Systemic Lupus Erythematosus (SLE)

Primary Efficacy Objective:  To evaluate the clinical efficacy of GDC-0853 in combination with SOC Secondary Efficacy Objectives:  To evaluate the clinical efficacy of GDC-0853 over time using the SRI-4 as a standardized disease activity measure  To evaluate if patients with high plasmablast signature levels have an enhanced clinical response to GDC-0853 relative to patients with low levels

GDC-0853

GDC-0853

tablet

50

Primary Outcome Measures :
Systemic Lupus Erythematosus Responder Index (SRI)-4 Response at Week 48 [ Time Frame: Week 48 ]
The Systemic Lupus Erythematosus Responder Index (SRI)-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity.

Secondary Outcome Measures :
SRI-4 Response at Week 48 With a Sustained Reduction of Oral Corticosteroids (OCS) Dose to Less Than (<)10 Milligrams Per Day (mg/Day) and Less Than or Equal to ( The SRI-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity. OCS tapering requires a sustained reduction of OCS from Week 36 through Week 48 [less than 10 milligram per day (mg/day) and less or equal to the dose received on Day 1].

SRI-4 Response at Week 24 With a Sustained Reduction of OCS Dose to < 10 mg/Day and The SRI-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity. OCS tapering requires a sustained reduction of OCS from Week 12 through Week 24 [less than 10 milligram per day (mg/day) and less or equal to the dose received on Day 1].

SRI-4 Response at Week 24 [ Time Frame: Week 24 ]
The SRI-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity.

SRI-4 Response at Week 48 in Patients With High vs. Low Plasmablast Signature Levels [ Time Frame: Week 48 ]
The SRI-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity. The Plasmablast Signature (PB) is a Bruton's Tyrosine Kinase (BTK)-dependent blood RNA signature comprised of three genes (IgJ, MZB1 and TXNDC5). Q1/2/3/4 = Quartile 1/2/3/4.

SRI-4 Response With a Sustained Reduction of OCS Dose to ≤ 10 mg/Day and ≤ Day 1 Dose During Week 36 Through 48 in Patients With High vs. Low Plasmablast Signature Levels [ Time Frame: Week 48 ]
The SRI-4 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥4 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity. The Plasmablast Signature (PB) is a Bruton's Tyrosine Kinase (BTK)-dependent blood RNA signature comprised of three genes (IgJ, MZB1 and TXNDC5). Q1/2/3/4 = Quartile 1/2/3/4.

SRI-6 Response at Week 24 and 48 [ Time Frame: Week 24, 48 ]
The Systemic Lupus Erythematosus Responder Index (SRI)-6 measures reduction in SLE disease activity and is a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 2004 and Physician Global Assessment. It is defined as: 1) Reduction of ≥6 points from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score; 2) no new British Isles Lupus Assessment Group (BILAG) A or no more than 1 new BILAG B disease activity scores and 3) no worsening (defined as an increase of ≥0.3 points [10 mm] from baseline) in the Physician's Global Assessment of Disease Activity. The score range is from 0 to 100, with higher scores indicating greater disease activity.

BILAG-based Composite Lupus Assessment (BICLA) Response at Week 24 and 48 [ Time Frame: Week 24, 48 ]
The BICLA is a composite index that is defined as follows: [1] At least one gradation of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (e.g., all A (severe disease) scores falling to B (moderate), C (mild), or D (no activity) and all B scores falling to C or D; [2] No new BILAG A or more than one new BILAG B scores; [3] No worsening of total SLEDAI-2K score from baseline; [4] No significant deterioration (=<10%) in physician's global assessment and [5] No treatment failure (initiation of non-protocol treatment).

Percentage of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to 8 weeks after the last dose of study drug (up to Week 56). ]
An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Plasma Concentrations of Fenebrutinib at Specified Timepoints [ Time Frame: Baseline (Pre-dose), Week 24 (Pre-dose and Post-dose) and Week 48 (Pre-dose) ]
The PK analyses includes tabulation of plasma concentration data and summarisation of plasma concentrations by visits with participants grouped according to treatment received. Descriptive summary statistics for the Arithmetic Mean and Standard Deviation are presented below.

Inclusion Criteria
Patients must meet the following criteria for study entry:
• Signed Informed Consent Form
• Age 18−75 years, inclusive
• Able to comply with the study protocol
• Fulfillment of SLE classification criteria according to either the current American College of
Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) criteria
at any time prior to or at screening
• At least one serologic marker of SLE at screening as follows:
− Positive antinuclear antibody (ANA) test by immunofluorescent assay with titer ≥ 1:80; OR
− Positive anti-double-stranded DNA (anti-dsDNA) antibodies; OR
− Positive anti-Smith antibody
• At both screening and Day 1, moderate to severe active SLE, defined as meeting all of the following:
− Safety of Estrogen in Lupus Erythematosus National Assessment- Systemic Lupus
Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥ 6 (with clinical
SELENA-SLEDAI score ≥ 4.0)
− Physician’s Global Assessment ≥ 1.0 (out of 3)
− Currently receiving at least one standard oral treatment for SLE
• If on an OCS, the dose must be ≤ 40 mg/day prednisone (or equivalent) and must have
been stable for at least 2 weeks prior to screening as well as during screening
• If on anti-malarial or immunosuppressive therapies, may only be receiving medications from
the following list within the specified dose range; dose and route of administration must be
stable for 8 weeks prior to screening as well as during screening:
− Azathioprine: 1 to 2.5 mg/kg/day
− Methotrexate: 7.5 to 25 mg/week
− Mycophenolate mofetil: 500 to 2500 mg/day
− Mycophenolic sodium: 360 to 1800 mg/day
− Hydroxychloroquine: 200 to 400 mg/day
− Chloroquine: 100 to 250 mg/day
Note: Any combination of azathioprine, methotrexate, mycophenolate mofetil, or
mycophenolic sodium is prohibited.
• For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1%
per year during the study treatment period and for a minimum of 60 days after the last dose
of study drug or longer as required by local requirements for other standard of care
medications. Women using estrogen-containing hormonal contraceptives as a method of
contraception must also use a barrier.
− A woman is considered to be of childbearing potential if she is postmenarcheal, has
not reached a postmenopausal state (> 12 continuous months of amenorrhea with no
identified cause other than menopause), and has not undergone surgical sterilization
(removal of ovaries and/or uterus).
− Examples of contraceptive methods with a failure rate of < 1% per year include bilateral
tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper
intrauterine devices. Established proper use of hormonal contraceptives that inhibit
ovulation also have a failure rate of < 1% per year; however, women using estrogencontaining hormonal contraceptives as a method of contraception must also use a
barrier, such as a male condom, in conjunction with the hormonal contraceptives.
− The reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and
withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm as defined below:
− Men with female partners of childbearing potential must remain abstinent or use a
condom plus an additional contraceptive method that together result in a failure rate of
< 1% per year during the treatment period and for at least 120 days (16 weeks) after
the last dose of study treatment. Men must refrain from donating sperm during this same period.
− Men with pregnant female partners must remain abstinent or use a condom during the
treatment period and for at least 28 days after the last dose of study treatment to avoid exposing the embryo.
− The reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and
withdrawal are not acceptable methods of contraception.

Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
• Evidence of lupus nephritis as demonstrated by the presence of any of the following:
− Spot urine protein:creatinine ratio > 3.5 based on a first morning urine (in mg/mg) at
screening
− Active urinary sediment as evidenced by SLE-related hematuria in the absence of
menses or an infection (> 5 red blood cells [RBCs]/high-power field [HPF] or
> 10 RBCs/μL), pyuria (> 5 white blood cells [WBCs]/HPF or > 10 WBCs/μL or WBC
casts in absence of infection), or red cell casts at any time within the 24 weeks prior to
or during screening; for female patients without prior samples who are menstruating at
the time of screening, this sample may be obtained later in the screening period
− History of class III or IV lupus nephritis on renal biopsy within 24 weeks of screening
− Increase in urine protein:creatinine ratio to > 0.5 or doubling of proteinuria to a urine
protein:creatinine ratio > 1.0 in the absence of any other explanation besides SLE
within 24 weeks prior to or during screening
− Sustained increase (for at least 12 weeks) in serum creatinine by at least 30% within
12 weeks prior to or during screening or acute unexplained increase in serum
creatinine by at least 30% within 12 weeks prior to or during screening
− Other evidence of active lupus nephritis, as judged by the physician, that requires
treatment with OCS and/or other immunosuppressants not permitted in the study or at
doses higher than permitted (e.g., as proposed by the ACR or European League
Against Rheumatism [EULAR]/European Dialysis and Transplant Association
[EDTA]/European Renal Association [ERA] recommendations
• Neuropsychiatric or central nervous system lupus manifestations, including but not limited
to: seizure, psychosis, or acute confusional state within 52 weeks of screening
• Estimated glomerular-filtration rate (based on the 4-variable Modification of Diet in Renal
Disease equation) < 30 mL/min or on chronic renal replacement therapy
• History of receiving a solid organ transplant
• Newly diagnosed (within the last 24 weeks) transverse myelitis
• History of anti–phospholipid antibody syndrome with or without associated consumptive
coagulopathy [catastrophic anti-phospholipid syndrome] at any time); presence of
anti-phospholipid antibodies or a history of fetal loss, but without a history of
thromboembolism or current requirement for anti-coagulation, are not exclusionary (Note:
Patients on low-dose aspirin (≤ 162 mg/day) are not excluded.)
• Evidence of active, latent, or inadequately treated infection with Mycobacterium tuberculosis
(TB) as defined by all of the following:
− A negative QuantiFERON TB-Gold® (QFT) or, if QFT unavailable, a Mantoux purified
protein derivative (PPD) skin test (performed per Centers for Disease Control and
Prevention [CDC] guidelines using 5 tuberculin units per 0.1 mL) result of < 5 mm of
induration, performed at the screening visit or within the 12 weeks prior to screening
− Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should be
screened using the QFT test only.
− An indeterminate QFT test should be repeated.
− A positive QFT test or two successive indeterminate QFT results should be considered
a positive diagnostic TB test.
− An indeterminate QFT test followed by a negative QFT test should be considered a
negative diagnostic TB test.
− A chest radiograph taken at the screening visit or documented results within the
12 weeks prior to screening (chest X-ray must be read by a radiologist), without
changes suggestive of active TB infection
− If a patient has previously received an adequate documented course of therapy for
either latent (36 weeks of isoniazid in a locale where rates of primary multi-drug
resistant TB infection are < 5% or an acceptable alternative regimen, according to
local guidelines) or active (acceptable multi-drug regimen, according to local
guidelines) TB infection, neither a PPD test nor a QFT test need be obtained, but a
chest radiograph must still be obtained if not performed within the prior 12 weeks; this
chest radiograph must be without changes suggestive of active TB infection
• Women who are pregnant or nursing (breastfeeding; within the last 12 weeks), or women
intending to become pregnant, donate eggs or breast milk, or participate in in vitro
fertilization during the study
− For women of childbearing potential: Positive serum pregnancy test result at screening
or on Day 1 (a serum pregnancy test is needed on Day 1 ONLY if the urine pregnancy
test is positive)
• Significant and uncontrolled medical disease within the 12 weeks prior to screening in any
organ system (e.g., cardiac, neurologic, pulmonary, renal, hepatic, endocrine [including
uncontrolled diabetes mellitus], metabolic, gastrointestinal [GI], or psychiatric [including
suicidality]) not related to SLE, which, in the investigator’s or Sponsor’s opinion, would
preclude patient participation
• Concomitant chronic conditions, in addition to SLE, (e.g., asthma, Crohn’s disease) that
required oral, intravenous (IV), or intramuscular (IM) steroids or immunosuppressive use in
the 24 weeks prior to screening or are likely to require these during the course of the study
• History of non-gallstone−related pancreatitis or chronic pancreatitis
• Evidence of autoimmune myositis
• History of cancer, including hematological malignancy and solid tumors, within 10 years of
screening; basal or squamous cell carcinoma of the skin that has been excised and is
considered cured and in situ carcinoma of the cervix adequately treated by curative therapy
more than 1 year prior to screening are not exclusionary
• History of alcohol, drug, or chemical abuse within the 1 year prior to screening as
determined by the investigator
• Major surgery requiring hospitalization within 4 weeks of screening
• History of cerebrovascular accident (CVA) within 10 years or any history of hemorrhagic
CVA
• Any history of spontaneous intracranial hemorrhage or a history of traumatic intracranial
hemorrhage within 10 years
• History of clinically uncontrolled cardiac arrhythmias
• Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant
abnormalities that may affect patient safety or interpretation of study results, including
− QT interval corrected using Fridericia’s formula (QTcF) > 450 msec for female patients
and > 430 msec for male patients demonstrated by at least two ECGs > 30 minutes
apart
• History of clinically significant ventricular dysrhythmias or risk factors for ventricular
dysrhythmias such as long QT syndrome or other genetic risk factors (e.g., Brugada
syndrome), structural heart disease (e.g., severe left ventricular systolic dysfunction, severe
left ventricular hypertrophy), coronary heart disease (symptomatic, or with ischemia
demonstrated by diagnostic testing, prior coronary artery bypass grafting, or coronary
lesions > 70% diameter stenosis that have not been or cannot be re-vascularized), or family
history of sudden unexplained death or cardiac ion channel mutations
• Current treatment with medications that are well known to prolong the QT interval with the
exception of chloroquine
• Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant
diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass);
procedures, such as gastric banding, that simply divide the stomach into separate
chambers are not exclusionary
• Need for systemic anticoagulation with warfarin, other oral or injectable anticoagulants, or
anti-platelet agents (e.g., clopidogrel) other than nonsteroidal anti-inflammatory drugs
(NSAIDs), aspirin (≤ 162 mg/day), or other salicylates
• Known bleeding diathesis
• Any history of hospitalization or transfusion for a GI bleed
• History of or currently active primary or secondary immunodeficiency, including known
history of HIV infection or IgG < 500 mg/dL
• Any known active infection during screening up to and including at the time of enrollment
(with the exception of fungal nail infections or oral herpes)
• History of recurrent bacterial, viral, mycobacterial, or fungal infections, defined as > 2 similar
episodes requiring anti-microbial treatment within the past 52 weeks, with the exception of
recurrent oral or genital herpes (herpes simplex virus 1 [HSV1]/ herpes simplex virus 2
[HSV2])
• Any history of opportunistic infections that, in the Investigator's or Sponsor’s judgment,
would raise safety concerns regarding the patient's participation in the study
• Any major episode of infection requiring hospitalization or treatment with IV or IM
antimicrobials within 4 weeks prior to or during screening or treatment with oral
antimicrobials within 2 weeks prior to and during screening (with the exception of
prophylaxis for Pneumocystis jiroveci pneumonia)
• History of severe and/or disseminated viral infections, particularly herpes viruses, such as
HSV1, HSV2, varicella zoster virus (VZV), cytomegalovirus (e.g., herpes encephalitis,
ophthalmic herpes, disseminated zoster, cytomegalovirus colitis); uncomplicated influenza
during a flu season is not exclusionary
• Evidence of chronic and/or active hepatitis B or C
− Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless of
treatment status)
− Positive hepatitis B core antibody (HBcAb)
• Received any of the following medications within the indicated period of time:
− Plasmapheresis or IV Ig in the last 12 weeks
− B cell–depleting therapy (e.g., anti-CD20 or anti-CD19) within 24 weeks prior to
screening
− Belimumab, blisibimod, tabalumab (or other anti-B-cell activating factor [BAFF] agents),
atacicept (or other anti-transmembrane activator and calcium-modulator and
cyclophilin ligand [CAML] interactor [TACI] agents), epratuzumab (or other anti-CD22
agents), or denosumab within 24 weeks prior to screening
− Cyclophosphamide or other alkylating agents within 12 weeks prior to screening
− Oral cyclosporine, dapsone, tacrolimus, topical calcineurin inhibitors, anakinra (inhibitor
IL-1), sirolimus (inhibitor IL-2), or other calcineurin inhibitors within 4 weeks prior to
screening
− Thalidomide or thalidomide derivatives within 24 weeks prior to screening
− Tumor necrosis factor (TNF)-antagonists, tocilizumab, or other biologics not previously
mentioned above within 90 days prior to screening
− Any investigational drug within 4 weeks or 5 half-lives, whichever is longer, of
screening
− Any parenteral (IV), IM, or intra-articular steroid administration within 30 days prior to
screening
− Any other immunosuppressive medication for SLE not listed in the inclusion criteria,
within 12 weeks or 5 half-lives prior to screening, whichever is longer, unless approved
by the Medical Monitor
− Live vaccines within 6 weeks prior to randomization; seasonal influenza and H1N1
vaccination are permitted if the inactivated vaccine formulation is administered
• Use of any of the medications, herbal supplements, or foods listed below or in the
Pharmacy Manual within 1 week or 5 half-lives, whichever is longer, prior to screening, on
the basis of possible drug interactions with GDC-0853 (the screening period may be
extended to meet this criteria if approved by the Medical Monitor):
− Moderate and strong CYP3A inhibitors, including but not limited to erythromycin,
itraconazole, verapamil, nefazodone, and grapefruit juice
− CYP3A inducers, including but not limited to rifampin, St. John’s wort, carbamazepine,
pioglitazone, modafinil, and bosentan
− Sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index,
including but not limited to dronedarone, felodipine, ticagrelor, simvastatin, lovastatin,
ergotamine, sildenafil, and quetiapine
• Any uncontrolled, clinically significant, laboratory abnormality that would affect safety,
interpretation of study data, or the patient’s participation in the study
• Any of the following laboratory results, for which testing may be repeated once if the initial
results are out of range during screening:
− Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN
− Total bilirubin > 1.2 ULN
− Amylase or lipase > 2 × ULN
− Hemoglobin < 7 g/dL
− Absolute neutrophil count (ANC) < 1.5 × 109/L
− Absolute lymphocyte count (ALC) < 0.5 × 109/L
− Platelet count < 50,000/μL