Sirolimus Injections for Autoimmune Scleritis

OBJECTIVE:

Scleritis is a chronic, painful and potentially blinding inflammatory disease characterized
by edema of the episcleral and scleral tissues and is commonly associated with systemic
autoimmune disorders. Sirolimus suppresses cytokine-driven T-cell proliferation and thus,
inhibits the production, signaling and activity of many growth factors relevant to
scleritis. Subconjunctival sirolimus administration could reduce or eliminate the need for
topical and/or systemic immunosuppressive drugs often taken with immunosuppressive disorders
that could result in reduced morbidity. The study objective is to investigate the safety,
tolerability and potential efficacy of subconjunctival sirolimus as a possible treatment for
active, autoimmune, non-necrotizing, anterior scleritis.

STUDY POPULATION:

Five participants with active, autoimmune, non-necrotizing, anterior scleritis with scleral
inflammatory grade ≥ 1+ in at least one quadrant will be initially enrolled. Participants
must have a history of past flares requiring oral non-steroidal anti-inflammatory drugs
(NSAIDS), or oral or topical corticosteroids or immunosuppressive medication. Up to seven
participants may be enrolled, as up to two participants may be accrued to account for
participants who withdraw from the study prior to receiving any investigational product.

DESIGN:

This is a phase I/II, single-center, open-label, non-randomized, prospective and
uncontrolled pilot study to evaluate the safety and possible efficacy of subconjunctival
sirolimus injections for active, autoimmune, non-necrotizing, anterior scleritis. If two
eyes are active, the eye with worse inflammation will be injected first (study eye) at
baseline followed two weeks later with injection of the second eye (fellow eye). If both
eyes have equal inflammation, the study eye will be chosen at the physician's discretion
after consultation with the participant. Participants that still demonstrate active
inflammation or experience a flare-up after the initial study eye injection may be eligible
for a re-injection at or after Week 4 (not to exceed a dose of 1,320 μg per eye within an
eight-week period).

OUTCOME MEASURES:

The primary outcome is the number of participants who experience at least a 2-step reduction
or reduction to grade 0 of scleral inflammation in the study eye according to a standardized
photographic scleritis grading system developed at the National Eye Institute (NEI) by the
Week 8 visit. Secondary outcomes include changes in visual acuity, step changes in scleral
inflammation, the number of participants who experience a disease flare, the number of
participants tapered from the standard immunosuppressive regimen after 16 weeks and, of the
participants who experience a disease flare, the number of days to disease flare from
baseline as well as the number of participants who require re-injection due to a flare.
Safety outcomes include the number and severity of systemic and ocular toxicities and
adverse events (AEs), the proportion of participants who experience vision loss ≥ 15 Early
Treatment Diabetic Retinopathy Study (ETDRS) letters and the number of participants who
experience a substantial rise in elevated intraocular pressure (IOP).

INCLUSION CRITERIA:

1. Participant has the ability to understand and sign the informed consent document.

2. Participant is 18 years of age or older.

3. Participant has a diagnosis of active, autoimmune, non-necrotizing, anterior
scleritis.

4. Participant, if currently taking immunosuppressive medications, is on a stable
regimen of immunosuppressive medications (no increase and/or start of new
immunosuppressive medications) over the last four weeks.

5. Participant has tried therapy such as oral non-steroidal anti-inflammatory drugs
(NSAIDs), or oral or topical corticosteroids or immunosuppressive medication at any
time in the past to control scleritis flares, or has intolerance or contraindications
to these medications.

6. Participant is willing and able to comply with the study procedures.

7. Female participants of childbearing potential must not be pregnant or breast-feeding,
have a negative pregnancy test at screening and must be willing to undergo pregnancy
tests throughout the study.

8. Both female participants of childbearing potential and male participants able to
father children must have (or have a partner who has) had a hysterectomy or
vasectomy, be completely abstinent from intercourse or must agree to practice two
acceptable methods of contraception throughout the course of the study and for four
months after the last investigational product injection. Acceptable methods of
contraception include: hormonal contraception (i.e., birth control pills, injected
hormones, dermal patch or vaginal ring), intrauterine device, barrier methods
(diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation).

EXCLUSION CRITERIA:

1. Participant has a significant active intraocular infection in either eye that
requires antibiotic treatment.

2. Participant has an active serious infection or a history of recurring serious
infections such as human immunodeficiency virus (HIV) or syphilis that in the best
medical judgment of the investigators would pose unnecessary risk to the participant.

3. Participant has active joint or systemic inflammation requiring immediate addition or
increase in systemic anti-inflammatory medications.

4. Participant is taking systemic azole anti-fungal medication (e.g., ketoconazole,
voriconazole, itraconazole).

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the
exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

1. Participant has anterior scleritis with greater than or equal to 1 plus in at least
one quadrant of the study eye.

2. Participant has visual acuity in the study eye of 20/640 or better.

3. Participant agrees not to undergo elective intraocular surgery in the study eye
(e.g., cataract extraction) for three months after the last injection.

4. Participant has not received a periocular or intravitreal injection in the study eye
in the last six weeks.

STUDY EYE EXCLUSION CRITERIA:

1. Participant has necrotizing scleritis in the study eye.

2. Participant had intraocular surgery in the study eye in the last four weeks.