ACTHAR GEL for Sarcoidosis-Associated Calcium Dysregulation: An Open-label Pilot Study

Sarcoidosis is a multisystem granulomatous disease of unknown cause. Although sarcoidosis
most commonly affects the lung, it may affect any organ. Although corticosteroids are
recognized as the drug of choice for sarcoidosis. ACTH(adrenocorticotropic hormone) is the
only drug that is FDA-approved for this disorder. However, there is limited data on the
efficacy of ACTH for this condition.

Calcium metabolism is disregulated in active sarcoidosis. The primary abnormality in calcium
metabolism stems from an increased 1-α hydroxylase activity in sarcoid alveolar macrophages
that converts 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D, the active form of the
vitamin. This can result in hypercalcemia, hypercalciuria, nephrocalcinosis,
nephrolithiasis, interstitial nephritis, glomerulonephritis, acute and chronic kidney
disease. Importantly, almost of the renal manifestations stem from disordered calcium
metabolism. Unlike other organ manifestations of sarcoidosis, the disorder of calcium
metabolism is more common in whites compared to african americans.Compared to hypercalcemia,
hypercalciuria is three times more common in sarcoidosis, nevertheless, it has largely been
ignored.

In general, the patient with hypercalcemia should be advised to avoid sunlight, curtail
intake of major sources of dietary calcium and vitamin D, and drink ample fluids.If the
patient is symptomatic, serum calcium is greater than 11 mg/dl, the serum creatinine is
elevated, or the patient has nephrolithiasis, drug therapy is usually required. The drug of
choice is prednisone at an initial daily dose of 20 - 40 mg/day.Unfortunately, prolonged
corticosteroid therapy may result in unacceptable side effects including osteoporosis. This
is particularly important as elevated calcitriol observed in patients with sarcoidosis can
further jeopardize bone structure by resorption. Alternative medications that have shown
benefit for sarcoidosis associated calcium dysregulation have included
chloroquine,hydroxychloroquine, ketoconazole.

Not only may ACTHER GEL have obvious anti-inflammatory effects by resulting in
corticosteroid production, but it may also activate melanocortin receptors. The melanocortin
system has powerful anti-inflammatory properties that may be beneficial in the treatment of
sarcoidosis.

We believe that there are several specific advantages of assessing the effectiveness of
anti-sarcoidosis therapy by examining sarcoidosis-associated disorders of calcium
metabolism.

1. The measures of granulomatous activity (serum calcium, urinary calcium, serum
25-hydroxyvitamin D, and serum 1, 25-dihydroxyvitamin D levels) are directly related to
the granulomatous inflammation of sarcoidosis.

2. These parameters can be accurately and objectively quantified. This is an important
issue in sarcoidosis as the endpoint for involvement of the lungs, skin, and eyes is
problematic because it is either inexact and/or not unidimensional.

3. These constituents can be easily used to clinically monitor sarcoidosis. This is not
the case for other forms of sarcoidosis including involvement of the lung and skin.

- Although hypercalciuria and disordered calcium metabolism is not as common a
manifestation of sarcoidosis as lung involvement, there is little evidence that
the anti-granulomatous response to this disease is organ specific. In a randomized
double-blind placebo control trial of infliximab for pulmonary sarcoidosis,
extrapulmonary sarcoidosis also responded to this therapy.

Inclusion Criteria:

1. Age greater than 18 years old.

2. Able to understand English to the point of comprehending the informed consent form.

3. Biopsy proven sarcoidosis.

4. Documented hypercalciuria (urinary excretion of > 4mg/kg of calcium/day) or
hypercalcemia within 4 weeks of study entry.

5. Historical evidence that the patient's hypercalciuria/hypercalcemia is related to
sarcoidosis. This should include a serum parathyroid hormone (PTH) level which is not
elevated.

Exclusion Criteria:

1. A change in anti-sarcoidosis medications within 3 months of study entry.

2. A history of hyperparathyroidism or another non-sarcoidosis cause of
hypercalcemia/hypercalciuria

3. A history of Cushing's disease.

4. Have a diagnosis of a medical disorder other than sarcoidosis that in the opinion of
the investigator would complicate the evaluation of response treatment.

5. Have used any investigational drug within 1 month prior to screening or within 5
half-lives of the investigational agent, whichever is longer.

6. Use of loop or thiazide diuretics for hypertension or other disorders.

7. Chronic use of antacids.