For over a decade, the pharmaceutical company Amgen has realized the value of utilizing the microgravity platform for preclinical testing of drugs. Two osteoporosis drugs, Evenity and Prolia, tested in mice under microgravity conditions, generated additional evidence to support the effectiveness of the active pharmaceutical ingredient (API) against the stated therapeutic area target. The results strengthened their FDA New Drug application which, in recent years, led to the drugs’ approval for human use. 

Bone Atrophy

Aging in humans leads to an imbalance of the bone remodeling process that gradually promotes bone resorption and reduces bone formation, leading to critical bone loss and increased risk of bone breakage – a condition known as osteoporosis. Interventions that help rebalance this process to promote bone formation and increase bone mineral density (BMD) would be useful in helping to reduce the incidence of bone breakage and injury which is critical in maintaining an active, healthy lifestyle, especially with advanced age. Before the development of Evenity and Prolia, the standard of care for osteoporosis included prescribing bisphosphonates which could stop the breakdown of bone but did not promote its rebuilding.

Exposure to the microgravity environment significantly increases the rate of bone loss, resulting in aged phenotypes within a couple of weeks of exposure. Microgravity, thereby, provides a course to create an accelerated and powerful osteoporosis model in which to test promising drugs. Evenity and Prolia were administered to spaceflown mice. The results provided valuable information in demonstrating and understanding the effects of the treatments on bone remodeling.

Evenity Study (FDA approved in 2019)

The FDA approved Evenity (romosozumab), developed by Amgen, in 2019 for the treatment of osteoporosis in postmenopausal women at high risk for osteoporotic fracture. This drug is prescribed as an initial and short-term treatment to quickly increase bone mineral density through the promotion of bone growth and concurrent slowing of bone resorption. Evenity is a humanized monoclonal antibody that binds and inhibits the activity of the glycoprotein sclerostin (SOST). This inhibition promotes osteoblast and bone formation by disinhibition of the canonical Wnt signaling pathway and reduces bone resorption by lowering levels of receptor activator of nuclear factor kappa-β-ligand (RANKL)1.

Ten-week-old mice (n=10) were treated with the sclerostin antibody or placebo (n=15) one day before launch in 2011 and housed in space inside the Commercial Biomedical Testing Module. Two other groups of mice were provided similar treatment on Earth to serve as ground control. Following two-weeks of exposure to microgravity, mice were returned to Earth and evaluated for bone morphology. Tests found that mice treated with the sclerostin antibody displayed increased bone formation and improved bone structure compared to controls. 

Prolia Study (FDA approved in 2010)

Prolia (Denosumab), similar to Evenity, is a drug prescribed for osteoporosis in postmenopausal women who are at high risk for fractures. In contrast to Evenity’s short-term usage, Prolia is intended for longer-term use to increase and maintain bone mass. Denosumab is a ligand inhibitor for the TNF-receptor superfamily receptor osteoprotegerin (OPG) that blocks bone resorption by osteoclasts.

During a 12-day mission in 2001-2002, denosumab was tested on female mice (n=12) to determine the drug’s ability to preserve bone structure in microgravity. In untreated mice (n=12), spaceflight led to increased bone resorption, reduced bone formation, and inhibition of mineralization when compared to ground control (n=12). Treatment with denosumab increased bone mineral density to levels higher than untreated mice in microgravity and on the ground (n=12). Treatment also improved other measures of bone stability, including bone strength and mineral composition, while reducing markers of bone resorption.

The success of bringing two osteoporosis drugs to market sets a precedent for the use of microgravity in supporting and enhancing drug testing that extends beyond bone physiology. Microgravity provides unique and powerful advantages in studying many other disease models like muscle atrophy, immune dysfunction, and cancer. Furthermore, space provides optimized conditions for cell culture (spheroid and organoid formation) and tissue modeling (3D bioprinting) to aid in the development of superior, in vitro drug testing platforms. This could help generate compelling data and support therapeutic applications of identified drug candidates for patients on Earth. Axiom provides direct access to the microgravity platform and a team of experts with nearly 300 years of cumulative space experience that will help accelerate your drug discovery efforts.

REFERENCES:

Sclerostin: https://www.nasa.gov/mission_pages/station/research/experiments/explorer/Investigation.html?#id=315

Prolia: https://www.nasa.gov/mission_pages/station/research/experiments/explorer/Investigation.html?#id=859

Prolia: Hanley DA, Adachi JD, Bell A, Brown V. Denosumab: mechanism of action and clinical outcomes. Int J Clin Pract. 2012;66(12):1139-46. doi: 10.1111/ijcp.12022. PubMed PMID: 22967310; PMCID: PMC3549483.

Prolia: Bateman TA. Molecular therapies for disuse osteoporosis. Gravitational and Space Biology. 2004 17(2): 83-89.

Prolia: Lloyd SA, Morony SE, Ferguson VL, Simske SJ, Stodieck LS, Warmington KS, Livingston EW, Lacey DL, Kostenuik PJ, Bateman TA. Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice. Bone. 2015 December; 81562-72. DOI: 10.1016/j.bone.2015.08.021.