have
demonstrated that VIS171 has a
robust and specific effect on regulatory T cell (Treg) expansion. The purpose
of this first-in-human (FIH) study is to assess the safety, tolerability,
pharmacodynamics (PD), and pharmacokinetics (PK) of subcutaneous (SC) VIS171 in
healthy participants (single ascending dose [SAD] - Part A) as well as in
participants with autoimmune diseases (multiple ascending dose [MAD] - Part B).
The autoimmune diseases that will be included in Part B (MAD) are systemic
lupus erythematosus (SLE), autoimmune hepatitis (AIH), immune-mediated focal
segmental glomerulosclerosis (FSGS), and alopecia
areata (AA). These diseases share an underlying mechanism of diminished Treg
responses contributing to disease pathogenesis and have been evaluated in prior
clinical studies investigating low-dose recombinant or modified human IL-2. The
data obtained from this FIH study will inform dose selection for subsequent
clinical development and will help prioritize indications for further study.
Study objective
The purpose of this first-in-human (FIH) study is to assess the safety,
tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of subcutaneous
(SC) VIS171 in healthy participants (single ascending dose [SAD] - Part A) as
well as in participants with autoimmune diseases (multiple ascending dose [MAD]
- Part B).
Study design
Study Design: This is a phase 1, multicenter, 2-part combined SAD and MAD FIH
study to investigate the safety, tolerability, PD, and PK of SC VIS171 in
healthy participants (Part A - SAD) and in participants with an autoimmune
inflammatory disease(s) (SLE, AIH, FSGS, or AA) (Part B - MAD). For Part A,
participants will be enrolled at a single study site in New Zealand. For Part
B, participants will be enrolled from approximately 20 study sites in up to 10
countries
Intervention
Intervention Groups and Duration: In Part A, participants in each cohort will
receive a single SC dose of VIS171 or placebo on Day 1. The starting dose in
Part A is 1 jig/kg. The proposed doses for Part A are 1, 4, 8, 16, and 32
jig/kg in Cohorts 1, 2, 3, 4, and 5, respectively.
The dosing frequency in Cohorts 1 and 2 in Part B will be once every 2 weeks
for 8 weeks (total of 4 doses). The doses for Cohorts 1 and 2 in Part B will be
derived from Part A. The dosing frequency for Cohort 3 in Part B will be
determined from Cohorts 1 and 2 of Part B, and may be increased to once every
week for 8 weeks (up to 8 doses).
Study burden and risks
2.3.1. Risk Assessment
VIS171 has not been evaluated in humans.
The active component of VIS171, IL-2, has been investigated in a clinical
setting for over 30 years and has a well-understood safety profile at a wide
range of doses. Recombinant human IL-2 (aldesleukin) has been a Food and Drug
Administration-approved therapy for metastatic melanoma and metastatic renal
carcinoma since 1992. Furthermore, in the past 30 years, there has been an
appreciation for the opportunity for low-dose IL-2 regimens to treat autoimmune
diseases prompting many academic and exploratory studies.
It is documented that IL-2 (high-dose infusion regimens) used in oncology
treatment can cause a reaction that may include dermatologic toxicity, low
blood pressure, increased heart rate or arrhythmias, shortness of breath,
nausea, diarrhea and joint and muscle stiffness.
· Dermatologic toxicity caused by higher doses of IL-2 generally manifests as
erythema, and pruritus that can develop on the face and neck and progress to
the trunk. Participants in this study will be reminded to protect their skin
from extreme sun exposure, harsh lotions or detergents, and other skin
irritants while participating in the study.13
· High-dose IL-2 therapy has been associated with reversible reduction in
kidney function, attributed at least in part to hemodynamic changes resulting
in acute kidney injury.14,15,16 In vitro studies have indicated the potential
for IL-2 to harm podocytes. Notably, however, the Protein Atlas suggests that
IL-2 receptor is minimally expressed on healthy human podocytes.17 A
meta-analysis concluded that low-dose recombinant IL-2 administered
subcutaneously had a favorable safety profile, and did not identify kidney
injury as a parameter of concern.13 While the sponsor does not believe low-dose
modified IL-2 (VIS171) carries a risk of kidney injury, healthy participants
will be monitored closely for the development of nonorthostatic albuminuria.
Studies with low-dose IL-2 consistently found reduced toxicity relative to
high-dose treatment, as demonstrated by a lack of serious adverse events (SAEs)
in the majority of low-dose studies.2,6,9,18
The safety of VIS171 was determined in vivo in 2 non-GLP and 2 GLP studies in
cynomolgus monkeys and rats. Cynomolgus monkeys are relevant for evaluating
VIS171 safety as well as pharmacological activity, based on similar binding
profiles of human and cynomolgus monkey IL-2 and its receptors. Rats have been
used historically to assess the safety of IL-2-containing compounds, and VIS171
is active in rats.
VIS171 was well tolerated in cynomolgus monkeys and rats. In the GLP studies,
animals were dosed once weekly for 12 weeks in the rat study and 8 weeks in the
cynomolgus monkey study. The NOAELs were determined to be 6000 .tg/kg in the
GLP rat study and 300 .tg/kg in the GLP cynomolgus monkey study. In the
cynomolgus monkey study dermatological reactions were observed in a dose
dependent fashion. All were monitorable and resolved when treatment was
discontinued. There were no VIS171-related changes to urinalysis parameters.
The potential for VIS171 to stimulate cytokine release was evaluated in an in
vitro cytokine release assay using whole blood and in each in vivo study
conducted. Overall, the in vitro human whole blood assays and the in vivo
cynomolgus monkey data both indicated that VIS171 has a low risk for cytokine
release in humans.
Monitoring for potential adverse events (AEs) is incorporated into the design
of this study through safety assessments of physical examinations, vital sign
measurements, electrocardiograms (ECGs), clinical laboratory assessments
(hematology, serum chemistry, coagulation, urinalysis, urine albumin/creatinine
ratio [uACR; Part A and Part B (participants with AIH and AA)], and urine
protein/creatinine ratio [uPCR; Part A]), and AE solicitation. Brief physical
examinations will include evaluations of the skin, so that the skin is
frequently observed and any risk is identified early. As described in Section
4.1.1 (Part A) and Section 4.1.2 (Part B), a Safety Monitoring Committee (SMC)
will be reviewing all available safety data and PD data during this study prior
to each dose escalation and prior to the start of Part B.
Herman Heijermansweg 20
Amsterdam 1077WL
NL
Herman Heijermansweg 20
Amsterdam 1077WL
NL
Listed location countries
Age
Inclusion criteria
Summary of Key Inclusion and Exclusion Criteria:
Inclusion Criteria
Male or female participant between 18 and 55 years of age, inclusive, at the
screening
visit (Part A and Part B [participants with AIH, FSGS, and AA]) or between 18
and
75 years of age, inclusive, at the screening visit (Part B [participants with
SLE]). Body
mass index between 17 and 35 kg/m2, inclusive, at the screening visit.
Additional inclusion criteria:
* Part A: Healthy, as determined by prestudy medical evaluation (medical
history,
physical examination, vital signs, 12-lead electrocardiogram, and clinical
laboratory
evaluations), as judged by the principal investigator.
* Part B (participants with SLE only): Diagnosis of adult SLE according to the
2019
American College of Rheumatology classification criteria for at least 6 months
prior
to signing the informed consent form (ICF) and an estimated glomerular
filtration rate
(eGFR) >= 30 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease
Epidemiology Collaboration [CKD-EPI] formula [2021]).
* Part B (participants with AIH only): Adult meeting criteria for autoimmune
hepatitis
(simplified diagnostic criteria) and must have completed induction therapy with
standard of care (eg, steroids) and be on maintenance therapy (eg, azathioprine
and/or
low dose steroids).
Exclusion criteria
Key Exclusion Criteria
Receipt of high dose corticosteroid therapy within 4 weeks prior to screening
as either
(a) intravenous (IV) pulse corticosteroid therapy or (b) daily oral
corticosteroid therapy of
>= 1 mg/kg or 80 mg/day prednisone (or equivalent), receipt of belimumab within
6 months prior to screening, history of treatment with rituximab or ocrelizumab
(or other
B cell-depleting agent) within 12 months prior to screening, history of
cytotoxic
medications (eg, cyclophosphamide) within the preceding 12 months, and receipt
of
blood products within 6 months prior to screening.
Participants with uncontrolled hypertension (systolic blood pressure [SBP] >
140 mmHg,
diastolic blood pressure [DBP] > 90 mmHg in any position) or symptomatic
hypotension,
any chronic infectious disease, or participants with a positive urine drug or
alcohol breath
screen test result at screening or Day *1.
Current symptoms of infection, diagnosis of Coronavirus Disease 2019 (COVID-19)
(reverse transcription polymerase chain reaction [RT-PCR], antigen testing, or
clinical
diagnosis) in 21 days prior to screening, or ongoing diagnosis of *Long-COVID*
symptoms due to a prior COVID-19 infection.
Received a vaccination, other than COVID-19 vaccination, during the 30 days
prior to
administration of the first dose of study intervention. A COVID-19 vaccination
cannot be
received within 7 days prior to the first dose of study intervention and until
14 days after
the last dose.
Additional exclusion criteria:
* Part B (participants with SLE only): Presence of life- or organ-threatening
manifestations of lupus requiring intense immunosuppressive therapy, organ
support
systems, or plasmapheresis. Lupus cerebritis, or active severe or unstable
neuropsychiatric SLE.
* Part B (participants with AIH only): Advanced cirrhosis/liver disease.
Protocol VIS171-101
11
Confidential - Proprietary Information Approval: 19 Nov 2021
* Part B (participants with FSGS only): Steroid resistant nephrotic syndrome
defined as
absence of complete or partial remission following at least 12 weeks of full
dose
corticosteroid therapy. Known secondary causes of FSGS (eg, genetic/familial,
viral,
reflux uropathy, toxic causes [eg, bisphosphonates]).
* Part B (participants with AA only): Participant has concomitant hair loss of
another
form, including but not limited to traction alopecia, central centrifugal
cicatricial
alopecia, lichen planopilaris, frontal fibrosing alopecia, or androgenetic
alopecia.
Presence of other severe autoimmune diseases - requiring additional
immunosuppressive treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-006246-12-NL |
| CCMO | NL81691.091.22 |