A Study of KZR-616 in Patients With Systemic Lupus Erythematosus With and Without Nephritis

Inclusion Criteria:

PHASE 1b:

1. Male or female patients aged 18 to 75 (inclusive)

2. Body Mass Index (BMI) of 18-40 kg/m2

3. Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC)
classification criteria for SLE

4. Have at least one of the following at screening per central lab:

1. Positive antinuclear antibody (ANA) test (1:80 or higher); or

2. Anti-double stranded deoxyribonucleic acid (dsDNA) antibodies elevated to above
normal (i.e. positive results); or

3. Anti-Smith antibody elevated to above normal (i.e., positive results)

5. Active SLE as indicated by a Systemic Lupus Erythematosus Disease Activity Index 2000
(SLEDAI-2K) total score ≥ 4 at screening

6. Must have received 1 or more therapies for SLE

7. Acceptable screening laboratory values of concern, including:

1. Adequate hematologic criteria:

2. Adequate hepatic function:

3. Pancreatic enzymes

4. eGFR ≥ 40 mL/min/1.73 m2 (estimated based on Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) formula)

5. IgG ≥ 500 mg/dL

8. If taking the following SLE therapies:

1. Oral glucocorticoids (up to 20 mg/day prednisone or equivalent): must be on a
stable dosage regimen of oral corticosteroid at least 4 weeks prior to screening
and maintain stable dose until randomization

2. Hydroxychloroquine (≤ 400 mg/day) or chloroquine (≤ 500 mg/day) orally or other
anti-malarials: must be started or stopped at least 12 weeks prior to screening,
with stable dosage regimen for at least 4 weeks prior to screening

3. Immunosuppressive agents: must be started or stopped at least 12 weeks prior to
screening, with stable dosage regimen, including route of administration, for at
least 4 weeks prior to screening:

- Mycophenolate mofetil (≤ 3 g/day) or mycophenolic acid (≤ 2.16 g/day) orally

- Azathioprine (≤ 200 mg/day) orally

- Methotrexate (≤ 25 mg/week) orally, SC, or intramuscularly (patients must be
on concomitant folic or folinic acid supplementation if using methotrexate)

- Leflunomide (≤ 20 mg/day) orally

9. Women of childbearing potential must have a negative serum beta-human chorionic
gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test
prior to the first dose and must agree to use a highly effective method of birth
control from signing the informed consent form (ICF) until their completion of the
study (or 30 days following the last dose of study drug in case of early withdrawal).
Hormonal contraception may not be effective in women on concomitant MMF/MPA; women on
MMF/MPA using hormonal contraception must agree to use a highly effective non-hormonal
method of contraception. Abstinence is not an acceptable method of birth control for
this study. Women of nonchildbearing potential must be postmenopausal (no menses for
at least 2 years before the screening visit), permanently sterilized (e.g., bilateral
tubal occlusion, hysterectomy, bilateral salpingectomy), or congenitally sterile

10. Male patients must use an effective contraception method (e.g., condom with
spermicide) from signing the ICF until their completion of the study (or 12 weeks
following the last dose of study drug in case of withdrawal) or be congenitally or
surgically sterile (e.g., vasectomy with documented confirmation of post-surgical
aspermia)

11. Willing and able to provide written informed consent prior to any study-related
procedures and to comply with all study requirements

PHASE 2:

1. Male or female patients aged 18 to 75 years (inclusive)

2. BMI of 18-40 kg/m2

3. Fulfills the 2012 Systemic Lupus International Collaborating Clinics (SLICC)
classification criteria for SLE.

4. Undergoing an ACR-recommended MMF- or MPA-based induction therapy regimen for lupus
nephritis for 4 to 12 weeks, and willing to continue at least the MMF/MPA portion of
the regimen unaltered throughout the duration of the study. Must be receiving a stable
regimen of oral corticosteroids for at least 2 weeks prior to screening

5. The patient has at least one of the following at screening per central lab:

1. Positive ANA test (1:80 or higher) or

2. Anti-dsDNA antibodies elevated to above normal (i.e., positive results); or

3. Anti-Smith antibody at screening elevated to above normal (i.e., positive
results)

6. Kidney biopsy within 26 weeks prior to randomization with a histologic diagnosis of LN
(International Society of Nephrology/Renal Pathology Society 2003 classification of
lupus nephritis [ISN/RPS]) Classes III, IV-S or IV-G, (A) or (A/C); Patients with
Class III or IV and concomitant Class V will be permitted (NOTE: Patients meeting all
inclusion criteria with a kidney biopsy of greater than 26 weeks will be allowed
following a repeat biopsy which shows the necessary histologic diagnosis prior to
study entry)

7. UPCR of ≥ 1.0 in 24-hour urine collection

8. Acceptable screening laboratory values of concern, including:

1. Adequate hematologic criteria:

2. Adequate hepatic function:

3. Pancreatic enzymes

4. eGFR ≥ 40 mL/min/1.73 m2 estimated based on CKD-EPI formula

5. IgG ≥ 500 mg/dL

9. Women of childbearing potential must have a negative serum beta-hCG pregnancy test at
screening and negative urine pregnancy test prior to the first dose and must agree to
use a highly effective method of birth control from signing the ICF until their
completion of the study (or 30 days following the last dose of study drug in case of
early withdrawal). Hormonal contraception may not be effective in women on concomitant
MMF/MPA; women on MMF or MPA using hormonal contraception must agree to use a highly
effective non-hormonal method of contraception. Abstinence is not an acceptable method
of birth control for this study. Women of nonchildbearing potential must be
postmenopausal (no menses for at least 2 years before the screening visit),
permanently sterilized (e.g., bilateral tubal occlusion, hysterectomy, bilateral
salpingectomy), or congenitally sterile

10. Male patients must use an effective contraception method (e.g., condom with
spermicide) from signing the ICF until completion of the study (or 12 weeks following
the last dose of study drug in case of early withdrawal) or be congenitally or
surgically sterile (e.g., vasectomy with documented confirmation of post-surgical
aspermia)

11. Willing and able to provide written informed consent prior to any study-related
procedures and to comply with all study requirements

Exclusion Criteria:

PHASE 1b:

1. Active central nervous system involvement by autoimmune disease requiring specific
therapeutic intervention within 60 days prior to first day of study treatment.
Headache treated only with acetaminophen, nonsteroidal anti-inflammatory drugs
(NSAIDs), or approved doses of triptans is permitted with medical monitor approval.

2. Presence of another rheumatic (overlap) disease that may confound clinical assessments
in the study. Secondary sicca or Sjogren's syndrome, antiphospholipid antibody
syndrome, and overlap with rheumatoid arthritis without erosive joint disease
("rhupus") are allowed

3. History of severe antiphospholipid syndrome within 12 months of screening or not on an
adequate anticoagulation regimen. However, presence of antiphospholipid antibodies
alone (without a history of thromboembolic event) is not exclusionary.

4. Receipt of any of the following treatments within the following timeframes before
screening

1. Systemic corticosteroids ≥ 100 mg prednisone or equivalent: 4 weeks

2. Intra-articular therapies, such as corticosteroids or hyaluronic acid
preparations: 4 weeks

3. Intravenous Immunoglobulin (IVIg): 4 weeks

4. Other non-biologic immunosuppressive agents, such as cyclosporine, tacrolimus: 4
weeks

5. Cyclophosphamide: 12 weeks

6. Cytokine antagonists: 12 weeks

7. B-cell-depleting therapies (e.g., rituximab): 24 weeks

8. Belimumab, abatacept, or atacicept: 12 weeks

9. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is
longer

10. Transfusion with blood, packed red blood cells, platelets or treatment with
plasmapheresis or plasma exchange: 6 weeks

5. Patient has had recent serious or ongoing infection, or risk for serious infection

6. History of any concurrent illness that has required treatment with oral or parenteral
corticosteroids for more than a total of 2 weeks within the last 24 weeks prior to
signing the ICF

7. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases
that, in the opinion of the investigator or sponsor, could confound the results of the
study, put the patient at undue risk, or interfere with protocol adherence

8. History of cancer, except for in situ cancer that has been completely excised or has
been curatively treated cancer with no sign of disease for > 5 years

9. Major surgery within 4 weeks before signing the ICF or major surgery planned during
the study period

PHASE 2:

1. Active central nervous system involvement by autoimmune disease requiring specific
therapeutic intervention within 60 days prior to first day of study treatment.
Headache treated only with acetaminophen, NSAIDs, or approved doses of triptans is
permitted with medical monitor approval.

2. Isolated Class V membranous LN on a renal biopsy obtained within 26 weeks prior to
signing ICF or during the screening period

3. Known intolerance to MMF or MPA

4. History of dialysis within 12 months prior to signing the ICF or expected need for
renal replacement therapy (dialysis or renal transplant) within a 6-month period after
enrollment

5. History of Rapidly Progressive Glomerulonephritis (RPGN) and/or other renal disease

6. History of chronic kidney disease not directly due to LN

7. Uncontrolled blood pressure (systolic blood pressure ≥160 mmHg and diastolic blood
pressure ≥100 mmHg at rest)

o If currently on RAS blockade (ACE-I, ARB, direct renin inhibitors), dose must be
stable for at least 4 weeks prior to screening

8. Receipt of any of the following treatments within the following timeframes before
first day of study treatment:

1. IVIg: 4 weeks

2. Corticosteroids ≥ 1 g/day prednisone or equivalent: 4 weeks

3. Intra-articular therapies, such as corticosteroids or hyaluronic acid
preparations: 4 weeks

4. Conventional disease-modifying antirheumatic drugs, including methotrexate,
leflunomide, sulfasalazine, cyclosporine, tacrolimus: 12 weeks

5. MMF of ≥ 3 g (or 2.16 g of MPA) for ≥ 4 weeks, cyclophosphamide: 24 weeks

6. Cytokine antagonists: 12 weeks

7. B-cell-depleting therapies (e.g., rituximab): 24 weeks

8. Other biologics or investigational drugs: 8 weeks or 5 half-lives, whichever is
longer

9. Hydroxychloroquine (>400 mg/day) or chloroquine (>500 mg/day) or other
antimalarials above the recommended dose. Antimalarials, if used, must have been
started or stopped at least 12 weeks prior to first dose, with stable dosage
regimen for at least 4 weeks prior to first dose of study treatment

10. Abatacept: 12 weeks

9. Major surgery within 4 weeks before signing the ICF or major surgery planned during
the study period

10. History of any other concurrent illness, including drug induced SLE, that has required
treatment with oral or parenteral corticosteroids for more than a total of 2 weeks
within the last 24 weeks prior to signing the ICF

11. Patient has had recent serious or ongoing infection, or risk for serious infection

12. Clinical evidence of significant unstable or uncontrolled acute or chronic diseases in
the opinion of the investigator

13. History of cancer, except for in situ cancer that has been completely excised or has
been curatively treated with no sign of disease for > 5 years

14. Presence of another rheumatic (overlap) disease that nay confound clinical assessment
in the study.

15. History of antiphospholipid syndrome with history of thromboembolic event within 12
months of screening or not an adequate anticoagulation regimen. However history of
antiphospholipid antibodies alone (without history of thromboembolic event) is not
exclusionary.