ACTIMMUNE in Intermediate Osteopetrosis

Osteopetrosis is a rare inherited metabolic bone disease characterized by impaired osteoclast
function resulting in defective bone resorption and generalized high bone mass and mineral
density (BMD). In patients with severe disease, this high bone mass compromises bone marrow
space leading to marrow failure and frequent infections, along with hepatosplenomegaly from
extramedullary hematopoiesis. Currently, the only treatment for individuals with severe forms
of osteopetrosis is hematopoietic cell transplantation (HCT), however survival in patients
with osteopetrosis treated with HCT is only around 55%. Therefore, this treatment is only
indicated in select individuals with life-threatening complications of their disease. Thus
additional treatments for osteopetrosis are needed both for individuals who are not
candidates for HCT and to prolong the time until HCT is needed.

Interferon gamma (IFN-γ) is a naturally occurring cytokine that has been shown to have
anti-microbial and anti-viral immunomodulatory effects, and is a potent stimulator of
superoxide anion production which in turn promotes the formation and activation of
osteoclasts. Two previous studies of IFN-γ1b in a small group of individuals with
osteopetrosis found a decrease in trabecular bone area, an increase in marrow space, a
decrease in the number of severe infections requiring antibiotic therapy, and an increase in
superoxide generation by granulocyte-macrophage colonies.

Therefore, the investigators will conduct an early phase 2, multi-center, open-label,
12-month clinical trial of ACTIMMUNE (IFN-γ1b) treatment of patients with intermediate
osteopetrosis to determine the following:

1. The feasibility and tolerability of interferon gamma-1b treatment for 1 year in patients
with intermediate osteopetrosis. Specifically, i) the ability to enroll patients, and
ii) continued treatment throughout the 1-year observational period.

2. Change in immunologic and hematologic function, bone mineral density and osteoclast
function, physical function and quality of life.

Inclusion Criteria:

- Diagnosis of osteopetrosis; and

- Anemia (Hemoglobin <12 g/dL) not related to iron deficiency, or

- Neutropenia (Neutrophil count <1000 neutrophils/ul unsupported with cytokines), or

- Thrombocytopenia (Platelet count <50,000 cells x 109/L), or

- History of impaired bone healing, or

- ≥ 1 serious infection over prior year defined as requiring hospitalization and/or IV
antibiotics, and

- Age > 1 year; and

- Ability to travel to a study center for every 3-6 month study visits; and

- Patient or parent/legal guardian is able and willing to provide informed consent. For
patients 7 to 17 years of age, assent must also be provided.

Exclusion Criteria:

- 12 months or fewer following HCT;

- Pregnancy or breastfeeding;

- Known or suspected allergy to interferon gamma-1b or related products;

- Participation in simultaneous therapeutic study that involves an investigational study
drug or agent within 4 weeks of study enrollment;

- ALT greater than 3 fold higher than normal; or

- Any other social or medical condition that the Investigator believes would pose a
significant hazard to the subject if the investigational therapy were initiated or be
detrimental to the study.