ACTIMMUNE in Intermediate Osteopetrosis

This study evaluates the effects of ACTIMMUNE (IFN-γ1b) in children and adults with intermediate osteoporosis. All participants will receive treatment with ACTIMMUNE for 12 months. The investigators hypothesize that ACTIMMUNE will be tolerated by participants for the full 12 months and result in decreased disease severity.

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

Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 defines a Grade 4 event as having life-threatening consequences, and/or urgent intervention indicated.

Survey name: RAND 36-Item Health Survey (Version 1.0) Scale name: Pain Scale range: 0-100; Higher score means less pain

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.

Lertwilaiwittaya P, Suktitipat B, Khongthon P, Pongsapich W, Limwongse C, Pithukpakorn M. Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis. Mol Genet Genomic Med. 2021 Jul;9(7):e1727. doi: 10.1002/mgg3.1727. Epub 2021 May 30.