Role of PPAR-y Agonists in Immunomodulation and Vascular Prevention in SLE (PPAR-SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear cause that affects
primarily women of childbearing age. Patients with lupus have a significantly increased risk
of developing complications of their blood vessels due to accelerated hardening of the
arteries (atherosclerosis). These complications include heart attacks and stroke. No drug to
date has proven to prevent this type of complication in lupus and premature vascular disease
significantly impacts the quality of life of these patients and enhances their risk of death.

The thiazolidinediones (TZD) are a class of drugs approved for the treatment of patients with
type 2 diabetes mellitus (DM); they belong to the family of drugs that activate the
peroxisome proliferator-activated receptor-gamma (PPAR-gamma). They have been proposed to
have strong anti-atherogenic and anti-inflammatory effects even in patients without diabetes.
Recent work from our group and others indicates that TZDs significantly improve vascular
damage, dysfunction of blood vessels and disease activity in mouse models of lupus and
abrogate atherosclerosis. We recently identified the TZD pioglitazone as an effective drug in
modulation of vascular function and disease activity in patients with rheumatoid arthritis.
In addition, we have found in mouse models of lupus and in in vitro experiments with human
lupus cells, that pioglitazone has important roles in modulating immune function and vascular
manifestations. Furthermore, this drug is not immunosuppressive, adding an additional
advantage when compared to other medications used in this disease.

We propose that TZDs could significantly improve blood vessel function and play a role in
atherosclerosis prevention in human SLE, in addition to modifying lupus disease activity. The
major goal of the proposed research is to assess the effects of the PPAR-gamma agonist
pioglitazone in SLE on vascular function and inflammation and on SLE disease activity. The
results of the study may lead to the characterization of a new therapeutic target with dual
effects on lupus and its associated blood vessel damage

-INCLUSION CRITERIA:

1. For females and males 18 years old or older: females should be on adequate
contraception if they are of child-bearing potential, which should be documented by a
clinician, unless patients or their spouse/partner(s) have previously undergone a
sterilization procedure. Adequate contraception will be considered:

- Intrauterine device (IUD),

- Hormone implants,

- Injectable contraceptives,

- Oral contraceptives plus a barrier method (male condom, female condom or
diaphragm),

- Abstinence, or

- A vasectomized partner.

2. Meet revised ACR criteria and 2012 SLICC criteria for SLE and have: a) a baseline
SLEDAI-2K greater than or equal to 4 and <20 or a clinical SLEDAI-2K greater than or
equal to 2 (not considering anti-dsDNA or complement levels) and b) lack of BILAG A
flare at baseline.

3. Stable doses of immunosuppressants and/or antimalarials for at least 3 months, and/or
corticosteroids for at least 2 weeks. The prednisone dose may be increased after
screening visit as long as the total dose is less than 20 mg of prednisone or
equivalent per

day and the subject is on stable dose for at least 2 weeks prior to their Day 1 visit.
If on statins, should have been on stable doses for at least 6 months.

4. Allowed concomitant lupus-related medications

Antimalarials,

Prednisone greater than or equal to 20mg daily or equivalent doses of other
corticosteroids;

Immunosuppressants:

- Mycophenolate mofetil, up to 3000 mg/day,

- Methotrexate, up to 30 mg/week,

- Azathioprine, up to 3 mg/kg/day,

- Leflunomide, up to 20 mg/day,

- Cyclosporine, up to 5 mg/kg/day

- Tacrolimus, up to 0.1 mg/kg/day

NSAIDS and aspirin

Note: While it would be highly desirable to maintain corticosteroid dosage at constant
level for trial duration, it is impractical to anticipate that all patients with active SLE
can be maintained without therapy modification for an 8-month period. Because
corticosteroids are acceptable agents for treatment of the vast majority of minor lupus
flares, and patients with major flares (BILAG 2004 A or recent change in medications) will
be excluded, this will provide standardized treatment across study population that can be
easily analyzed. An increase in prednisone dose of less than or equal to <10 mg/day from
their prednisone dose at study entry will be permitted during the trial for increased
disease activity with a standardized taper allowable in small monthly decrements to the
patient s baseline dose or 5 mg/day, whichever is less.

EXCLUSION CRITERIA:

1. Pregnant or lactating women

2. Expected need for major surgery during trial.

3. Current or previous diagnosis of malignant disease, except for basal cell or squamous
cell carcinoma of the skin with complete excision and clear borders or adequately
treated in situ carcinoma of the cervix.

4. Acute infections identified during screening that require antibiotics. These subjects
would be eligible to participate following resolution of infection before Day 1 visit
within the allowed 46 days screening period. The subject will re-screen if it extends
beyond the

allowed 46 days screening period.

5. Chronic infections such as hepatitis B, hepatitis C, HIV or Tuberculosis.

6. Current use of cyclophosphamide or having received cyclophosphamide within the last
year.

7. Prior history of hemorrhagic cystitis or hematuria while receiving cyclophosphamide
that could not be explained by other causes.

8. Current use (within 3 months) of tocilizumab, rituximab, belimumab, intravenous
gammaglobulin or other biologic.

9. History of poor compliance with medical care, study visits and/or medication use.

10. Receipt of any investigational new drug or device within 30 days prior to screening or
5 half-lives of the agent (whichever is longer), or any investigational new drug
with known long-term effects.

11. Pioglitazone is not recommended in patients with symptomatic heart failure. Patients
with current heart failure (NYHA class II, III or IV) and/or a left ventricular
ejection fraction of <45% by echocardiogram at screening will be excluded.

12. 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.

13. Known hypersensitivity to TZDs

14. Serum hepatic transaminase levels > 2 times upper normal limit, or clinical evidence
of active liver disease at screening. The only exception is patients with confirmed
non-alcoholic fatty liver disease (NAFLD) where pioglitazone has been reported to have
a therapeutic role.

15. Diagnosis of DM or meeting DM criteria at screening visit, as established by new
classification criteria: Patients with diabetes are excluded because diabetes by
itself will induce profound changes in endothelial function and we want to assess the
effects of PPAR agonists in vascular risk beyond changes in insulin resistance.

16. Known latex allergy for EndoPAT test

17. Patients with severe Raynaud's phenomenon, history of finger ulcers or finger gangrene
will not undergo Endopat testing.

18. Patients with severe SLE at baseline, as quantified as SLEDAI-2K >20.

19. Patients with active lupus nephritis or active CNS lupus at baseline even if SLEDAI-2K
<20. Active disease will be considered as CNS or renal disease that require aggressive
immunosuppression. Active CNS disease will be diagnosed based on clinical presentation
and physical exam, exclusion of other conditions that could explain symptomatology
and, when warranted, ancillary tests (imaging) that support the diagnosis.

Patients that are not on induction therapy for lupus nephritis and have chronic (more
than 6 months), stable proteinuria <750 mg/gram in protein:creatinine ratio but
otherwise considered to have no evidence of active lupus nephritis (e.g. no cellular
casts and stable serum creatinine < 2 mg/dL) over the last 6 months, will be included
in the study.

In selected patients with potentially confounding clinical factors, consults will be
requested to help clarify the nature of any underlying renal disease that may affect
inclusion.

20. Postmenopausal women who have not undergone a DEXA scan over the last year will
undergo a DEXA scan at screening. Patients with a better than -2.5 will be included.
Postmenopausal women who have undergone a DEXA scan during the last year and have a T
score better than -2.5 will be included without repeating the DEXA scan prior to
enrollment. If the T score is worse than -2.5, they will be excluded from
participating unless the subject is willing to begin appropriate treatment for
osteoporosis by Visit Day 1. Postmenopausal women who have undergone a DEXA scan
during the last year, have a T score worse than -2.5 and are not on bisphosphonates or
other appropriate therapy will be excluded.