Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Systemic Lupus Erythematosus

BACKGROUND:

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with variegated clinical
presentation resulting from involvement of multiple biologic pathways. The pathways that lead
to loss of tolerance in SLE include: multiple autoreactive cell types (B, T, dendritic, Th17
and regulatory T cells) and abnormal cytokine milieus, genetic factors, environmental and
hormonal influences, all of which can influence cell differentiation patterns and reset
tolerance checkpoints. In addition, recent studies indicate a putative role for neutrophils
in lupus pathogenesis and associated end-organ damage. Currently available therapeutics are
frequently inadequate to treat disease flares and simultaneously expose patients to
potentially serious toxicities. Further, premature cardiovascular disease not explained by
the Framingham risk equation has become one of the most important causes of morbidity and
mortality in this patient population. To date, no treatment used in lupus appears to
significantly decrease cardiovascular risk. Identifying a drug that has immunomodulatory
effects and is also vasculoprotective is an unmet need in this disease.

Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has recently been
approved by the Food and Drug Administration for the treatment of moderate to severe
rheumatoid arthritis (RA).

The JAKs are a family of intracellular enzymes (JAK1, 2 and 3 and TYK2) that mediate
signaling via a broad range of cytokine receptors. Targeting JAKs is an attractive
therapeutic possibility for SLE for many reasons. Many of the inflammatory cytokines
implicated in the pathogenesis of SLE signal via the JAK-STAT pathways. JAK inhibitors have
been found to have efficacy in various murine models of lupus. Mice treated with a JAK2
inhibitor exhibited reduced serum levels of IL-6, and IL-17 along with reduced numbers of
long-lived autoantibody producing plasma cells in the spleen and bone marrow. Furthermore, we
have found that administration of tofacitinib reduced serum levels of ANA, IL-6, and
IFN-gamma; and ameliorated glomerulonephritis (unpublished data).

This study therefore represents an innovative investigative measure of the safety and
efficacy of JAK inhibition in SLE that is predicted by genetic predisposition. We will also
investigate effects of tofacitinib on vascular function in SLE subjects and identify
biomarkers that may be useful as endpoints in future studies.

PRIMARY OBJECTIVE:

To determine the safety and tolerability of tofacitinib in patients with SLE and mild to
moderate disease activity.

STUDY DESIGN:

This is a Phase Ib, randomized, double blind, placebo controlled clinical trial of orally
administered tofacitinib, 5 mg twice daily, for the treatment of SLE subjects with mild to
moderate disease activity stratified by the presence or absence of STAT4 risk alleles.

- INCLUSION CRITERIA:

- Subject is capable of providing written informed consent.

- Subject is greater than or equal to 18 years old.

- Meets at least 4 of 11 modified American College of Rheumatology (ACR) (1997) Revised
Criteria for the Classification of Systemic Lupus Erythematosus.

- Has mild to moderate disease activity defined as a SLEDAI 2K more than or equal to 2
and less than or equal to 14 at the screening visit.

- If on glucocorticoids, the dose must be less than or equal to 20 mg daily and stable
for the 4 weeks prior to screening visit.

- If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, the
dose must have been stable for the 12 weeks prior to screening visit. The maximum
allowed dose is hydroxychloroquine up to 400 mg/day or 6.5 mg/kg/day if more than 400
mg/day. The maximum allowed dose for chloroquine phosphate is up to 500 mg daily and
for quinacrine up to100 mg daily.

- Males and females with potential for reproduction must agree to practice effective
birth control measures. Females should be on adequate contraception if they are of
child-bearing potential documented by a clinician, unless patients or spouse have
previously undergone a sterilization procedure. Adequate will be considered
intrauterine device (IUD) alone or hormone implants, hormone patches, injectables, or
oral contraceptives plus a barrier method (male condom, female condom or diaphragm),
abstinence or a vasectomized partner

- If patients are on ACE inhibitors or ARB medications, dose of this medication must be
stable for 4 weeks prior to study entry.

- Patients may be on lipid lowering medications if initiated at least 6 months prior to
the screening visit.

EXCLUSION CRITERIA:

- Pregnant or lactating women. Women of childbearing potential are required to have a
negative pregnancy test at screening.

- Current or prior treatment with rituximab, belimumab or any other biologic agent in
the 6 months prior to screening.

- Current treatment with immunosuppressive drugs (methotrexate, azathioprine,
mycophenolate mofetil, cyclosporine, tacrolimus). Glucocorticoids are allowed as per
the inclusion criteria. At the investigator s discretion, glucocorticoids may be
tapered during the study.

- Patients previously on methotrexate, mycophenolate mofetil, cyclosporine or tacrolimus
should have stopped it for at least 8 weeks at the time of screening.

- Treatment with cyclophosphamide, pulse methylprednisolone or IVIG within the 6 months
prior to screening.

- Increase in glucocorticoid dose within 4 weeks of screening.

- A history of drug or alcohol abuse within the 6 months prior to screening.

- History of chronic liver disease or elevated LFTs:

- ALT or AST greater than or equal to 2x upper limit of normal at screening

- serum unconjugated bilirubin > 2mg/dL at screening

- Dialysis or serum creatinine >1.5mg/dL.

- Protein to creatinine ratio of more than 1 mg/mg or 24 hours urine protein of more
than 1000 mg.

- Active urinary sediment (WBC, RBC or mixed cellular casts 1+ or more /hpf).

- Hypercholesterolemia: Values after an 8-12 hour fasting blood specimen: total
cholesterol >250 mg/dL or LDL >180 mg/dl or hypertriglyceridemia (triglyceride >300
mg/dL) within plus or minus 45 days of screening visit.

- Active infection that requires the use of oral or intravenous antibiotics and has not
resolved at least 2 weeks prior to the administration of the first dose of study
medication.

- Active chronic infections including but not limited to HIV, Hepatitis B, Hepatitis C,
and BK viremia at screening visit.

- History of cancer.

- Known active tuberculosis or untreated latent tuberculosis.

- History of opportunistic infections.

- Subjects with active renal or central nervous system disease or a BILAG A in any organ
system.

- WBC <2500/Microlitre or ANC <1,000/Microlitre, Hgb <9.0 g/dL or platelets
<70,000/Microlitre or absolute lymphocyte count < 500/Microlitre.

- Current treatment with potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g.,
ketoconazole) or receiving one or more concomitant medications that result in both
moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole)
that would increase serum availability of tofacitinib. Past treatment with the above
mentioned agent is allowed if it was more than a week prior to the administration of
the first dose of study medication.

- Significant impairment of major organ function (lung, heart, liver, kidney) or any
condition that, in the opinion of the Investigator, would jeopardize the subject s
safety following exposure to the study drug.