A Study of NKTR-358 in Participants With Systemic Lupus Erythematosis (SLE)

NKTR-358 is a potential first-in-class therapeutic that may address an underlying immune
system imbalance in patients with many autoimmune conditions. It targets the interleukin
(IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune
cells known as regulatory T cells. By activating these cells, NKTR-358 may act to bring the
immune system back into balance.

This study will evaluate the safety, tolerability, PK, and immunologic effects of multiple
doses of NKTR-358 in patients with minimal to moderate SLE. The effects on SLE disease
activity will also be evaluated. SLE patients will be randomized to receive multiple SC doses
of NKTR-358 or receive placebo. After receiving the last dose of NKTR-358 or placebo,
patients will be followed for an additional 50 days to evaluate safety, PK, PD, and
preliminary efficacy.

Inclusion Criteria:

- Willing and able to give written informed consent and comply with study procedures and
requirements.

- Body mass index (BMI) between 18.0 and 32.0 (kg/m2).

- Systolic blood pressure between 90 to 140 millimeters of mercury (mm Hg), diastolic
blood pressure between 50 to 90 mm Hg, and resting heart rate between 40 to 100 beats
per minute.

- Diagnosis of adult SLE according to the 1997 ACR classification criteria for at least
6 months prior to signing the informed consent form (ICF).

- Minimal to moderate SLE disease activity (active SLE clinical disease is not required
for enrollment into the study and patients with severe SLE clinical disease activity,
based on the evaluation of the investigator, should be excluded).

- If a patient is taking oral prednisone (or prednisone equivalent) for their SLE, the
dose must be ≤ 10 mg/day for a minimum of 8 weeks prior to screening. In addition, the
dose of oral prednisone or prednisone equivalent the patient is taking must be stable
for a minimum of 2 weeks prior to screening.

- If a patient is taking any of the medications below for their SLE, the medication must
have been administered for a minimum of 12 weeks prior to signing the ICF, and at a
stable dose for a minimum of 8 weeks prior to signing the ICF:

- Azathioprine ≤ 200 mg/day

- Antimalarial (e.g., chloroquine, hydroxychloroquine, quinacrine)

- Mycophenolate mofetil ≤ 2 g/day or mycophenolic acid ≤ 1.44 g/day

- Oral, SC, or intramuscular methotrexate ≤ 15 mg/week

- Willing and able to participate in the study for a duration of up to 4 months.

- Willing and able to abstain from participating in another clinical study for a
duration of up to 4 months.

- Female subjects will be non-pregnant, non-lactating, and either postmenopausal for at
least 2 years, or surgically sterile for at least 3 months, or will agree to use
double barrier contraception from period prior to study enrollment until 5 months
following the last dose received; women of child-bearing potential must have a
negative serum β- hCG test at screening and randomization prior to administration of
investigational product.

- Male subjects with female partners of childbearing potential must agree to use double
barrier contraception during the study (until 5 months following the last dose
received). Sperm donation is also restricted during the time-frame that males must be
using double barrier contraception. This criterion may be waived for male subjects who
have had a vasectomy > 6 months prior to enrollment.

Exclusion Criteria:

Medical Conditions:

- Current active bacterial, viral, or fungal infection.

- Evidence of significant hematologic dysfunction

- Evidence of significant liver or kidney dysfunction

- History of, or current diagnosis of, a clinically significant non SLE-related
vasculitis syndrome.

- Active severe or unstable neuropsychiatric SLE.

- Active severe SLE-driven renal disease or history of severe active lupus nephritis
with persisting proteinuria levels greater than 0.5 g/24 hours.

- Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any
history of overlap syndromes of SLE.

- History of, or current, inflammatory joint or skin disease other than SLE.

- History of any non-SLE disease that has required treatment with oral or parenteral
corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the
ICF.

- Active TB on the basis of positive medical history or chest radiograph (OR) evidence
of latent TB or by positive (or persistently indeterminate) Quantiferon-TB Gold or
T-Spot test.

- Known history of a primary immunodeficiency, splenectomy, or any underlying condition
that predisposes the patient to infection.

- Confirmed positive serology for hepatitis B, hepatitis C (anti-HCV), or a positive
result for HIV antibody screen.

- Any severe herpes infection at any time prior to screening per judgement of the
investigator.

- History of opportunistic infection requiring hospitalization or intravenous
antimicrobial treatment within 3 years prior to randomization.

- History of major surgery within 12 weeks of screening or will require major surgery
during the study.

- Clinically significant electrocardiographic abnormalities

- History of any significant cardiovascular disease (e.g., myocardial infarction,
congestive heart failure, uncontrolled hypertension, cerebrovascular accident),
thrombotic episode, or any severe non-SLE medical illness within the previous 1 year.

- History of cancer, apart from:

- Squamous or basal cell carcinoma of the skin that has been successfully treated

- Cervical cancer in situ that has been successfully treated

Medications:

- Receipt of any investigational product (small molecule or biologic agent) within 4
weeks or 5 half-lives prior to signing of the ICF, whichever is greater.

- Receipt of belimumab in 6 months prior to screening.

- History of treatment with rituximab or ocrelizumab (or other B cell depleting agent)
within 6 months prior to screening. For patients who received their last treatment
with rituximab or ocrelizumab more than 6 months earlier, evidence of significant and
persisting low B cell levels in blood

- History of cytotoxic medications (e.g., cyclophosphamide) within preceding 12 months.

- Receipt of any intra-articular, intramuscular, or IV glucocorticoids within 6 weeks
prior to screening.

- Receipt of blood products within 6 months prior to screening.

General:

- Receipt of blood products within 6 months prior to screening and donation of blood or
plasma to a blood bank or for a clinical study (except for screening of this study)
within 28 days prior to screening.

- Subjects who have a history of organ or bone marrow transplant.