Sjögren’s Syndrome (SS)

Primary Objective in Population #1 To evaluate the clinical efficacy of multiple doses of VIB4920 in glandular and extraglandular manifestations of SS patients with moderate to high systemic disease activity. Secondary Objectives in Population #1 1. To evaluate the effect of VIB4920 on systemic activity and patient-reported outcomes in subjects with SS. 2. To evaluate the safety and tolerability of multiple doses of VIB4920 in subjects with SS. 3. To characterize the PK of VIB4920 in subjects with SS. 4. To assess the immunogenicity of VIB4920 in subjects with SS. Exploratory Objectives in Population #1 1. To evaluate the PD of VIB4920 on CD40/CD40L pathways and disease biomarkers in subjects with SS. 2. To evaluate changes in T- and B-cell populations and markers of inflammation and autoantibodies in subjects with SS upon treatment with VIB4920. 3. To evaluate the effects of VIB4920 on systemic disease activity and salivary and lacrimal function in subjects with SS. 4. To evaluate changes in key subjective complaints associated with SS. Primary Objective in Population #2 To evaluate the clinical efficacy of multiple doses of VIB4920 in the key subjective complaints of SS (dryness, fatigue, and pain). Secondary Objectives in Population #2 1. To evaluate the effect of VIB4920 on patient-reported outcomes in subjects with SS. 2. To evaluate the safety and tolerability of multiple doses of VIB4920 in subjects with SS. 3. To characterize the PK of VIB4920 in subjects with SS. 4. To assess the immunogenicity of VIB4920 in subjects with SS. Exploratory Objectives in Population #2 1. To evaluate the PD of VIB4920 on CD40/CD40L pathways and disease biomarkers in subjects with SS. 2. To evaluate changes in T- and B-cell populations and markers of inflammation and autoantibodies in subjects with SS upon treatment with VIB4920. 3. To evaluate the effects of VIB4920 on systemic disease activity and salivary and lacrimal function in subjects with SS. 4. To evaluate changes in key subjective complaints associated with SS.

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Primary Endpoint for Population #1
Change from baseline in ESSDAI at Day 169.
Secondary Endpoints for Population #1
1. Change from baseline in ESSPRI at Day 169.
2. Proportion of subjects achieving ESSDAI[3] and ESSDAI[4] response, defined as a
decrease of at least 3[4] points from baseline in the ESSDAI at Day 169 without
premature discontinuation from the study and without receiving rescue therapy.
3. Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-
Fatigue score at Day 169.
4. Change from baseline in Ocular Surface Disease Index (OSDI©) at Day 169.
5. Patient’s Global Impression of Severity (PGIS) at Day 169.
6. Safety and tolerability of multiple IV doses of VIB4920 as measured by the incidence of
TEAEs, treatment-emergent serious adverse events (TESAEs), adverse events of special
interest (AESIs), and laboratory, vital sign, and electrocardiogram (ECG) abnormalities.
7. PK during the study.
8. Proportion of subjects with positive immunogenic response measured by anti-VIB4920
antibodies until the completion of the study.
Primary Endpoint for Population #2
Change from baseline in ESSPRI at Day 169.
Secondary Endpoints for Population #2
1. Proportion of subjects achieving ESSPRI response, defined as ≥ 1 point or 15% reduction
from baseline in ESSPRI score at Day 169 without premature discontinuation from the
study and without receiving rescue therapy.
2. Change from baseline in FACIT-Fatigue score at Day 169.
3. Change from baseline in OSDI at Day 169.
4. Patient’s Global Impression of Severity at Day 169
5. Safety and tolerability of multiple IV doses of VIB4920 as measured by the incidence of
TEAEs, TESAEs, AESIs, and laboratory, vital sign, and ECG abnormalities.
6. PK during the study.
7. Proportion of subjects with positive immunogenic response measured by anti-VIB4920
antibodies until the completion of the study.

To be included in Population #1 of this study, each individual must satisfy all the following criteria:
Inclusion Criteria for Population #1
1. Adults, 18 years or older at time of informed consent (the minimum age for adult
participants can be higher than 18 years in countries with different regulations).
2. Diagnosed with SS by meeting the 2016 ACR/EULAR Classification Criteria.
3. Have an ESSDAI score of ≥ 5 at screening; the following domains will be scored but they
will not contribute to the minimum ESSDAI score of 5 required for inclusion: Peripheral
nervous system, Central nervous system, and Pulmonary.
4. Positive for either anti-Ro autoantibodies or RF, or both at screening, as per the definition
of the standard central laboratory test.
5. Written informed consent and any locally required authorization (eg, Health Insurance
Portability and Accountability Act in the United States, European Union [EU] Data
Privacy Directive in the EU) obtained from the subject/legal representative prior to
performing any protocol-related procedures, including screening evaluations.
6. Females of childbearing potential who are sexually active with a nonsterilized male
partner must use a highly effective method of contraception from signing the informed
consent form (ICF), and must agree to continue using such precautions through the end of the study follow-up; cessation of contraception after this point should be discussed with a
responsible physician. Highly effective methods of contraception include:
• combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
− oral
− intravaginal
− transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation:
− oral
− injectable
− implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomized partner
• sexual abstinence
Sexual abstinence is considered a highly effective method only if it is the preferred
and usual lifestyle of the subject and the subject agrees to refrain from heterosexual
intercourse from signing the ICF through the end of the study follow-up. Periodic
abstinence, the rhythm method, and the withdrawal method are not acceptable
methods of contraception. A recommendation that the female partners (of
childbearing potential) of male study participants should use a highly effective
method of contraception other than a barrier method is made.
− Females of childbearing potential are defined as those who are not surgically
sterile (surgical sterilization includes bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy) or those who are not postmenopausal (defined as
12 months with no menses without an alternative medical cause).
− Vasectomized partner is a highly effective birth control method provided that
partner is the sole sexual partner of the woman of childbearing potential trial
participant and that the vasectomized partner has received medical assessment of
the surgical success.
7. Nonsterilized male subjects who are sexually active with a female partner of childbearing
potential must use a condom with spermicide from Day 1 through the end of the study.
8. Meets all of the following tuberculosis (TB) criteria:
a. No history of latent or active TB prior to screening, with the exception of latent TB
with documented completion of appropriate treatment.
b. No signs or symptoms suggestive of active TB from medical history or physical
examination.
c. No recent (≤ 12 weeks of screening) close contact with a person with active TB (close
contact is defined as ≥ 4 hours/week OR living in the same household OR in a house
where a person with active TB is a frequent visitor).
d. Negative Interferon Gamma Release Assay (IGRA) test result for TB obtained within
12 weeks prior to randomization. Subjects with an indeterminate test result can repeat
the test, but if the repeat test is also indeterminate, they are excluded.
e. A chest radiograph (obtained during the screening period or any time within 12 weeks
prior to signing of the ICF) with no evidence of current active TB or other infection,
or old active TB, malignancy, or clinically significant abnormalities suggesting an
active process (unless due to SS).
Inclusion Criteria for Population #2
To be included in Population #2 of this study, each individual must satisfy all the following
criteria.
1. Adults, 18 years or older at time of informed consent (the minimum age for adult
participants can be higher than 18 years in countries with different regulations).
2. Diagnosed with SS by meeting the 2016 ACR/EULAR Classification Criteria.
3. Have an ESSPRI score of ≥ 5 at screening.
4. Have an ESSDAI score of < 5 at screening.
5. Positive for either anti-Ro autoantibodies or RF, or both at screening, as per the definition
of the standard central laboratory test available.
6. Residual salivary gland function as defined by whole stimulated salivary flow
> 0.1 mL/min.
7. Written informed consent and any locally required authorization (eg, Health Insurance
Portability and Accountability Act in the United States, EU Data Privacy Directive in the
EU) obtained from the subject/legal representative prior to performing any protocolrelated procedures, including screening evaluations.
8. Females of childbearing potential who are sexually active with a nonsterilized male
partner must use a highly effective method of contraception from signing the ICF, and
must agree to continue using such precautions through the end of the study follow-up;
cessation of contraception after this point should be discussed with a responsible
physician. Highly effective methods of contraception include:
• combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
− oral
− intravaginal
− transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation:
− oral
− injectable
− implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomized partner
• sexual abstinence
Sexual abstinence is considered a highly effective method only if it is the preferred
and usual lifestyle of the subject and the subject agrees to refrain from heterosexual
intercourse from signing the ICF through the end of the study follow-up. Periodic
abstinence, the rhythm method, and the withdrawal method are not acceptable
methods of contraception. A recommendation that the female partners (of
childbearing potential) of male study participants should use a highly effective
method of contraception other than a barrier method is made.
− Females of childbearing potential are defined as those who are not surgically
sterile (surgical sterilization includes bilateral tubal ligation, bilateral
Module 5.3.5.1 Clinical Study Protocol VIB4920
VIB4920.P2.S2 - VIB4920 in Subjects with Sjögren’s Syndrome
Version 2.0 (21Jul2020)
CONFIDENTIAL AND PROPRIETARY Page 45 of 100
oophorectomy, or hysterectomy) or those who are not postmenopausal (defined as
12 months with no menses without an alternative medical cause).
− Vasectomized partner is a highly effective birth control method provided that
partner is the sole sexual partner of the woman of childbearing potential trial
participant and that the vasectomized partner has received medical assessment of
the surgical success.
9. Nonsterilized male subjects who are sexually active with a female partner of childbearing
potential must use a condom with spermicide from Day 1 through to the end of the study.
10. Meets all of the following TB criteria:
a. No history of latent or active TB prior to screening, with the exception of latent TB
with documented completion of appropriate treatment.
b. No signs or symptoms suggestive of active TB from medical history or physical
examination.
c. No recent (≤ 12 weeks of screening) close contact with a person with active TB (close
contact is defined as ≥ 4 hours/week OR living in the same household OR in a house
where a person with active TB is a frequent visitor).
d. Negative IGRA test result for TB obtained within 12 weeks prior to randomization.
Subjects with an indeterminate test result can repeat the test, but if the repeat test is
also indeterminate, they are excluded.
e. A chest radiograph (obtained during the screening period or anytime within 12 weeks
prior to signing of the ICF) with no evidence of current active TB or other infection,
or old active TB, malignancy, or clinically significant abnormalities suggesting an
active process (unless due to SS).

If an individual for Population #1 meets any of the following criteria, he or she is ineligible for
this study:
Exclusion Criteria for Population #1
1. Patients with medical history of confirmed deep venous thrombosis or arterial
thromboembolism within 2 years of signing the ICF.
2. Patients with risk factors for venous thromboembolism or arterial thrombosis (eg,
immobilization or major surgery within 12 weeks before screening), prothrombotic status
(including, but not limited to, congenital or inherited deficiency of antithrombin III,
protein C, protein S, or confirmed diagnosis of catastrophic antiphospholipid syndrome).
3. Patients requiring treatment with anticoagulant drugs (clopidogrel, prasugrel, warfarin,
low molecular weight heparin, others). Low-dose aspirin treatment (up to 325 mg/day) is
allowed.
4. Concomitant polymyositis or dermatomyositis or systemic sclerosis.
5. Active malignancy or history of malignancy, except as follows:
a. In situ carcinoma of the cervix treated with apparent success with curative therapy
> 12 months prior to screening; or
b. Cutaneous basal cell carcinoma following apparently curative therapy.
6. Subjects who are pregnant or lactating or planning to become pregnant during the
duration of the study.
7. Subjects who have a positive test for, or have been treated for hepatitis B, hepatitis C, or
HIV infection.
Regarding hepatitis B, positive test for chronic hepatitis B infection at screening, defined
as either (1) positive hepatitis B surface antigen (HBsAg) or (2) a positive hepatitis B
core antibody (anti-HBc).
8. Subjects with:
a. A history of more than one episode of herpes zoster and/or opportunistic infections in
the last 12 months, with the exception of oral candidiasis, vaginal candidiasis, and
cutaneous fungal infections.
b. Active viral, bacterial or other infections requiring systemic treatment at the time of
screening or through randomization, or history of more than 2 infections requiring IV
antibiotics within 12 months prior to signing the ICF.
c. Epidemiologic risk of COVID-19 (recent exposures, high-risk housing) and for
health-related risk of COVID-19 severity based on current understanding of risk
factors for severe disease when making a decision regarding the individual subject’s
risk of participation. Subjects who have active COVID-19 infection or disease or
other significant infection, or, in the judgment of the investigator, who may be at
unacceptable risk of COVID-19 or its complications should not be randomized.
d. A documented positive SARS-CoV-2 test within 2 weeks prior to randomization.
Subjects with a positive test for SARS-CoV-2 may be rescreened at least 2 weeks
after a positive test if asymptomatic and at least 3 weeks after symptomatic COVID19 illness.
9. Subjects with known history of severe allergy or reaction to any component of the IP
formulation or to any other biologic therapy.
10. Subjects with any severe cardiovascular, respiratory, endocrine, gastrointestinal,
hematological, neurological, psychiatric, or systemic disorder or any other condition that
in the opinion of the Investigator, would place the subject at unacceptable risk of
complications, interfere with evaluation of the IP or confound the interpretation of
subject safety or study results.
11. Subjects who are unable or unwilling to comply with protocol requirements (eg, active
drug or alcohol abuse).
12. Subjects who have received live (attenuated) vaccine within the 4 weeks prior to ICF
signature.
13. Last administration of experimental biologic (other than those listed in Point 14) or oral
agents < 3 months or 5 half-lives before randomization.
14. Subjects who have had previous treatment with any biologic B-cell-depleting therapy (eg,
rituximab, ocrelizumab, or ofatumumab) within 12 months or other B-cell targeting
therapy (eg, belimumab) < 3 months before randomization.
15. Injectable corticosteroids (including intra-articular) or treatment with > 10 mg/day dose
oral prednisone or equivalent within 6 weeks prior to randomization. Concomitant
treatment with oral corticosteroids ≤ 10 mg/day prednisone or equivalent is permitted
provided that the dose is stable ≥ 2 weeks prior to screening through randomization
(Day 1) and is expected to remain stable for the duration of the treatment period. Inhaled
or topical corticosteroids given for asthma, chronic obstructive pulmonary disease or
dermatological conditions are allowed provided doses are expected to be stable during the
study.
16. Subjects treated with systemic corticosteroids for indications other than SS, RA, and SLE
for more than a total of 2 weeks within 24 weeks prior to screening visit.
17. Use of the following medications:
a. Antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) if they have been
initiated or if the dose has changed within 8 weeks prior to signing the ICF or during
the screening period.
b. MTX, if the dose is > 20 mg/week; or if there is any change or initiation of new dose
within 4 weeks prior to signing the ICF through randomization (Day 1), or if there has
been any change in route of administration.
c. Azathioprine (AZA), if the dose is > 150 mg/day and there is any change or initiation
of new dose within 4 weeks prior to signing the ICF through randomization (Day 1)
and any change in route of administration.
d. Leflunomide, if the dose is >20 mg/day; or if there is any change or initiation of new
dose within 4 weeks prior to signing the ICF through randomization (Day 1).
e. Mycophenolate mofetil (MMF), if the dose is >2g/day; or if there is any change or
initiation of new dose within 4 weeks prior to signing the ICF through randomization
(Day 1).
f. Any other DMARD, immunosuppressant, or antiproliferative agents, if last dose was
taken within:
− 4 weeks prior to signing ICF or
− Drug-specific 5 half-lives elimination period (if longer than 4 weeks).
g. Any medication that, in the opinion of the Investigator, would interfere with
evaluation of the IP or interpretation of subject safety or study results.
h. Any increase or initiation of new doses of cevimeline or pilocarpine and cyclosporine
eye drops (Restasis®) within 2 weeks prior to signing the ICF through randomization
(Day 1).
18. Subjects who have received previous treatment with anti-CD40L compounds at any time
before screening.
19. Subjects with blood tests, at screening, of any of the following:
• Aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) > 2 x ULN
• Total bilirubin (TBL) > 2 x ULN
• Hemoglobin < 75 g/L
• Neutrophils < 1.0 x 109/L
• Platelets < 100 x 109/L
• Prothrombin or partial thromboplastin time (PTT) > ULN
Exclusion Criteria for Population #2
If an individual for Population #2 meets any of the following criteria, he or she is ineligible for
this study:
1. Patients with medical history of confirmed deep venous thrombosis or arterial
thromboembolism within 2 years of signing the ICF.
2. Patients with risk factors for venous thromboembolism or arterial thrombosis (eg,
immobilization or major surgery within 12 weeks before screening), prothrombotic status
(including, but not limited to, congenital or inherited deficiency of antithrombin III,
protein C, protein S, or confirmed diagnosis of catastrophic antiphospholipid syndrome).
3. Patients requiring treatment with anticoagulant drugs (clopidogrel, prasugrel, warfarin,
low molecular weight heparin, etc). Low-dose aspirin treatment (up to 325 mg/day) is
allowed.
4. Concomitant polymyositis or dermatomyositis or systemic sclerosis.
5. Active malignancy or history of malignancy, except as follows:
Module 5.3.5.1 Clinical Study Protocol VIB4920
VIB4920.P2.S2 - VIB4920 in Subjects with Sjögren’s Syndrome
Version 2.0 (21Jul2020)
CONFIDENTIAL AND PROPRIETARY Page 46 of 100
a. In situ carcinoma of the cervix treated with apparent success with curative therapy
> 12 months prior to screening; or
b. Cutaneous basal cell carcinoma treated with apparent success with curative therapy
6. Subjects who are pregnant or lactating or planning to get pregnant during the duration of
the study.
7. Subjects who have a positive test for, or have been treated for, hepatitis B, hepatitis C, or
HIV infection.
Regarding hepatitis B, a positive test for chronic hepatitis B infection at screening is
defined as detection of either (1) hepatitis B surface antigen (HBsAg); or (2) hepatitis B
core antibody (anti-HBc).
8. Subjects with:
a. A history of more than one episode of herpes zoster and/or opportunistic infections in
the last 12 months, with the exception of oral candidiasis, vaginal candidiasis, and
cutaneous fungal infections.
b. Active viral, bacterial or other infections requiring systemic treatment at the time of
screening or through randomization, or history of more than 2 infections requiring IV
antibiotics within 12 months prior to signing the ICF.
c. Epidemiologic risk of COVID-19 (recent exposures, high-risk housing) and for
health-related risk of COVID-19 severity based on current understanding of risk
factors for severe disease when making a decision regarding the individual subject’s
risk of participation. Subjects who have active COVID-19 infection or disease or
other significant infection, or, in the judgment of the investigator, who may be at
unacceptable risk of COVID-19 or its complications should not be randomized.
d. A documented positive SARS-CoV-2 test within 2 weeks prior to randomization.
Subjects with a positive test for SARS-CoV-2 may be rescreened at least 2 weeks
after a positive test if asymptomatic and at least 3 weeks after symptomatic COVID19 illness.
9. Subjects with known history of severe allergy or reaction to any component of the IP
formulation or to any other biologic therapy.
10. Subjects with any severe cardiovascular, respiratory, endocrine, gastrointestinal,
hematological, neurological, psychiatric, or systemic disorder or any other condition that,
in the opinion of the Investigator would interfere with evaluation of the IP or
interpretation of subject safety or study results.
11. Subjects who are unable or unwilling to comply with protocol requirements (eg, active
drug or alcohol abuse).
12. Subjects who have received live (attenuated) vaccine within the 4 weeks before ICF
signature.
13. Last administration of experimental biologic (other than those listed in Point 14) or oral
agents < 3 months or 5 half-lives before randomization.
14. Subjects who have had previous treatment with any biologic B cell-depleting therapy (eg,
rituximab, ocrelizumab, ofatumumab) within 12 months or other B-cell targeting therapy
(eg, belimumab) < 3 months before randomization.
15. Use of the following medications:
a. Antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) if they have been
initiated or if the dose has changed within 8 weeks prior to signing the ICF or during
the screening period.
b. Oral, intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to
signing the ICF through randomization (Day 1).
c. MTX, AZA, leflunomide, other cDMARD, or immunosuppressive or antiproliferative
medications, if last dose was taken within:
− 4 weeks prior to signing ICF or
− Drug-specific 5 half-lives elimination period (if longer than 4 weeks).
d. Any medication that in the opinion of the Investigator would interfere with evaluation
of the IP or interpretation of subject safety or study results
e. Any increase or initiation of a new dose of regularly scheduled nonsteroidal antiinflammatory drugs within 2 weeks prior to signing the ICF through randomization
(Day 1).
f. Any increase or initiation of new doses of cevimeline or pilocarpine and cyclosporine
eye drops (Restasis) within 2 weeks prior to signing the ICF through randomization
(Day 1).
16. Subjects who have received previous treatment with anti-CD40L compounds at any time
before screening.
17. Subjects with blood tests, at screening, of any of the following:
• AST > 2 x ULN
• ALT > 2 x ULN
• TBL > 2 x ULN
• Hemoglobin < 75 g/L
• Neutrophils < 1.0 x 109/L
• Platelets < 100 x 109/L
• Prothrombin or PTT > ULN