Baricitinib in Relapsing Giant Cell Arteritis

Baricitinib, an orally administered, potent, selective and reversible inhibitor of JAK1 and
JAK2 has shown preliminary safety and efficacy in chronic, immune-mediated inflammatory
conditions such as rheumatoid arthritis and psoriasis. This small molecule is uniquely suited
as a potential novel therapeutic agent in GCA because of its suppressive effect on both the
Th17 (IL-6, IL-23) andTh1 (IL-12, IFN-γ) pathways.

This study will evaluate the safety and tolerability of baricitinib in a population of
patients with relapsing GCA. The study is an open-label pilot study assessing the safety and
tolerability of baricitinib (4 mg daily, oral, for 52 weeks) in addition to a standardized
glucocorticoid taper. It is anticipated that adjunct baricitinib will be safe and well
tolerated by patients with GCA and demonstrate preliminary efficacy as measured by reducing
inflammatory markers, decreasing steroid requirements and increasing relapse-free survival.

Inclusion Criteria:

1. Diagnosis of Giant Cell Arteritis (GCA) defined by the following Revised GCA Diagnosis
Criteria:

- Age ≥50 years.

- History of Erythrocyte Sedimentation Rate (ESR) ≥ 50 mm/hour or C-Reactive
Protein (CRP) ≥ 10 mg/L.

- Presence of at least one of the following:

- Unequivocal cranial symptoms of GCA (new onset localized headache, scalp or
temporal artery tenderness, otherwise unexplained mouth or jaw pain upon
mastication).

- Unequivocal symptoms of Polymyalgia Rheumatica (PMR), defined as shoulder
and/or hip girdle pain associated with inflammatory stiffness.

- Systemic inflammatory disease in which the presence of the fever (>38
degrees Celsius for ≥ 7 days), weight loss (> 5 pounds or 10% premorbid
weight), and/or night sweats were attributable to GCA and no other cause was
identified.

- Presence of at least one of the following:

- Temporal artery biopsy revealing features of GCA.

- Evidence of large-vessel vasculitis by angiography or cross-sectional
imaging, including but not limited to magnetic resonance angiography (MRA),
computed tomography angiography (CTA), positron emission tomography-computed
tomography (PET-CT) or evidence of large-vessel or temporal artery
vasculitis by ultrasound (US).

2. Relapse with active GCA within 6 weeks of study entry where active disease is defined
by an ESR ≥30 mm/hr or CRP ≥10 mg/L AND the presence of at least one of the following:

- Unequivocal cranial symptoms of GCA (new onset or recurrent localized headache,
scalp or temporal artery tenderness, otherwise unexplained mouth or jaw pain upon
mastication [i.e., jaw claudication]).

- Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain
associated with inflammatory stiffness.

- Other feature(s) judged by the clinician investigator to be consistent with GCA
or PMR flares (e.g. fever of unknown origin, weight loss, fatigue/malaise, etc.)

3. Clinically stable at baseline visit (study drug initiation) such that the subject is
able to safely participate in the standardized taper regimen in the opinion of the
investigator.

Exclusion Criteria

1. Presence of any other autoimmune disease (such as systemic lupus erythematosus,
rheumatoid arthritis, inflammatory arthritis, other vasculitides, scleroderma,
polymyositis, dermatomyositis, or other similar systemic connective tissue diseases).

2. Subjects demonstrating symptoms of visual loss (transient or permanent blindness) or
diplopia attributable to GCA.

3. Subjects with history of aortic dissection, myocardial infarction, or cerebrovascular
attack attributable to GCA.

4. Has received, or is expected to receive, any live virus vaccinations (with the
exception of herpes zoster vaccination) within 3 months before the first dose of study
drug, during the study, or within 3 months after the last administration of the study
drug. All patients who have not received the herpes zoster vaccine at screening will
be encouraged (per local guidelines) to do so prior to randomization; vaccination must
occur >4 weeks prior to randomization and start of investigational product. Patients
will be excluded if they were exposed to herpes zoster vaccination within 4 weeks of
planned randomization.

5. Organ transplant recipients.

6. Have had a major surgery within 8 weeks prior to screening or will require major
surgery during the study that, in the opinion of the investigator would pose an
unacceptable risk to the patient.

7. Have experienced any of the following within 12 weeks of screening: myocardial
infarction (MI), unstable ischemic heart disease, stroke, or New York Heart
Association Stage IV heart failure

8. Have a history or presence of cardiovascular (including but not limited to
uncontrolled hypertension), respiratory, hepatic, gastrointestinal, endocrine,
hematological, neurological, or neuropsychiatric disorders, or any other serious
and/or unstable illness that, in the opinion of the investigator, could constitute an
unacceptable risk when taking investigational product or interfere with the
interpretation of data.

9. Are largely or wholly incapacitated permitting little or no self-care, such as being
bedridden or confined to a wheelchair.

10. Have an estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73 m^².

11. Have a history of chronic liver disease with the most recent available aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of
normal (ULN) or the most recent available total bilirubin ≥1.5 times ULN (if
available).

12. Have a history of lymphoproliferative disease; or have signs or symptoms suggestive of
possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or
have active primary or recurrent malignant disease; or have been in remission from
clinically significant malignancy for < 5 years.

1. Subjects with uterine cervical carcinoma in situ that has been resected with no
evidence of recurrence or metastatic disease for at least 3 years may participate
in the study

2. Subjects with basal cell or squamous epithelial skin cancers which have been
completely resected with no evidence of recurrence for at least 3 years may
participate in the study.

13. Active infections, or history of recurrent infections or have required management of
acute or chronic infections as evidenced by any of the following:

1. Currently on any suppressive therapy for a chronic infection (such as
tuberculosis, cytomegalovirus, herpes simplex, herpes zoster, or atypical
mycobacteria).

2. History or suspicion of chronic infection (e.g. prosthetic joint infection)

3. Hospitalization for treatment of infection within 60 days of baseline visit

4. Use of parenteral (IV or IM) antimicrobials (antibacterial, antifungals,
antivirals, or antiparasitic agents) within 60 days of baseline or oral
antimicrobials within 30 days of baseline visit for treatment of an active
infection. This does not include the use of antibiotics for prophylaxis against
pneumocystis pneumonia since this is considered standard of care for patients on
prednisone ≥ 20 mg/day for longer than 3 consecutive months.

14. Have had symptomatic herpes zoster infection within 12 weeks prior to screening.

15. Have a history of disseminated/complicated herpes zoster [for example, multidermatomal
involvement, ophthalmic zoster or Central Nervous System (CNS) involvement]

16. In the opinion of the investigator, are at an unacceptable risk for participating in
the study.

17. Have known or documented diagnosis of human immunodeficiency virus (HIV).

18. Have known or documented primary immunodeficiency.

19. Have had household contact with a person with active tuberculosis (TB) and did not
receive appropriate and documented prophylaxis for TB.

20. Have had evidence of active TB or have previously had evidence of active TB and did
not receive appropriate and documented treatment.

21. Have evidence of latent TB as documented by a local lab positive QuantiFERON®-TB Gold
test and a normal chest x-ray, unless a patient completes at least 4 weeks of
appropriate treatment prior to study entry and agrees to complete the remainder of
treatment while in the trial.

1. If the QuantiFERON®-TB Gold test results are positive, the patient will be
considered to have latent TB and will be excluded. If the test is indeterminate,
the test may be repeated once within 2 weeks of the initial value. If the repeat
test results are again not negative, the subject will be considered to have
latent TB (for purposes of this study) and will be excluded.

2. Exceptions include subjects with a history of active or latent TB who have
documented evidence of appropriate treatment and with no history of re-exposure
since their treatment was completed. (Such subjects would not be required to
undergo the protocol specific TB testing, but would require a baseline chest
x-ray).

22. Have a positive test for Hepatitis B Virus (HBV) defined as:

1. Positive for hepatitis B surface antigen (HBsAg), or

2. Positive for anti-hepatitis B core antibody (HBcAb) If any of the Hepatitis B
tests have an indeterminate result, confirmatory testing will be performed by an
alternate method.

23. Have Hepatitis C Virus (HCV) (positive for anti-hepatitis C antibody with confirmed
presence of HCV).

24. Have any of the following specific abnormalities on screening tests:

1. ALT or AST > 2 x ULN

2. Total bilirubin ≥1.5 x ULN

3. Hemoglobin < 10 grams/deciliter

4. Total white blood cell count (WBC) < 2500 cells/μL)

5. Neutropenia (absolute neutrophil count [ANC] < 1200 cells/μL

6. Lymphopenia (lymphocyte count < 750 cells/μL)

7. Thrombocytopenia (platelets < 100,000 cells/μL)

8. eGFR < 50 mL/min/1.73m²

In the case of any of the aforementioned laboratory abnormalities, the tests may be
repeated once within approximately 2 weeks from the initial values, and values
resulting from repeat testing may be accepted for enrollment eligibility if they meet
the eligibility criterion.

25. Are pregnant or breast feeding at the time of screening or enrollment.

26. Are females of childbearing potential who do not agree to use 2 forms of highly
effective birth control when engaging in sexual intercourse with a male partner while
enrolled in the study and for at least 4 weeks following the last dose of the study
drug

1. Females of non-childbearing potential are defined as women ≥60 years of age,
women

≥40 but <60 years of age what had had cessation of menses for at least 12 months,
or whom who are congenitally or surgically sterile (that is have had a
hysterectomy, or bilateral oophorectomy or tubal ligation)

2. The following birth control methods are considered highly effective (the subject
should choose 2 to be used with their male partner

i. Oral, injectable, or implanted hormonal contraceptives ii. Condom with spermicidal
foam, gel film, cream or suppository iii. Occlusive cap (diaphragm or cervical/vault
caps) with a spermicidal foam, gel, film, cream or suppository iv. . Intrauterine
device v. Intrauterine system (for example progestin-releasing coil) vi. Vasectomies
male (with appropriate post-vasectomy documentation of the absence of sperm in the
ejaculate)

27. Are males who do not agree to use 2 forms of highly effective birth control (see
above) while engaging in sexual intercourse with females partners of childbearing
potential while enrolled in the study and for 4 weeks after the last dose of the study
drug.

28. Have donated more than a single unit of blood within 4 weeks prior to screening or
intend to donate blood during the course of the study.

29. Have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug above
within the 2 years prior to screening.

30. Have previously received baricitinib for other investigational study.

31. Are unable or unwilling to make themselves available for the duration of the study
and/or are unwilling to follow study restrictions/procedures

32. Are currently enrolled in, or discontinued within 4 weeks prior to screening from any
other clinical trial involving an investigational product or nonapproved use of a drug
or device or concurrently enrolled in any other type of medical research judged not to
be scientifically or medically compatible with this study.

33. Are investigator site personnel directly affiliated with this study and/or their
immediate families. Immediate family is defined as a spouse, parent, child, or sibling
whether biological or legally adopted.

34. Have a chronic medical illness requiring the use of oral of IV glucocorticoid
treatment (e.g. asthma or emphysema) during the trial or requiring long term
glucocorticoid treatment such that they would not be able to safely undergone a
standardized glucocorticoid taper.