A Clinical Study to Evaluate the Potential Role of ACTH Gel in Patients With Scleritis

ATLAS is an Investigator-initiated, open-labelled, multi-center, randomized, phase II
clinical trial, to evaluate the effect of two dose regimens of subcutaneous ACTH gel in
subjects with non-infectious anterior scleritis over a period of 12 months (52 weeks), with
the primary endpoint at month 4 (week 16). ATLAS study will be conducted at up to 6 clinical
sites in USA. The study will be coordinated by the Ocular Imaging Research and Reading Center
(OIRRC), which will serve as the coordinating and reading center for the ATLAS Study.

The ATLAS Study aims to evaluate the potential role of subcutaneous adrenocorticotropic
hormone (ACTH) gel, in the management of non-infectious anterior scleritis. Specifically, the
ATLAS Study aims to evaluate the safety and tolerability of 2 different dose regimens of ACTH
gel administered by subcutaneous (SC) injection in patients with non-infectious anterior
scleritis and to evaluate the bioactivity of 2 different dose regimens of ACTH gel
administered by SC injection in patients with non-infectious anterior scleritis.

Scleritis refers to red and painful inflammation, centered in the sclera that may involve
adjacent ocular structures including the cornea, episclera and uvea. Scleritis may results in
vision threatening ocular complications (corneal ulceration, cataract, glaucoma, retinal
detachment, choroidal effusion) and subsequent blindness. Up to 50% of patients with
scleritis have an associated systemic inflammatory disorder, such as sarcoidosis, rheumatoid
arthritis, systemic lupus erythematosus, and polyangiitis with granulomatosis. Scleritis is
classified based on the anatomic site, as anterior or posterior, with 90% of cases anterior.
Anterior scleritis may manifest as necrotizing or non-necrotizing. Non-necrotizing,
noninfectious scleritis is the most prevalent form. The course of scleritis is usually
chronic, similar to uveitis, and requires systemic therapy with non-steroidal
anti-inflammatory drugs and glucocorticoids, along with immunosuppression, as steroid-sparing
therapy. Due to its treatment resistance nature, scleritis remains a therapeutic challenge
for many ophthalmologists. The ultimate goal is to control the inflammation, which serves as
the cornerstone of the scleritis pathophysiological basis.

Adrenocorticotropic hormone (ACTH) is a member of a group of peptide hormones, called
melanocortins (MCs). ACTH is released from the pituitary gland and acts primarily on the
adrenals to stimulate and regulate steroid hormones production. It has been demonstrated that
MCs can be produced by immune cells at the inflammation site, which created a special
interest in immunomodulatory properties of these peptides. Latest evidence proposes other
anti-inflammatory mechanisms of ACTH actions in addition to steroidogenesis, including
leukocyte transmigration inhibition, cytokine synthesis reduction and generation of
anti-inflammatory signals locally at the inflammation site. ACTH gel has been reported to be
effective in various systemic inflammatory diseases including nephrotic syndrome, multiple
sclerosis, opsoclonus myoclonus,dermatomyositis and polymyositis. These reports also include
cases that were resistant to steroids and other immunomodulatory drugs, supporting the
immune-modulating properties of ACTH. H.P. Acthar® Gel (Repository Corticotropin Injection,
Mallinckrodt Pharmaceuticals) is a 39-amino-acid, pituitary-derived ACTH analogue. ACTH gel
has been demonstrated to have additional therapeutic effects on the humoral immune system,
independent of its role in the adrenal steroidogenesis regulation. It is approved by the US
FDA for treatment of a number of inflammatory conditions, including multiple sclerosis,
rheumatic and collagen disorders, as well as ophthalmologic diseases, such as ocular allergy,
keratitis, uveitis and optic neuritis. However, due to the scarcity of data from clinical
studies, many physicians are unaware of ACTH gel as a treatment option for inflammatory
diseases.

The proposed study aims to evaluate the potential role of ACTH gel in the management of
non-infectious anterior scleritis. Given the established role of inflammation in the
pathogenesis of scleritis and the ability of ACTH to bind to cellular and tissue melanocortin
receptors, thus blocking various inflammatory pathways, a beneficial outcome could be
anticipated from ACTH analogue in patients with scleritis.

Thirty (30) subjects with non-infectious anterior scleritis will be enrolled in the study.

The primary endpoint of the study will be at week 16, with an active, as-needed treatment
extension phase from week 17 to week 52.

All study participants will be randomized (1:1) at their Baseline (BL) visit (visit 2) to one
of the two treatment arms. All subjects will be started on oral corticosteroids (at a maximum
dosage of 1 mg/kg of prednisone or equivalence a day) at the screening visit which will
continue to be administered at the same dose throughout the screening period until BL/Visit
2. Steroid dose will be tapered from BL/Visit 2 onwards until week 9 (Visit 5). If the
scleritis is still greater than 0.5+ on the grading scale, the investigators have the
discretion to continue on the tapering course of steroid while the subjects are also being
treated with ACTH gel.

The two treatment arms are as follows:

1. Mandatory 80 U twice weekly treatment with SC ACTH gel, starting at the Baseline visit
(Day 0) until end of week 16.

2. Mandatory 80 U thrice weekly treatment with SC ACTH gel, starting at the Baseline visit
(Day 0) until end of week 16.

Starting at week 17, treatment regimen will be determined according to clinical response to
treatment as follows:

1. No evidence of active disease/disease resolved - treatment dose will be reduced to 80 U
once a week with SC ACTH gel.

2. Evidence of disease improvement, but still active/partial response - ACTH treatment will
continue alone at the pre-assigned treatment dose. Steroids will not be added to the
treatment due to several side effects of the combination of the drugs.

3. No evidence of improvement/disease progression - treatment with ACTH gel will be
discontinued and rescue therapy will be initiated as per investigator based on standard
of care.

At the primary end point (week 16) and at the end of follow-up period (week 52) efficacy will
be assessed by standard ophthalmic examination procedures and response to treatment, which
will be graded according to established scleritis grading scale. Evaluation of response will
be based on changes in scleral inflammation grade at various time points during the study,
changes in pain grade scale at various time points during the study, changes in the dosage of
prednisone required to maintain disease quiescence and stability and changes on ancillary
testing such as FA, OCT, among others. Retreatment will be offered to study subjects who have
demonstrated any level of response during the first 16 weeks and who meet any of the
Retreatment Criteria listed below. Subjects receiving retreatment will receive the dose that
was assigned to them at randomization. There is no placebo arm in this study.

Inclusion Criteria:

- Adults, age ≥ 18 years;

- Able to give informed consent and attend all study visits;

- Have diagnosis of non-necrotizing scleritis determined by the Investigator to be
non-infectious;

- Have active scleirits, defined as:

- Characteristic clinical presentation of active disease: painful inflammation, edema
and tenderness to touch radiating to the forehead, the brow, the jaw, or the sinuses.
Severity of pain associated with scleritis will be based on pain intensity, NRS scale.

- Scleral inflammation ranging from +1 to +3 as assessed by central reading center based
on standardized scleritis grading scale.

and:

- are receiving no other treatment; or,

- are receiving prednisone (or equivalent dose of another corticosteroid) and/or at
least 1 other systemic immunosuppressant;

- Have anterior scleritis.

- Sufficient inflammation to require systemic treatment or long-term regional treatment.

- Subjects whom the investigators feel may only need short-term topical therapy should
not be enrolled.

- Best-corrected visual acuity (ETDRS method) of 20/20 to 20/400 in the study eye;

- Best- corrected visual acuity (ETDRS method) of 20/400 or better in the fellow eye

- Must have a chest radiograph within 3 months prior to enrollment with no evidence of
malignancy, infection or fibrosis.

- Females of childbearing potential must have a negative urine pregnancy test at
screening. In addition, sexually active females of childbearing potential must agree
to use TWO of the following adequate forms of contraception while on study medication:
oral, injectable, or implantable hormonal contraceptives; tubal ligation; intrauterine
device; barrier contraceptive with spermicide; or vasectomized partner.

- Males must agree to use barrier contraception (latex condoms) when engaging in sexual
activity while on study medication and for 28 days after taking the last dose of study
medication.

- Prior to study screening, potential subjects must have been evaluated and screened for
infectious etiologies by the investigators, possibly as part of standard clinical
acre; all testing to rule out infectious causes must be performed within 3 months of
screening for the ATLAS study.

- Currently active and uncontrolled scleritis, that at the determination of the
investigator, requires the initiation of corticosteroid monotherapy (or equivalent),
or prednisone therapy and immunomodulatory therapy or injections of corticosteroid
(periocular); or scleritis in subjects for whom oral corticosteroid is
contraindicated, relatively or absolutely.

- Evidence of active non-infectious scleral inflammation that at the determination of
investigator requires therapy. Such evidence can be documented by clinical
examination, photography, or ancillary testing (e.g. B-scan ultrasonography,
fluorescein angiography, optical coherence tomography). As long as the investigator
determines that the degree of inflammation can be monitored for regression or
progression, the inflammation criterion can be met.

- Not planning to undergo elective ocular surgery during the first 6 months of the
study.

- Subjects who have developed scleritis as ocular manifestation of an underlying
systemic disease can be enrolled in the study only if the systemic therapy will not be
altered throughout the study span. If at any point during the study, the ongoing
systemic therapy needs to be altered (e.g. increase in the dose), the subject will
have to exit the study.

- If scleritis is the initial manifestation of an underlying systemic disease, and the
subjects need to be started on systemic therapy in the form of corticosteroids or
immunomodulatory therapy for the underlying disease, then the subjects will not be
eligible to participate in the study.

- Subjects with any or all of the following ocular complications associated with or
secondary to scleritis may also be eligible for enrollment:

- Evidence of active anterior uveitis (defined as +1 cells or more in the anterior
chamber or evidence of anterior vitreous inflammation on slit-lamp examination at
presentation).

- Ocular hypertension, defined as intraocular pressure of ≥ 21 mmHg.

- Peripheral keratitis; defined as peripheral interstitial keratitis or thinning with
either ulcerative or non-ulcerative component.10

- Subjects who have been on immunomodulatory therapy (IMT) prior to enrollment may
participate in the study if they have been on a stable dose of IMT (at least 4 weeks
with no change in IMT dosing or addition of new IMT agents).

Exclusion Criteria:

- Any significant ocular disease that could compromise vision in the study eye. These
include, but are not limited to:

- Diabetic retinopathy: proliferative diabetic retinopathy (PDR) or
non-proliferative diabetic retinopathy (NPDR) that compromise the vision.

- Age-related macular degeneration;

- Myopic degeneration with active subfoveal choroidal neovascularization.

- Advanced glaucoma status post trabeculectomy or tube/valve placement

- Any of the following treatments within 90 days prior to Day 0 or anticipated use of
any of the following treatments to the study eye:

- Intravitreal injections (including but not limited to steroids or anti-vascular
endothelial growth factors);

- Posterior subtenon's steroids.

- Intraocular surgery within 90 days prior to Day 0 in the study eye;

- Capsulotomy within 30 days prior to Day 0 in the study eye;

- Any known ocular surgery (including cataract extraction or capsulotomy) of the study
eye anticipated within the first 180 days following Day 0;

- Presence of posterior scleritis as the only type of scleritis (without concurrent
presence of any type of anterior scleritis;

- Intraocular pressure ≥25 mmHg in the study eye (glaucoma subjects maintained on no
more than 2 topical medications with IOP <25 mmHg are allowed to participate);

- Pupillary dilation inadequate for quality stereoscopic fundus photography in the study
eye;

- Media opacity that would limit clinical visualization;

- Presence of any form of ocular malignancy in the study eye, including choroidal
melanoma;

- History of herpetic infection in the study eye or adnexa;

- Presence of known active or inactive toxoplasmosis in either eye;

- Presence of ocular or periocular infection in either eye;

- Participation in other investigational drug or device clinical trials within 30 days
prior to Day 0, or planning to participate in other investigational drug or device
clinical trials within 180 days following Day 0. This includes both ocular and
non-ocular clinical trials.

- Major surgery (including joint surgery) within 8 weeks prior to screening or planned
major surgery within 6 months following randomization.

- Prior treatment with any cell-depleting therapies, including investigational agents or
approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti¬CD3, anti-CD19
and anti- CD20.

- Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6
months of baseline.

- Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.

- Previous treatment with ACTH within 3 months of day 0 of study visit.

- Any previous treatment with alkylating agents such as chlorambucil, or with total
lymphoid irradiation.

Exclusions for General Safety:

- History of severe allergic or anaphylactic reactions to proteins of porcine origin.

- Evidence of serious uncontrolled concomitant cardiovascular (including history of
congestive heart failure, uncontrolled hypertension), nervous system (include
myasthenia gravis), pulmonary (including obstructive pulmonary disease), renal,
hepatic, endocrine (includeAdrenocortical hyperfunction and primary adrenocortical
insufficiency, uncontrolled diabetes mellitus, hypothyroidism), gastrointestinal
disease (including history of or presence peptic ulcer disease, complicated
diverticulitis, ulcerative colitis, or Crohn's disease), Scleroderma or Osteoporosis.

- Current liver disease as determined by principal investigator unless related to
primary disease under investigation.

- Known active current or history of recurrent bacterial, viral, fungal, mycobacterial
or other infections (including but not limited to tuberculosis and atypical
mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal
infections of nail beds).

- Any major episode of infection requiring hospitalization or treatment with IV
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to
screening.

- Active TB requiring treatment within the previous 3 years. Subjects should be
evaluated for latent and/or active TB within one month of the screening as part of the
evaluation by the investigator to rule out infectious scleritis or uveitis before
referring the patient to the study. If positive, subjects should be managed following
local practice guidelines prior to initiating ACTH Gel. Subjects treated for TB with
no recurrence in 3 years are permitted.

- Primary or secondary immunodeficiency (history of or currently active)

- Evidence of active malignant disease, malignancies diagnosed within the previous 5
years (including hematological malignancies and solid tumors, except basal and
squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has
been excised and cured).

- Pregnant women or nursing (breast-feeding) mothers.

- Subjects with reproductive potential not willing to use an effective method of
contraception.

- History of alcohol, drug or chemical abuse within 1 year prior to screening.

- Neuropathies or other conditions that might interfere with pain evaluation unless
related to primary disease under investigation.

Laboratory Exclusion Criteria (at screening):

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper
limit of normal (ULN)

- Total Bilirubin>ULN

- HbA1c > 10.0 %

- White Blood Cells < 3.0 x 109/L (3000/mm3)

- Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)

- Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)

- TSH > 4U/ml or greater than normal cut-off for the lab conducting the test

- BMD (Bone Mineral Density) < -2.5 T score