ACTH as A Re-emerging theRapy for Uveitis (The ACTHAR Study)

Uveitis is a term used to describe a group of inflammatory disorders involving the uveal tract (iris, ciliary body and choroid). It is amongst the most common causes in the list of preventable cause of blindness in the developed world.

H.P. Acthar Gel is a highly purified sterile preparation of the adrenocorticotropic hormone (ACTH) gelatin to provide a prolonged release after intramuscular or subcutaneous (SC) injection.

ACTH is part of a group of molecules called melanocortins (MC) (ACTH, α, β, γ-MSH) that are produced, in human bodies, by breakdown of a common larger precursor called proopiomelanocortin (POMC). A very well-known anti-inflammatory mechanism of action of ACTH is the production glucocorticoids by stimulating the adrenal glands. ACTH has also been shown to bind with all five melanocortin receptors (MCRs). MCRs have a variety of roles including cortisol production and regulation of immune modulation by ACTH.

ACTHAR is an open-label, multi-center, randomized, phase II study to evaluate the effect of two dose regimens of repeated SC injections of ACTH gel in patients with active non-infectious intermediate, posterior, or pan-uveitis followed over a period of 12 months.

ACTHAR study will be conducted at up to 7 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 ACTHAR Study.

The primary endpoint of the study will be at month 6, with an active, as-needed treatment extension phase from month 6 to month 12.

Thirty-six (36) patients with non-infectious intermediate, posterior, or pan-uveitis will be enrolled and randomized (1:1) to one of the two treatment arms:

• Mandatory twice a week (Mondays and Thursdays) treatment with SC ACTH gel 80 U/day starting at BL until month 6. Starting at month 6, the treatment will be administered on as needed basis, based on the retreatment criteria.
• Mandatory thrice a week (Mondays, Wednesdays, and Fridays) treatment with SC ACTH gel 80 U/day starting at BL until month 6. Starting at month 6, the treatment will be administered on as needed basis, based on the retreatment criteria.

Starting at month 6, retreatment will be offered to study subjects who have demonstrated any level of response during the first 6 months and who meet any of these Retreatment Criteria listed below. Patients receiving retreatment will receive the dose that was assigned to them at randomization.

Inclusion criteria

In order to be eligible for the study, patients will be required to meet the criteria of 1 of the 3 following disease cohorts:

• Active disease and are receiving no treatment. Active disease is defined as having at least 1+ Vitreous Haze using the Standardized Uveitis Nomenclature (SUN) Working Group scale and/or at least 1+ Vitreous Cell Count using Foster & Vitale scale.
• Active disease and are receiving prednisone ≥10 mg/day (or equivalent dose of another corticosteroid) or at least 1 other systemic immunosuppressant (all systemic immunosuppressants other than corticosteroids will be discontinued 30 days prior to the first administration of the study drug on Day 0). Patients receiving combination of prednisone ≥10 mg/day and at least one other systemic immunosuppressant are also eligible in this category.
• Have inactive disease, defined as having <= 0.5+ Vitreous Haze OR <= 0.5+ Vitreous Cell Count (SUN scale), and are receiving prednisone ≥10 mg/day (or equivalent dose of another corticosteroid) or at least 1 other systemic immunosuppressant (all systemic immunosuppressants other than corticosteroids will be discontinued 30 days prior to the first administration of the study drug on Day 0). Patients receiving combination of prednisone ≥10 mg/day and at least one other systemic immunosuppressant are also eligible in this category.

Exclusion criteria

Subjects who have any of the following at the screening visit are not eligible for enrolment in this study:

• 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;
• Intraocular pressure(IOP) ≥25 mmHg in the study eye (glaucoma patients 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 anti-cluster of differentiation (CD) 4, anti- cluster of differentiation (CD)5, anti-cluster of differentiation (CD) 3, anti-cluster of differentiation (CD)19 and anti-cluster of differentiation (CD)20.
• 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 ACTHAR 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 (include 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 Tuberculosis (TB) requiring treatment within the previous 3 years. Patients 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 uveitis before referring the patient to the study. If positive, patients should be managed following local practice guidelines prior to initiating H.P. ACTHAR gel. Patients 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.
• Patients 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.